NHMRC Research Achievements - SUMMARY
END OF GRANT REPORTS
OUTCOMES OF NHMRC FUNDED RESEARCH INTO
ALZHEIMERS DISEASE AND DEMENTIA
GRANTS ENDING 2000 TO 2013
CONTENTS
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Alfred Health
Australian National University
Charles Sturt University
CSIRO Division of Human Nutrition
Curtin University of Technology
Edith Cowan University
Flinders University
Garvan Institute of Medical Research
Griffith University
Heart Research Institute
La Trobe University
Macfarlane Burnet Institute for Medical Research and Public Health
Macquarie University
Menzies Research Institute
Monash University
St Vincent's Health
St Vincent's Institute of Medical Research
University of Adelaide
University of Melbourne
University of New South Wales
University of Newcastle
University of Queensland
University of South Australia
University of Sydney
University of Tasmania
University of Technology Sydney
University of Western Australia
University of Wollongong
Walter and Eliza Hall Institute
NHMRC Research Achievements - SUMMARY
Grant ID: 415006
CIA Name: Dr Katherine Thompson
Admin Inst: Alfred Health
Main RFCD: Medical Virology
Total funding: $358,463
Start Year: 2007
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Understanding viral replication in the brain of HIV-infected patients with and without HAART
treatmentUnderstanding viral replication in the brain of HIV-infected patients with and without HAART
treatment
Lay Description (from application):
Not Available
Research achievements (from final report):
Research is needed to understand where, when and how to intervene therapeutically to prevent the
establishment of a HIV reservoir within infected, long-lived brain cells. To address this, we developed the use
of laser microdissection to isolate single cells from autopsy brain tissue. DNA extracted from these brain cell
populations is then used in highly sensitive PCR strategies to molecularly characterize any HIV strains present
in each cell population. The use of these techniques is currently the only way to identify cellular viral
reservoirs in the brain. Our studies demonstrate that infected macrophage act as the "Trojan horse" within the
brain, bringing HIV into the brain, concurrent with increasing plasma viral load and decreasing peripheral CD4
count. Our studies suggest that macrophages may be pivotal in advancing HIV brain infection at times of
increasing immunosuppression and that maintaining CD4 cell levels may be crucial for controlling a critical
entry point of HIV from the systemic circulation into the brain. These are the first demonstrations of specific
brain cell populations as reservoirs of virus prior to the onset of encephalitis.
Expected future outcomes:
Our work suggests preventing CD4 cell decline by earlier anti-viral treatment may reduce entry of HIV
infected macrophage from the blood into the brain. Physicians treating HIV positive patients may be inclined to
begin anti-retroviral treatment earlier than currently recommended.
Name of contact:
Catriona Mclean
Email/Phone no. of contact:
c.mclean@alfred.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 122815
CIA Name: Dr Shin-Ho Chung
Admin Inst: Australian National University
Main RFCD: Biophysics
Total funding: $677,293
Start Year: 2000
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of Biological Ion Channels: Theoretical Formulation, Computer Simulation and Experimental
VerificationInvestigation of Biological Ion Channels: Theoretical Formulation, Computer Simulation and
Experimental Verification
Lay Description (from application):
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, undertanding
their mechanisms at a molecular level is a fundamental problem in neurobiology. There are many different
types of ion channels, each type fulfilling a different role. For the first time, a group of American scientists
have determined the shape of one type of ion channels. Using this newly unveiled information, we propose to
build a mathematical theory of ion channels. And then, making use of a powerful supercomputer, we propose
to follow the motion of ions as they move through the channel, study how a channel can select only the correct
type of ions to traverse it and determine how many ions a single channel is capable of processing per second.
The predictions made by our theory and computer simulations will be checked experimentally. If the
predictions and experimental findings do not agree, we will modify the theory and make new predictions.
Research achievements (from final report):
Ionic channels of living membranes play a crucial role in the existence of all living organisms. All electrical
activities in the nervous system, including communication between cells and the influence of hormones and
dugs on cell function, are regulated by opening and closing of membrane ion channels. Thus, understanding
their mechanism at a molecular level is a fundamental problem in biology. Moreover, elucidation of how single
channels work will ultimately help us find the causes of, and possibly cures for, a number of neurological and
muscular disorders. In the last few years, we have successfully constructed exact physical models of several
different types of ion channels. The physical models of the ion channels we constructed enable us to trace the
motion of ions as they move through the narrow pore, study how a channel can select only the correct type of
ions to traverse it and determine how many ions a single channel is capable of processing per second. Also,
using powerful supercomputers, we can examine how a channel opens and closes, and make many testable
predictions that can be tested experimentally. Thus, for the first time, we have been able to describe on
channels in precise, quantitative terms using the principle of electrodynamics and Newton's law.
Expected future outcomes:
The physical models we have constructed will be further modified and refined so that they can provide the
complete understanding of many types of membrane channels in terms of rigorous molecular physics. The
techniques of modelling ion channels utilizing modern high-performance computers will be extended for
designing and screening pharmaceutical products.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 179839
CIA Name: Prof Kaarin Anstey
Admin Inst: Australian National University
Main RFCD: Mental Health
Total funding: $450,250
Start Year: 2002
End Year: 2006
Grant Type: Career Development Fellowships
Title of research award:
Antecedents and consequences of cognitive decline and depression in late lifeAntecedents and consequences of
cognitive decline and depression in late life
Lay Description (from application):
Not Available
Research achievements (from final report):
A large range of research on risk factors for poor cognitive performance and brain aging was published. This
work was important because it included adults aged in their 20s, 40s and 60s, as well as adults in late life.
Some risk factors that have previously been associated with cognition only in late life, were found to be
significant in young adults. Factors examined included smoking, alcohol consumption, physical activity, HRT,
and medical conditions. , , Research also focussed on risk factors for suicidality and depression in late life and
identified for example, that older men who would like to be in the work force but are not, are at very high risk
of suicidal ideation. Psychological distress and potential cognitive impairment associated with visual
impairment and cataract surgery were also evaluated in a clinical trial. The first population-based study of
mental health problems associated with head injury in Australia was published. , Further work investigated
how cognitive decline in late life is associated with falls in adults without cognitive impairment, and made
recommendations that current screening instruments for falling include brief cognitive measures. Other work
focussed on driving cessation showing that health perception is more important than actual medical conditions
in predicting driving cessation, and that giving up driving is associated with increased risk of depression. ,
Expected future outcomes:
Work in progress or submitted includes systematic reviews of risk factors for cognitive decline and dementia,
an evaluation of depression in relation to transition to residential care, and evaluation of subtle changes in brain
function associated with mild cognitive disorders.
Name of contact:
Kaarin Anstey
Email/Phone no. of contact:
Kaarin.anstey@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316907
CIA Name: Dr Shin-Ho Chung
Admin Inst: Australian National University
Main RFCD: Biophysics
Total funding: $381,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Theoretical Studies on the Dynamics of Ion Permeation Across Membrane ChannelsTheoretical Studies on the
Dynamics of Ion Permeation Across Membrane Channels
Lay Description (from application):
All electrical activities in the brain are regulated by opening and closing of ion channels. Thus, understanding
their mechanisms at a molecular level is a fundamental problem in biology. There are many different types of
ion channels, each type fulfilling a different role. We now know the exact atomic structures of several types of
the proteins forming ion channels. Using this newly unveiled information, we propose to build exact physical
models of many different types of ion channels. Then, making use of powerful supercomputers, we propose to
follow the motion of ions as they move through the channel, study how a channel can select only the correct
type of ions to traverse it and determine how many ions a single channel is capable of processing per second.
The predictions made by our theory and computer simulations will be checked experimentally. Once we fully
understand how these channels work, we will be able to understand the causes of, and possibly find the cures
for, many neurological, muscular and renal disorders.
Research achievements (from final report):
We have provided a comprehensive physical description of several important classes of biological ion
channels. The theoretical models we constructed are capable of predicting channel function from channel
structure, capable of revealing certain aspects of atomic structures of protein macromolecules, and link the
macroscopic observables to the details of the inter-molecular potential operating between ions, water molecules
and atoms that form the channel. , Among the channel models we constructed are two classes of anionic
channels and two classes of cationic channels. We built atomic models of two eukaryotic ClC channels, the
GABA receptor, and several classes of potassium and calcium channels. The channels are important for the
control of membrane excitability in nerves and muscles. Genetic alterations of these channels are known to be
associated with muscular and renal disorders, epilepsy and hypertension. The properties of each model so
constructed were examined, using macroscopic calculations, semi-microscopic Brownian dynamics and fully
microscopic molecular dynamics. Each virtual channel we created was then modified and refined until the
salient properties deduced from computer simulations reproduce those obtained experimentally. With these
theoretical model channels, we could test highly detailed hypotheses about the mechanisms of ion permeation
across the membrane. Our studies not only provided a detailed mechanistic understanding of ion conduction in
these highly selective pores, but also they have unraveled new information on the mechanism of action of small
molecule blockers and basis of selectivity. Our technique of building and studying virtual channels can be
readily extended for designing and screening potential drugs.
Expected future outcomes:
New theoretical tools we have devised and the virtual biological channels we have constructed will provide
quantitative physical explanations of the mechanisms of ion permeation, selectivity and gating. Computational
approaches we have adopted will lead to hosts of pharmaceutical products, specifically targeted at biological
ion channels.
Name of contact:
Shin-Ho Chung
Email/Phone no. of contact:
shin-ho.chung@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316913
Start Year: 2005
CIA Name: Prof Ian Hendry
End Year: 2007
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $243,000
Title of research award:
The proteins associated with the neurotrophin retrograde transport signalling endosomeThe proteins associated
with the neurotrophin retrograde transport signalling endosome
Lay Description (from application):
According to estimates taken from the Australian Bureau of Statistics population projection series, during the
next forty years the incidence of Alzheimer's disease or a related dementia in Australia is predicted to increase
by 254%. One of the key issues in neurobiology is to understand the mechanisms regulating the survival of
nerve cells. Nerve Growth Factor (NGF) acts to cause nerve cell survival by being transported from the target
tissue to the cell body in a discrete organelle described as the Signalling Endosome. This process is termed
Retrograde Axonal Transport. The signalling endosome is assembled in the nerve terminal and also contains
proteins normally activated by NGF known as Second Messengers. Neurodegenerative diseases, such as
Alzheimer's disease, occur due to the death of nerve cells and a disturbance of the retrograde axonal transport
of NGF may contribute to this death. NGF has been shown to have clinical potential as it can promote neuronal
repair and survival after injury. However clinical trials have demonstrated an unacceptable toxicity for this
protein. Therefore, another approach taken to produce the restorative benefits of NGF is to stimulate second
messenger pathways downstream from the NGF receptor. This approach could provide important new
therapeutic potentials as we can target more selective components of these survival pathways and have a
greater chance to find less toxic drugs. This project will identify the second messengers normally
accompanying NGF from the nerve terminal which promote nerve cell survival. We will describe the way these
proteins are recruited to the signalling endosome. Survival of nerve cells requires the activation of these
proteins and we shall determine where this occurs. Understanding the molecular basis for the delivery of the
retrograde survival signal in neurons is vital if new therapeutic strategies for the treatment of
neurodegenerative disease and traumatic nerve damage are to be developed.
Research achievements (from final report):
According to estimates taken from the Australian Bureau of Statistics, during the next forty years the incidence
of Alzheimer's disease or a related dementia in Australia is predicted to increase by 254%. Neurodegenerative
diseases, such as Alzheimer's disease, occur due to the failure of the repair and survival mechanisms for
neurons, including the disturbance of the retrograde axonal transport of Nerve Growth Factor (NGF). NGF has
been shown to have clinical potential as it can promote neuronal repair and survival after injury. However
clinical trials have demonstrated an unacceptable toxicity for this protein. Second messenger pathways
downstream from the NGF receptor provide important new therapeutic potentials as we can target more
selective components of these survival pathways. NGF acts as a signal by being retrogradely transported, in a
discrete organelle described as the signalling endosome, from the target tissue to the cell body thus resulting in
neuronal survival. This signalling endosome which is assembled in the nerve terminal also contains many
second messenger molecules. Understanding the molecular basis for the delivery of the retrograde survival
signal in neurons is vital if new therapeutic strategies for the treatment of neurodegenerative disease and
traumatic nerve damage are to be developed., We have determined the relationship between NGF, TrkA and
p75 during retrograde axonal transport in signalling endosomes. We have also determined the association of
NGF and its receptors with other molecules including the Rab proteins and dopamine-beta-hydroxylase (DBH).
These studies have been completed at the 18 hour time point. The extent of the associations of molecules cell
bodies were measured by determining the extent of co-localization using Image Pro software., The outcome of
this research sheds light on the understanding of the NGF retrograde axonal transport and hence, augments the
knowledge on neuronal development.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
It is necessary to define the activation of different second messenger pathways in the nerve terminal and axon
during the transport of NGF.
Name of contact:
Selma Kaasinen
Email/Phone no. of contact:
selma.kaasinen@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 316932
CIA Name: Prof Greg Stuart
Admin Inst: Australian National University
Main RFCD: Central Nervous System
Total funding: $258,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms and consequences of cholinergic signaling in neocortical pyramidal neuronsMechanisms and
consequences of cholinergic signaling in neocortical pyramidal neurons
Lay Description (from application):
Dementia, including Alzheimer s Disease, represents the second highest non-fatal disease burden in Australia.
Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer s Disease result in
part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of
acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works
at the cellular level. We have recently discovered that acetylcholine produces opposing phasic and tonic actions
on the excitability of brain cells in the cortex. The data collected in this study will reveal the receptor type,
intracellular signalling pathways, and ionic mechanisms through which acetylcholine influences information
processing in the brain. Together, these results will provide a framework for understanding the biological basis
by which acetylcholine influences cognitive function. This new knowledge will in turn increase our
understanding of why dysfunction of this important neurotransmitter system leads to the functional deficits
observed in Alzheimer s Disease and other forms of dementia, and will hopefully suggest new targets for
therapeutic intervention.
Research achievements (from final report):
Dementia, including Alzheimer's Disease, represents the second highest non-fatal disease burden in Australia.
Modern theories suggest that cognitive deficits associated with disorders such as Alzheimer's Disease result in
part from impairment of the action of the neurotransmitter acetylcholine. Despite the obvious importance of
acetylcholine in brain function, there is currently a lack of basic knowledge regarding how this chemical works
at the cellular level. The research in this Project Grant application was designed to reveal the receptor type,
intracellular signalling pathways, and ionic mechanisms through which acetylcholine influences information
processing in the brain. We discovered that acetylcholine produces opposing phasic and tonic actions on the
excitability of brain cells in the cortex and the hippocampus. Together, these results will provide a framework
for understanding the biological basis by which acetylcholine influences cognitive function. This new
knowledge will increase our understanding of why dysfunction of this important neurotransmitter system leads
to the functional deficits observed in Alzheimer's Disease and other forms of dementia, and will hopefully
suggest new targets for therapeutic intervention.
Expected future outcomes:
Future outcomes include a better understanding of the cellular mechanisms involved in dementia. It is hoped
this will lead to advances in both drug design and treatment.
Name of contact:
Prof. Greg Stuart
Email/Phone no. of contact:
greg.stuart@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366731
Start Year: 2006
CIA Name: Prof Philip Board
End Year: 2008
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Pharmacology not elsewhere classified
Total funding: $490,021
Title of research award:
Pharmacogenetic and structural investigation of the Omega class glutathione transferasesPharmacogenetic and
structural investigation of the Omega class glutathione transferases
Lay Description (from application):
Members of the family of enzymes known as glutathione transferases are known to be responsible for the
metabolism and detoxification of a wide range of compounds including therapeutic drugs and cancer causing
chemicals. Genetic variation in an individual's compliment of glutathione transferases can alter their response
to drug treatment or their susceptibility to cancer. The Omega class of glutathione transferases are important
because they are involved in the metabolism of arsenic and because they have been shown to influence the ageat-onset of both Alzheimer s and Parkinson s diseases. The present studies will investigate the structure and
function of different Omega class glutathione transferases and determine how they interact with arsenic based
drugs. These studies will attempt to determine why the toxicity of arsenic varies between individuals and aims
to prevent adverse reactions to arsenic containing drugs used in cancer therapy. These studies will also
investigate the mechanism by which the inheritance of certain forms of Omega class glutathione transferase
can affect the age at-onset of Alzheimer s disease and Parkinson s disease. The understanding of this
mechanism may provide the basis for a therapy that could delay or prevent the onset of these common diseases.
Research achievements (from final report):
This project has resulted in the discovery that the Omega class glutathione transferase GSTO1-1 is identical to
S-phenacylglutathione reductase. This allowed us to develop a novel highly specific biochemical assay for
GSTO1-1 activity. The use of this assay permitted the characterization of GSTO1-1 deficiency caused by the
polymorphic deletion of Glu155 or the substitution of Ala for Val 236. We were also able to use T47D breast
cancer cells that are deficient in GSTO1-1 and GSTO2-2 to show that although these enzymes can catalyse the
reduction of some methylated arsenic species, they do not change the cytotoxicity of arsenic trioxide that is
used in cancer therapy. In addition, our studies of mine-workers exposed to high levels of environmental
arsenic found that the inheritance of GSTO1-1 deficiency variants does not alter the urinary excretion of
arsenic. Our data indicates that genetic variation in GSTO1-1 is not a significant factor contributing to adverse
reactions to arsenic trioxide therapy. In this project we also determined the crystal structure of GSTO2-2 and
the polymorphic variant of GSTO1-1 with a deletion of Glu155. The structure of GSTO2-2 is very similar to
that of GSTO1-1 but the differences allowed us to identify residues that promote its high rate of
dehydroascorbate reductase activity.
Expected future outcomes:
The techniques developed in this study will allow the further investigation of the role of Omega class GSTs in
Alzheimer's disease.
Name of contact:
Philip Board
Email/Phone no. of contact:
Philip.Board@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 366756
Start Year: 2006
CIA Name: Prof Kaarin Anstey
End Year: 2010
Admin Inst: Australian National University
Grant Type: Established Career Fellowships
Main RFCD: Developmental Psychology and Ageing
Total funding: $548,878
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
Research undertaken during the fellowship focussed on the conduct and analysis of epidemiological studies,
and smaller studies on older driers. Publications arising from the fellowship identified modifiable risk factors
for dementia that were used by the US National Institutions of Health to inform their consensus statement on
the Prevention of Alzheimer disease. Other research undertaken led to the development of two different types
of screening tools for older drivers that were validated through crash records and on-road driving test. Another
achievement was the successful conduct of the DYNOPTA Project led by the CI. This involved pooling 9
longitudinal datasets to create the largest availabe resource on ageing in Australia. This dataset is now being
used to produce policy relevant research on dementia, driving, sensory disability and health expectancies.
Expected future outcomes:
Further identification of risk factors for dementia, development of dementia prevention strategies, outcomes
from DYNOPTA.
Name of contact:
Kaarin Anstey
Email/Phone no. of contact:
kaarin.anstey@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 410215
Start Year: 2006
CIA Name: Prof Kaarin Anstey
End Year: 2013
Admin Inst: Australian National University
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $2,162,631
Title of research award:
Using health outcome data from pooled Longitudinal Studies of Ageing to develop statistical and
microsimulation models tUsing health outcome data from pooled Longitudinal Studies of Ageing to develop
statistical and microsimulation models t
Lay Description (from application):
This project draws together data from nine Australian Longitudinal Studies of Ageing (LSAs), including 53484
participants, that will be used to identify factors capable of preventing disease, reducing ill-health, and
promoting engaged and successful ageing for Australians. The focus is upon conditions that significantly
contribute to the burden of disease including cognitive decline and dementia, sensory impairment, impairment
in mobility and common mental disorders such as depression. Although individual studies contain rich data on
particular topics, there is only a small number of individuals in each study with specific medical conditions, or
combinations of different conditions, especially at the older ages. Pooling data from nine studies will overcome
this problem. This innovative and interdisciplinary study also involves development of the first Australian
dynamic micro-simulation model of the health and social outcomes of the baby boomer and older cohorts. The
simulation will allow for evaluation of the impact of modifying risk factors, and costs associated with different
trajectories of health and ageing. Our program takes an interdisciplinary life course approach, incorporating
interdependencies among demographic, behavioural, social, economic and health factors. Our multidisciplinary
team and collaborative pooling of existing studies adds value and builds upon experience, as recommended in
the Prime Minister's Science, Engineering and Innovation Council 2003 report. The outcomes will direct health
and social policy to promote health behaviour, and social and medical interventions to compress morbidity and
optimize healthy ageing in Australian society over the next 40 years.
Research achievements (from final report):
The Dynamic Analyses to Optimise Ageing Well (DYNOPTA) project pooled nine Australian longitudinal
studies of ageing to produce the largest research database on older adults in Australia. From this database key
outcomes were achieved in areas of policy significance for an ageing Australia. These included estimating the
prevalence of dementia, estimating the prevalence of vision impairment, hearing impairment and dual sensory
loss, estimating the prevalance of depression among the old and very old, describing trajectories of late-life
development, estimating trajectories of depressive symptoms in very late life up until death, estimating
cognitive impairment free health expectancies for Australia, estimating rates of chronic disease among older
Australian adults, methodological developments in variable harmonization, development of complex survey
weights and missing data techniques, and the development of a microsimulation model (DYNOPTASIM). The
microsimulation model has been used to evaluate the impact of risk reducation on future prevalence of
dementia in the Australian baby boomer cohort. DYNOPTA was also used to evaluate trends in driving
participation in Australia and evaluate policies of age-based licensing between states and territories.
DYNOPTA also addressed the question of Indigenous Australian participation in existing longitudinal studies
concluding that there is a need for specific studies of ageing in Indiginous Australians because of lack of
representation in DYNOPTA. Finally, our project contributed significantly to capacity building of PhD
students and postdoctoral fellows who have progressed to international tenure track positions, Australian
academic posts and other research roles in ageing.
Expected future outcomes:
Australian estimates of disability free life expectancy across sensory, functional, cognitive and mental health
impairment, microsimulation estimates of costs of chronic disease and benefits of risk reduction
Name of contact:
Prof. Kaarin Anstey
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
kaarin.anstey@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 418039
CIA Name: Prof Kaarin Anstey
Admin Inst: Australian National University
Main RFCD: Mental Health
Total funding: $2,068,955
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal study of depression, anxiety, substance use and cognitive change: PATH Through Life Wave
3A longitudinal study of depression, anxiety, substance use and cognitive change: PATH Through Life Wave 3
Lay Description (from application):
The PATH Through Life study is a longitudinal study of depression, anxiety, alcohol and drug use. It is also a
study of normal cognitive development, mild cognitive impairment and dementia. PATH involves three
cohorts of adults who were aged 20-24, 40-44 and 60-64 at baseline. They are followed up at four yearly
intervals. This application seeks funding for Wave 3 of the study, which will allow for 8 years of follow-up of
the baseline sample to be conducted. The key aims are to discover the relationships between biological and
psychological processes in depression, anxiety, substance abuse and cognitive ageing; to identify the sociodemographic factors contributing to these disorders, and to quantify more fully the range of social and
economic consequences of mental illness and cognitive decline. Such consequences include reduced
workforce participation, relationship breakdown, family and carer burden, suicide attempts, use of health
services and need for social welfare. Wave 3 will also focus on transitions into parenthood, fertility and mental
health, menopause, and retirement. Factors in early and mid-adulthood that influence healthy ageing and
cognitive decline in late life will be identified. Information is obtained on physical health, health habits , social
networks, employment and work stress, lifestyle activities, personality, family structure, physical function and
cognitive performance. DNA has also been obtained and a sub-sample of the oldest cohort also participate in a
study of brain MRIs. Longitudinal analysis is the only means of distinguishing the causes of disorders and
tracking their development within individuals. PATH is unique in its narrow age-group design and breadth of
measures, allowing for detailed understanding of the pathways to mental health and illness, and for
identification of how to prevent mental illness and dementia.
Research achievements (from final report):
This project has documented the change and stability in mental health in early, middle and late adulthood over
another 4 years of a longitudinal study, bringing the total follow-up to 8 years. This has enabled evaluation of
predictors of who develops mental disorders, factors influencing resilience, risk factors, and how changes in
cognitive function and mental health relate to brain structure over time. The project has identified vulnerable
groups indicating where mental health services need to be directed, and documented the impact of financial
hardship and low quality jobs on mental health. Importantly, the project identified risk factors for older adults
converting to preclinical dementia, which has informed dementia prevention strategies.
Expected future outcomes:
Currently there are 4 papers In Press, 9 submitted and 58 papers in preparation involving analysis of the Wave
3 PATH data. These data will be used in the training of researchers and in capacity building. The data from the
PATH projectare currently influencing ACT Mental Health policy.
Name of contact:
Kaarin Anstey
Email/Phone no. of contact:
kaarin.anstey@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 471501
CIA Name: Dr Nicolas Cherbuin
Admin Inst: Australian National University
Main RFCD: Epidemiology
Total funding: $291,629
Start Year: 2008
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
An investigation of the role of the pre-frontal cortex in cognitive ageing and dementiaAn investigation of the
role of the pre-frontal cortex in cognitive ageing and dementia
Lay Description (from application):
This project will investigate the role of the pre-frontal cortex in cognitive ageing and dementia. New
neuroimaging techniques will be used to precisely measure this cerebral structure in a large ageing cohort The
new brain measures will be used to identify risk and protective factors of cognitive ageing and dementia. This
project is highly significant because it will contribute to the identification of at risk individuals and guide future
intervention and clinical studies.
Research achievements (from final report):
The aims of this project were to investigate associations between the structure of the human pre-frontal cortex
and cognitive ageing and dementia, identify risk factors for pre-frontal structural and functional health and
assess the role of this structure in cognitive impairment and dementia. A major finding was that structure of the
pre-frontal cortex significantly differs in middle-age individuals in their 40s and in older cognitively healthy
individuals in their 60s. Additionally, it was found that variability in frontal cortical structure in middle-age
was weakly associated with cognition while in older individual this association became greater, showed some
sex differences, and surprisingly showed a negative relationship between frontal structure and some cognitive
functions. Another important findings were that pathological changes seen on MRI and thought to be
associated with cerebro-vascular disease were already detectable in the 40s and were associated with small
differences in cognition. Differences in neuropsychological function known to be supported by the frontal
lobes were found to be associated with the development of mild cognitive impairment. Risk factors for cerebral
health were investigated and one particularly interesting finding was that individuals free of diabetes with a
higher blood sugar level but within the normal range were found to have greater shrinkage in the hippocampus
and lower volumes in the frontal cortices. These findings are important because they significantly contribute to
our understanding of how frontal structure relates to function and changes in ageing and neurodegeneration.
They also provide valuable information to guide policy and public health in the domains of cognitive decline
and dementia.
Expected future outcomes:
N/A
Name of contact:
Nicolas Cherbuin
Email/Phone no. of contact:
nicolas.cherbuin@anu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 585442
Start Year: 2010
CIA Name: Prof Ryszard Maleszka
End Year: 2012
Admin Inst: Australian National University
Grant Type: NHMRC Project Grants
Main RFCD: Epigenetics (incl. Genome Methylation and Epigenomics)
Total funding: $482,843
Title of research award:
Molecular memory: how DNA methylation contributes to spatial memoryMolecular memory: how DNA
methylation contributes to spatial memory
Lay Description (from application):
The brain stores memories that can last a lifetime and our memory is core to mental health, but we still do not
know how memories are stored. Here we explore a radical new theory that memory storage involves chemical
modification of the DNA molecule - DNA-methylation. We will examine how memory changes patterns of
DNA-methylation, and how modifying DNA-methylation can change memory. Our work will examine the
biochemical basis of memory, and will inspire new strategies to treat memory disorders.
Research achievements (from final report):
We have taken advantage of a highly conserved mammalian-like epigenetic machinery encoded by the honey
bee genome and the ease of experimental manipulations in this organism to develop an innovative model
system for neuroepigenetic research. A small, manageable number of methylated sites in a relatively small
honey bee genome provides an excellent opportunity to overcome some of the hurdles associated with analyses
of complex methylation patterns in large mammalian genomes. We have confirmed the applicability of the
honey bee system to study epigenetic aspects of brain function by showing that memory processing in this
organism is susceptible to DNA methylation inhibitors used in a prior mammalian study. In the rat model we
have shown that inhibition of DNA methylation in the dorsal hippocampus prevents long-term recognition
memory in a time dependent manner. Evidence from this project supports the emerging view that modulation
of memory is an ancient and highly conserved function of epigenetic processes.
Expected future outcomes:
Epigenetic systems are increasingly known to be involved in mental illness, Alzheimers, and related dementias.
Our basic work with the honey bee will develop a model for studying epigenetic memory that is a cost effective
and ethically defensible compliment to the use of mammals in research.
Name of contact:
Prof. Ryszard Maleszka
Email/Phone no. of contact:
RYSZARD.MALESZKA@ANU.EDU.AU
NHMRC Research Achievements - SUMMARY
Grant ID: 569886
CIA Name: Dr Adam Hamlin
Admin Inst: Charles Sturt University
Main RFCD: Central Nervous System
Total funding: $320,803
Start Year: 2009
End Year: 2012
Grant Type: Early Career Fellowships (Australia)
Title of research award:
The role of p75 neurotrophin receptor-mediated neurodegeneration of basal forebrain cholinergic neuronsThe
role of p75 neurotrophin receptor-mediated neurodegeneration of basal forebrain cholinergic neurons
Lay Description (from application):
Alzheimer’s disease is a progressive neurodegenerative disorder characterized by clinical symptoms of
memory deficits and cognitive function. It remains unclear what causes Alzheimer’s disease, but loss of a
specific population of brain cells that are critical to cognitive function is generally accepted as a key feature of
this condition. The aim of this project is to understand the mechanisms by which this cell loss occurs and how
this relates to the loss of brain function.
Research achievements (from final report):
Alzheimer's disease is a progressive neurodegenerative disorder characterised by amyloid plaques and neuronal
death that leads to the classic clinical symptoms of memory deficits with subsequent erosion of judgment,
reasoning, verbal fluency and other cognitive functions. It is generally accepted that loss of basal forebrain
cholinergic neurons is as an early and key feature of this condition, however, it remains unclear what causes
this neurodegeneration in Alzheimer's disease. This study employed mouse models of Alzheimer's disease to
elucidate the underlying mechanism of cholinergic cell loss, to explore the precise behavioural deficits
associated with this loss and to develop techniques to detect this loss using magnetic resonance imaging (MRI).
One of the key findings of this research was identifying the precise behavioural deficit associated with the early
loss of cholinergic basal forebrain neurons. This research showed that the cholinergic basal forebrain plays a
very specific role in the self-movement kinaesthetic cues that are critical for spatial navigation. Furthermore, it
was shown that this loss can be detected using MRI technology. Together these finding have the potential to be
used for early detection of Alzheimer's disease and be used as a model for validating new therapeutic
treatments.
Expected future outcomes:
These finding are now being examined in patients with mild cognitive impairment using a computer based
navigational task in combination with magnetic resonance imaging as a potential bio-marker for pro-dromal
Alzheimer's disease.
Name of contact:
Adam Hamlin
Email/Phone no. of contact:
ahamlin@csu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 578800
Start Year: 2009
CIA Name: Dr Vanessa Danthiir
End Year: 2011
Admin Inst: CSIRO Division of Human Nutrition Grant Type: NHMRC Project Grants
Main RFCD: Complementary-Alternative Medicine not elsewhere classified
Total funding: $738,908
Title of research award:
Testing the effect of long-chain Omega-3 polyunsaturated fatty acids on cognitive ageing in the elderlyTesting
the effect of long-chain Omega-3 polyunsaturated fatty acids on cognitive ageing in the elderly
Lay Description (from application):
The ageing profile of our population holds challenges for society, with some of the major impact due to loss of
independence and quality of life in older people, arising from decline in cognitive functioning. Evidence
suggests a benefit of Omega-3 fatty acids on cognitive functioning in older people but claims that Omega-3
slows cognitive decline have not been adequately tested. This study tests the effect of Omega-3
supplementation on cognition in healthy older people, over an 18-month period.
Research achievements (from final report):
This study is one of only a few to examine the effect of fish-oil supplementation on cognitive decline in
cognitively-healthy older adults. It aimed to examine the effect of fish-oil supplementation on cognitive decline
over 18-months, across numerous cognitive domains, as well as subjective well-being and functional capacity,
within the broader context of examining nutritional and health factors associated with better cognitive and
well-being outcomes in the elderly. Participants (N=390) completed a broad battery of assessments at baseline,
6-,12-, and 18-months (N=352). When analyses are completed the study will provide strong scientific evidence
on the question of the efficacy of fish-oil supplementation for slowing cognitive decline in cognitively-healthy
older adults. This information can then be used to guide both health professionals as well as the general public.
Expected future outcomes:
Knowledge of the effect of fish-oil supplementation on cognitive decline, subjective well-being, functional
capacity, and on biomarkers of inflammation, oxidative stress, and DNA damage in older adults. Knowledge
on relationships between historical and current diet and nutritional factors and cognitive health and subjective
wellbeing in older age is also expected.
Name of contact:
Vanessa Danthiir
Email/Phone no. of contact:
vanessa.danthiir@csiro.au
NHMRC Research Achievements - SUMMARY
Grant ID: 533531
CIA Name: Prof John Mamo
Admin Inst: Curtin University of Technology
Main RFCD: Geriatrics and Gerontology
Total funding: $567,789
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
An investigation into the mechanisms of how dietary fats influence Alzheimers Disease risk.An investigation
into the mechanisms of how dietary fats influence Alzheimers Disease risk.
Lay Description (from application):
There is some evidence to suggest that diet may influence the risk for developing Alzheimer's Disease. This
project will explore if dietary fats that are 'bad-for-the-heart', are also 'bad-for-the-head'. Conversely, these
researchers will test whether heart-healthy-oils are brain-healthy. The researchers will investigate the
mechanisms by which dietary fats influence risk and hope to be able to develop nutritional guidelines for the
prevention or slowing of Alzheimer's Disease.
Research achievements (from final report):
The brain is critically supported by microscopic blood vessels called capillaries which function to provide
nutrientsand protect the brain from infection and inflammation. This project demonstrated for the first time that
dietary fatscan profoundly alter the integrity and function of these vessels. Disturbances in capillary function
led to heightenedinflammation and cellular stress. Intervention studies demonstrated partial restoration of
dietary induced capillarydysfunction. The findings demonstrates mechansism of how diet may be associated
with risk for neurodegenerativedisorders. The project highlights potential new strategies for prevention and
treatment of neurodegenerative diseases.
Expected future outcomes:
N/A
Name of contact:
John Mamo
Email/Phone no. of contact:
J.Mamo@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005792
CIA Name: Prof James Semmens
Admin Inst: Curtin University of Technology
Main RFCD: Aged Health Care
Total funding: $186,354
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
A longitudinal population based study of Alzheimer's disease: prescription drug use and survivalA longitudinal
population based study of Alzheimer's disease: prescription drug use and survival
Lay Description (from application):
Population linked health data (2002-2009) will be used to study patterns of care and outcomes for people with
Alzheimer's disease. Use of prescription drugs to treat Alzheimer's disease, the survival experience from time
of first supply of Alzheimer medication and the identification of inequalities in accessing medications will be
examined. The research will provide critical data for strategic sustainable healthcare planning and assist in the
development of dementia-specific healthcare policies.
Research achievements (from final report):
Since 2001 cholinesterase inhibitors have been listed on the Australian Pharmaceutical Benefits Scheme (PBS)
for exclusive use in patients with mild-moderate Alzheimer's disease to reduce rates of functional decline. The
age, sex, socio-economic and geographic breakdown of all Australian first-time users of this medication for
years 2003 to 2010 was examined using de-identified National PBS claims date of over 95,000 first-time users.
The effect of socio-economic disadvantage was found to play a significant role in the first-time prescription
rate of cholinesterase inhibitors, with the most disadvantaged less likely to be dispensed these medications than
the more advantaged groups. Advancing age also appeared to have been a barrier to treatment. Although
increasing remoteness was associated with reduced access compared with that observed in major cities, this
impact was not as great as that seen for socio-economic disadvantage. The results of this project have been
presented to the Australian Society for Psychiatric Research held at their conference in December 2012 and
accepted for publication in the international journal Alzheimer's and Dementia: The Journal of the Alzheimer's
Association. These findings will provide policy makers and healthcare planners with Australian quantitative
information necessary for optimising the planning of future healthcare services for this increasing vulnerable
population.In 2008 memantine was PBS listed for exclusive use in patients with more severe Alzheimer's
disease. We will be presenting our findings on the Australian national rates of memantine use for years 2009
and 2010 at the National Dementia Research Forum to be held in Brisbane in September 2013.
Expected future outcomes:
The identification of socio-economic, demographic and clinical factors associated with mortality outcomes in
over 13,000 Western Australian identified as having mild-moderate Alzheimer's disease based on first-time
prescription for cholinesterase inhibitors (2002-2003). The rates of documentation of Alzheimer's dementia in
hospital and death records will also be evaluated.
Name of contact:
Renate Zilkens
Email/Phone no. of contact:
r.zilkens@curtin.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 324100
CIA Name: Prof Ralph Martins
Admin Inst: Edith Cowan University
Main RFCD: Neurogenetics
Total funding: $429,500
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Molecular & Neuropsychological Predictive Markers of Cognitive Decline.Molecular & Neuropsychological
Predictive Markers of Cognitive Decline.
Lay Description (from application):
Alzheimer's disease (AD) is a major cause of dementia in the elderly. As populations worldwide are living
longer the prevalence of AD is predicted to rise markedly and in addition to the huge emotional burden on
families the economic implications to the community at large is severe. Thus our aging veteran population and
their spouses are particularly vulnerable to this devastating disease. Recent developments in AD research have
resulted in a number of therapeutic strategies being undertaken with several of these now in phase 2 clinical
trials. However for these treatments to be most effective early diagnosis is crucial. Currently, definite diagnosis
is restricted to post-mortem examination of the brain for the presence of characteristic neuropathological
features. This project proposes to identify individuals at high risk of developing cognitive decline leading to
AD by using a battery of biochemical, genetic and neuropsychological markers. This study builds on our earlier
work which followed a cohort of memory complainers and demonstrated that subjects in this group have lower
cognitive scores and an increased frequency of the genetic risk factor, the e4 allele of apolipoprotein E. Follow
up of this well studied cohort with more sensitive and extensive neuropsychological tests together with other
genetic and biochemical markers will be important in identifying those risk factors that have positive predictive
value for cognitive decline thereby contributing towards enhancing the therapeutic efficacy of current
symptomatic and future drugs directed at the cause of AD.
Research achievements (from final report):
The aim of this project was the invesitgate the association between genetic, biochemical and
neuropsychological factors which may contribute to cognitive decline and the development of Alzheimer's
disease (AD). We have been able to establish longitudinal cognitive and clinical data, along with blood samples
for 322 participants throughout the course of the study, and have 470 active participants. We have not been
able to establish a group of people in our cohort who are undergoing a phase of cognitive decline that could be
characterised as Mild Cognitive Impairment (MCI), however this may not be unexpected given the age of our
cohort and the time taken for cognitive decline that has been published elsewhere. During the course of the
study, we have established the relationship between subjective memory complaint and adverse outcomes on
self-reported measures of depression, anxiety and mental health, olfactory dysfunction and brain glucose
hypometabolism in brain regions associated with AD. We have also found an association between lipid
metabolism and the Alzheimer's related protein beta-amyloid. Lastly, we have provided evidence which may
explain some of the mechanisms underlying the association of the ε4 variant with increased risk for AD. The
project has resulted in 1 published journal article, numerous conference presentations and 3 maunscripts which
have been submitted for publication (with 2 additional manuscripts in preparation). These data suggest that
subjective memory complainers may be at increased risk for future cognitive dysfunction and represent a
potentially important group of clinical and public health interest worthy of future investigation.
Expected future outcomes:
We have collected a bank of blood samples and cognitive data that can be utilised for retrospective analysis
once cohort members undergo cognitive decline. We aim to continue this study and include further brain
imaging methods and cerebrospinal fluid analysis with the aim to develop surrogate biomarkers for cognitive
decline.
Name of contact:
Ralph Martins
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 426406
Start Year: 2008
CIA Name: Prof Ralph Martins
End Year: 2009
Admin Inst: Edith Cowan University
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $400,278
Title of research award:
The role of gonadotropins in regulating the production of Alzheimer's beta amyloidThe role of gonadotropins
in regulating the production of Alzheimer's beta amyloid
Lay Description (from application):
Currently, about 160,000 Australians suffer from dementia; of which 50-70% are Alzheimer's disease (AD)
cases. AD is characterised clinically by memory and personality changes and pathologically by deposition of
amyloid. Of particular importance in the disease pathogenesis, is a small molecule called beta amyloid, of
which the overproduction is thought to be central to the development of AD. Changes in the levels of the
reproductive hormones, particularly low levels of oestrogen during menopause or testosterone during
andropuase, has been associated with the increased risk of developing AD and in altering the levels of beta
amyloid. Furthermore, menopause and andropause are also characterised by changes in other reproductive
hormones such as the gonadotropins. High levels of the gonadotropins have also been associated with the
increased risk of developing AD. Therefore it is important to identify how these changes modify the risk of
developing AD. This study examines the role of the gonadotropins in regulating beta amyloid levels in cell
culture and in an animal model for AD. Furthermore, this study will assess, in the animal model, the use of
gonadotropin lowering agents to reduce levels of beta amyloid. The results from this study will provide
important data on how reproductive hormones regulate beta amyloid. Further insight into these mechanisms
will provide therapeutic or preventative strategies for AD.
Research achievements (from final report):
This study focused on lutenizing horomone (LH) and its contribution to the metabolisom of a protein called
beta amyloid which has a key role in Alzheimer's disease (AD) pathogenesis. Our findings show a direct role
for LH in promoting acumualtion of beta amyloid, a protein central to AD pathology. We have begun to tease
apart the relative contributions of sex hormones and gonadotropins in AD pathology. We also show that
gonadotropins impaired memory in a mouse model. In summary this study has also provided possible
mechanisms of action for LH in promoting beta amyloid accumulation. This work resulted in 1 published
journal article, 2 book chapters, numerous conference presentations and 3 mansucripts that are in preparation.
Two additional publications during the funding period led to a future direction of invesitigating LH as a
candidate biomarker for AD. In these publications we showed that increases in LH (rather than low oestrogen
levels) are associated with lower cogntive performance in post-menopausal women and that increases in LH
levels (rather than low testoterone levels) in eldelry men were associated with increases in blood beta amyloid
levels. Through the Australian imaging and lifestyle study (AIBL) we have now shown that LH levels are
associated with increased amyloid deposition (as assesed by brain imaging), prior to the onset of clinical
symptoms. Overall, this study has provided significant evidence for a role of LH in AD risk and pathogenesis
through experimental methods that have seperated the actions of sex hormones from gonadotropins. Further
insight into these mechanisms will provide therapeutic or preventative strategies for AD.
Expected future outcomes:
We have established that LH can directly impact on the accumulation of beta amyloid and have commenced
investigating mechanisms by which this can occur. The data generated here has led us towards a new direction
in which we will also investigate further, sex steroids and LH as candidate biomarkers for cognitive decline.
Name of contact:
Professor Ralph Martins
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480102
Start Year: 2008
CIA Name: Prof Ralph Martins
End Year: 2011
Admin Inst: Edith Cowan University
Grant Type: NHMRC Strategic Awards
Main RFCD: Neurosciences not elsewhere classified
Total funding: $484,675
Title of research award:
Evaluation of Combination Nutritional Supplement Therapies in the Prevention of Alzheimers disease
inEvaluation of Combination Nutritional Supplement Therapies in the Prevention of Alzheimers disease in
Lay Description (from application):
Age-related diseases are becoming a major concern as the world’s population grows older due to advances in
medical technology, health and nutrition. Dementia accounts for a large proportion of agerelated diseases and
is characterised clinically by deterioration in memory and cognitive processing. AD is the most common form
of cerebral degeneration leading to dementia. Currently over 200,000 Australians suffer from dementia, with
AD, accounting for 50-70% of all cases. At this rate, the number of people in Australia with dementia will
increase to 730,000 by the year 2050. Thus, there is an urgent need for effective preventative treatments for this
devastating disease, as dementia will soon be the major cause of disability in Australia. As a result, the social
and economic consequences of this disease present a significant challenge to society, and it is imperative that
strategies to prevent or delay the onset of AD are developed. If complimentary and alternative medicine
(CAM) therapies could be developed to prevent or delay the onset for Alzheimer’s disease, the impact on
disease burden could be substantial. However, these CAM therapies need to be critically evaluated for their
mechanisms, efficacy and safety before human clinical trial are undertaken. The proposed research plan will
evaluate the efficacy of the nutritional supplements of polyphenols (EGCG from green tea and curcumin),
omega-3 essential fatty acids (docosahexaenoic acid) and lipoic acid to determine whether these treatments in
combination offer preventative therapies for AD. The findings from the current study will provide important
information concerning the effects of combination supplements in preventing cognitive deficits and AD
pathology in a transgenic mouse model. Combination treatments may reduce cognitive deficits (memory and
learning), oxidative stress and AD pathology, thereby providing an important insight into possible CAM
preventative treatment strategies for AD. The development of effective preventative strategies for the treatment
of AD is critical if we are to reduce the number of people that are expected to develop AD over the next 50
years, due to the rapidly aging population. The outcomes of this research may provide disease modifying
therapies for the prevention of AD.
Research achievements (from final report):
This research project was designed to evaluate the efficacy of nutritional supplements derived from green tea,
the curry spice turmeric, omega-3 essential fatty acids from fish oils and the antioxidant lipoic acid to
determine whether these treatments in combination offer preventative therapies for delaying the onset of
Alzheimer's disease (AD). Currently, over 266,000 Australians suffer from dementia, with AD accounting for
most of these cases. At the present rate, this number will increased to 924,000 by the year 2050. The social and
economic consequences of this disease presents a significant challenge to society, and it is imperative that
strategies to prevent or delay the onset of AD are developed. The findings obtained from this project
demonstrate that combination of these nutritional components can assist in preventing cognitive deficits and
AD pathology in a transgenic mouse model. The results showed decreases in AD pathology in animals that
were fed combinations of green tea, turmeric, fish oil and lipoic acid. Importantly, it was also observed that
combinations of these nutritional components helped to prevent memory loss in this mouse model of AD.
These results will help shape the design of future studies trialling these nutritional components in elderly
Australians, to help prevent the number of increased cases of dementia, specifically Alzheimer's disease which
is expected to occur in Australia over the next several decades. The findings also support the notion that dietary
based lifestyle interventions are most effective when initiated early in life before the development of
Alzheimer's disease in order to have the greatest preventative effect.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The results are expected to assist with the development of lifestyle interventions comprising specific detary
components in combatting the increased number of cases of Alzheimer's disease in Australia. They provide
valuable information supporting development of clinical trials using dietary components early in life for
preventing or delaying Alzheimer's disease.
Name of contact:
Prof Ralph Martins
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595300
Start Year: 2010
CIA Name: Prof Ralph Martins
End Year: 2013
Admin Inst: Edith Cowan University
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $548,681
Title of research award:
Enhancing peripheral clearance of beta amyloid as a treatment for Alzheimers diseaseEnhancing peripheral
clearance of beta amyloid as a treatment for Alzheimers disease
Lay Description (from application):
Amyloid-beta (abeta) accumulation in the brain is a key step in the development of Alzheimer's disease, with
potential therapies focusing on its clearance. Compounds that bind abeta in blood have been shown to alter
brain abeta levels. We will assess the efficacy of a novel abeta-binding peptide to promote peripheral clearance
of brain-derived abeta in a mouse model of AD. Such a drug would be effective in sporadic AD, where the
efflux transport, clearance and degradation systems are defective.
Research achievements (from final report):
The accumulation of beta amyloid within the brain is a key event in the neurodegenerative process that occurs
in Alzheimer's disease and its removal is a potential therapeutic approach. In this project, we have identified a
small molecle (peptide, termed amyloid neutralising agent-ANA) that is resitant to degradation and binds beta
amyloid and attenuates its toxicity. We show that this peptide can bind various forms of beta amyloid including
small aggregates called oligomers which accumualte early in the disease process and are widely thought to
iniate neurodegeneration. In addition to demonstrating that the peptide can enhance removal of beta amyloid
from the periphery (blood), the ability to bind different forms of beta amyloid indicated that it could have
potential in Alzheimer's disease diagnosis. Our findings led into a new and exciting direction to validate the
peptide as a potenital brain imaging agent that is specific for smaller beta amyloid aggreates, rather than larger
amyloid plaques that are detected by current agents. Current agents are also not specific for beta amyloid and
detect all forms of amyloid. As accumulation of smaller aggregates occur early in the disease process, our
peptide has the potenial to be a specific imaging agent for early diagnosis of AD. Early diagnosis is critical for
the development of effective treatments that prevent the neurodegenerative process that occurs in AD.
Expected future outcomes:
We have identified a beta amyloid binding peptide that has therapeutic potenital but have also commenced the
new direction of a potenital imaging agent for the early diagnosis of Alzheimer's disease.
Name of contact:
Professor Ralph Martins
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 595312
CIA Name: Prof Ralph Martins
Admin Inst: Edith Cowan University
Main RFCD: Medical Biochemistry: Lipids
Total funding: $424,802
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The effect of human apoE isoforms and apoE receptors on the clearance of oligomeric A 42 by hepatocytes in
vitroThe effect of human apoE isoforms and apoE receptors on the clearance of oligomeric A 42 by
hepatocytes in vitro
Lay Description (from application):
Alzheimer's disease (AD) is a progressive memory disorder. Increased production of a short peptide called
amyloid- (A ) aggregates to form the sticky masses in the brains of AD patients. The amount of A in the brain
is a balance between production and clearance. Surprisingly, we recently demonstrated that the liver clears the
majority of A . These results connect AD and cardiovascular disease (CVD), enabling current CVD
therapeutics to target A clearance by the liver.
Research achievements (from final report):
This research project was designed to evaluate the role of the liver, apoE status and plasma lipid levels in
clearing a protein called amyloid beta, thought to be central to the pathogenesis of Alzheimer's disease (AD).
Dementia and AD account for a large proportion of the age-related chronic disease in Australia. Currently, over
266,000 Australians suffer from dementia with AD accounting for most of these cases. At the present rate, this
number will increase to 924,000 by the year 2050. The social and economic consequences of this disease
presents a significant challenge to society, and it is imperative that strategies to prevent or delay the onset of
AD are developed. The findings obtained from this project demonstrate that the liver is unique in that it is
responsible for the assembly and control of a variety of lipids and lipid receptors that play important roles in
maintaining lipid levels, and also in the clearance of the AD-related protein amyloid beta. Our findings also
demonstrate that this control over lipids can be affected by apoE status and high or low plasma lipid levels,
with apoE4 status and high plasma lipid levels decreasing the clearance of the AD-related protein amyloid beta.
These results will help further research elucidating the connection between AD and cardiovascular disease
(CVD) in elderly Australians, to help prevent the number of increased cases of dementia, specifically AD
which is expected to occur in Australia over the next several decades. The findings also support the notion that
controlling plasma lipid levels may contribute to decreasing the risk of developing AD later in life.
Expected future outcomes:
The results are expected to assist with furthering the connection between Alzheimer's disease (AD) and
cardiovascular disease (CVD). This will enable the development of therapeutic strategies targeting plasma lipid
levels to be used to increase factors that control the liver clearance of amyloid beta in AD pathology.
Name of contact:
Prof Ralph Martins
Email/Phone no. of contact:
r.martins@ecu.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 160042
Start Year: 2001
CIA Name: Dr Michael Clark
End Year: 2003
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Health, Clinical and Counselling Psychology
Total funding: $237,322
Title of research award:
The role of allostatic load as a mediator between chronic stress and poor health for dementia caregiversThe role
of allostatic load as a mediator between chronic stress and poor health for dementia caregivers
Lay Description (from application):
The potential risk to caregivers of dementia patients of poor health outcomes is well documented. The burden
imposed by caregiving is most often described in terms of chronic stress. While it is apparent that some stressrelieving social interventions (e.g. respite) may have short-term benefits, it is also clear that many caregivers
are unable or unwilling to avail themselves of such programs. The way in which chronic stress leads to poor
health is not well understood. Our study of spouse caregivers seeks to identify the groups of physiological
systems that suffer cumulative wear and tear as a result of chronic stress. This wear and tear is called allostatic
load, and is thought to lead to poor health. It is expected that caregivers in our study will have greater allostatic
load than people who are not caregivers. Should this be the case, our results will provide the basis for the
design of tailored interventions to maintain caregivers in good health. The potential of such preventive health
measures is to reduce caregivers' health care costs and reliance on community support, and to help caregivers to
continue providing care for their spouses at home.
Research achievements (from final report):
Outcomes still to be achieved, A number of journal publications are either planned or in preparation, and will
emerge over the next twelve months., , Future directions, In the current research, we have observed an increase
in primary mediators, which is precisely what allostatic load theory predicts should develop first in the
presence of sustained stress. We are seeking funding to determine whether this increase will lead in time to a
rise in secondary outcomes and ultimately to poorer health status, as predicted by allostatic load theory. , For
ex-caregivers there was physiological evidence of the burden of prior caregiving (again as predicted by
allostatic load theory). We are seeking funding to determine whether this process of wear and tear continues or
whether the observed psychological recovery translates with time to lower allostatic load scores and reduced
health risk. This is potentially a unique contribution to allostatic load theory., Finally, a number of new
potential indices of allostatic load are emerging, and we are seeking funding to address which indices best
characterise the concept of allostatic load.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 187636
Start Year: 2002
CIA Name: Dr Wei-Ping Gai
End Year: 2004
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $381,430
Title of research award:
alpha-synuclein metabolism in human neurodegenerative diseasealpha-synuclein metabolism in human
neurodegenerative disease
Lay Description (from application):
Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare
cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of
Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as
synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies
suggest alpha-synuclein may also contribute to many other human diseases, including Alzheimer s disease. The
reason how and why alpha-synuclein is involved in so many human neurological diseases is not clear. We
recently discovered that alpha-synuclein in normal human brain exists in multiple form of N-terminal
fragments, presumably generated through certain endogenous enzymes. These cleaved products are markedly
increased in Parkinson s disease. Studies by other groups suggest alpha-synuclein and fragments may be
released to the cerebrospinal fluids. Based on these findings, we hypothesize that alpha-synuclein is modified
by specific enzymes in neurons and released. This is probably a normal alpha-synuclein metabolic pathway
whose homeostasis may be, for reasons yet to be understood, altered in synucleinopathies. Similar mechanism
may be also involved in other common diseases in which the protein is believed to play a role. This project
aims to elucidate the potential role of alpha-synuclein metabolism in Parkinson s and related diseases by
examining alpha-synuclein metabolites in the brains affected by these diseases. Results from this grant will
provide new information about alpha-synuclein metabolism in neurons, new insights into the mechanistic
involvement of alpha-synuclein in these neurodegenerative diseases. Antibody reagents generated from this
study may be valuable in neuropathological and clinical assessment of changes in synucleinopathies.
Research achievements (from final report):
Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy are the major types of a growing
group of neurodegeneative diseases called synucleinopathies, where the central pathogeneic event is
mismetabolism of alpha-synuclein which aggregates in large inclusions and eventually lead to degeneration of
neurons and glial cells. Alpah-synuclein gene mutation, though can cause Parkinson's and related diseases, is
not relevant to the vast majority of patients who do not have the mutation. We aim to find out what exactly
wrong with the alpha-synuclein protein in the brain of parkinson's and related diseases by investigating the
molecular pathology of alpha-synuclein species purified from patients' brains. We also investigate how and
where these metabolites occur in neurons under normal and oxidative stress conditions. This information is
essential in designing diagnosistic and theraputical strategies for the cure of Parkinson's disease. , , ,
Expected future outcomes:
Findings from this project is expected to lead to diagnosistic and theraputical reagents or drugs targeting
pathogenic process specific for Parkinson's disease and related synucleinopathies.
Name of contact:
Wei-Ping Gai
Email/Phone no. of contact:
weiping.gai@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 229922
Start Year: 2003
CIA Name: Prof Mary Luszcz
End Year: 2004
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $397,200
Title of research award:
Late life transitions and pathways to healthy ageingLate life transitions and pathways to healthy ageing
Lay Description (from application):
The rapid ageing of the oldest-old segment of the population calls for a concerted effort to determine the ways
to healthy ageing. This project aims to identify ways in which older adults deal with key transitions or points of
major change that occur in late life. Such transitions or events might include widowhood, change in living
arrangements, or ceasing to drive. They may pose a challenge to healthy ageing if ones choice of a coping
strategy is poor, others are not available to assist during the transition, or thinking and health problems are
extensive. We plan to extend an existing longitudinal study that commenced in 1992 with 2087 adults, mostly
over the age of 70. Repeat interviews and assessments of surviving participants (numbering about 800) will be
completed, covering a wide range of social, health, psychological and functional domains. In addition, we
intend to identify participants' particular transitions on the basis of previously collected data or incidents arising
since we last saw them. A series of questions will be devised to gain more information concerning perceptions
of these transitions, how they responded to them and what their impact was. We are interested in the
consequences for the individual participant, those with whom they associate and the health care system more
broadly. Hence the second part of the research strategy involves seeking information from other informants
known to the ALSA participant and identified by them at baseline. The final component is to gather relevant
additional data (e.g., from Health Insurance Commission files) to determine wider implications of transitions
for social networks and health care systems. The outcomes include a better understanding of which transitions
are most consequential for healthy ageing; how to effectively use existing resources to maintain or enhance
healthy ageing; and the interpersonal and societal implications of transitions. (1940 characters with spaces)
Research achievements (from final report):
The project comprised the 7th wave of Australian Longitudinal Study of Ageing and the 4th multidisciplinary
home interview and evaluation, augmented by secondary data from informants, the Health Insurance
Commission (HIC) and service providers. It aimed to understand how major transitions occurring late in life
are negotiated by individuals and facilitated by social and family networks and access to health care.
Participants (N=487 Interviewed + 395 Objective Assessments; Informants n=449; HIC & Service Providers'
data n=438) reported 400 transitions in the previous 3 years. Particular attention was focused on social
networks, and their protection against transitions in disability, death and relocation to residential care. Family
networks are crucial in protecting against disability, while friends have a stronger role in deterring death.
Cognitive factors, rather than physiological ones, were shown to be more important in protecting against falling
and driving cessation. These findings have significant benefits for practice and policy development. In the case
of social networks, interventions could focus on facilitating maintenance or renewal of acquaintances with
friends and support for families with ageing members. Cognitive screening should form an integral part of
screening for driving continuation and the likelihood of falls. Our examination of characteristics of the oldest
old cohort revealed many examples of resilience in the face of losses and late life disabilities. Case studies of
these individual could form the basis of public awareness campaigns aimed at better informing attitudes toward
ageing. Publications and conference presentations provide a further indication of the breadth of the study.
Expected future outcomes:
Further mining of ALSA data for policy relevant evidence on ageing well is substantial. ALSA data also are
central to the successful AWAP project 410215, and will be pooled with other Longitudinal Ageing Studies to
develop best practice models of how to compress morbidity and optimize healthy and productive ageing.
Name of contact:
Mary Luszcz
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
mary.luszcz@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 441112
CIA Name: Dr Damien Keating
Admin Inst: Flinders University
Main RFCD: Central Nervous System
Total funding: $352,319
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
The role of Down syndrome candidate region 1 (DSCR1) in neurotransmitter release, vesicle recycling and
Down syndrome.The role of Down syndrome candidate region 1 (DSCR1) in neurotransmitter release, vesicle
recycling and Down syndrome.
Lay Description (from application):
Individuals with Down syndrome (DS) have three copies of human chromosome 21 (HSA21), rather than the
normal two. The symptoms observed in DS individuals are therefore due to the overexpression of HSA21
genes. Since all individuals with DS develop symptoms in the brain similar to those see in Alzheimer's disease
(AD), there may be a common mechanism that can be traced to the extra gene dosage from HSA21. We are
interested in one of these genes, Down syndrome candidate region 1 (Dscr1), which is overexpressed in both
DS and AD brains. We hypothesise that Dscr1 has a role in regulating exocytosis, a process in which chemical
messengers are released from cells. Exocytosis is highly specialised in the brain where neurotransmitters are
released from neuronal synapses in a process known as synaptic transmission. Reduced synaptic transmission
is one of the earliest hallmark of DS and AD occurring long before the classical neurological traits of DS and
AD such as plaque formation and dementia. We propose that alterations in Dscr1 expression are responsible for
the reduced neuronal exocytosis observed in the early stages of DS and AD. We have generated mice in which
Dscr1 expression is altered, as occurs in DS and AD brains, and our preliminary studies indicate that
exocytosis is reduced in these mice. We now wish to find the intracellular changes responsible for regulating
exocytosis when Dscr1 expression is altered. We also aim to compare this to exocytosis in classical DS mouse
models which have an extra chromosome 21 and in similar DS mouse models which have normal levels of
Dscr1. This project will uncover the currently unknown functions of Dscr1 in exocytosis in an animal model,
allow us to gauge whether Dscr1 is solely responsible for altering exocytosis in DS amongst other HSA21
genes, enable us to better understand the mechanisms initiating DS and AD and possibly lead to new targets of
early intervention in these diseases.
Research achievements (from final report):
This projecy focused on the role of the Down syndrome gene Dscr1 in cell communicaiton. We identified that
Dscr1 controls cell communication at several steps in the pathway and the mechanisms associated with this
regulation. We also idetified that Dscr1 controls the rleease of insulin and may be associated with diabetes.
Expected future outcomes:
This work has increased our understanding on how genes overexpressed in Down syndrome may alter brain
function.
Name of contact:
Damien Keating
Email/Phone no. of contact:
damien.keating@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 480422
Start Year: 2008
CIA Name: Prof Xin-Fu Zhou
End Year: 2010
Admin Inst: Flinders University
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $550,951
Title of research award:
Developing a novel therapy for Alzheimers diseaseDeveloping a novel therapy for Alzheimers disease
Lay Description (from application):
Alzheimer's disease is the most common brain disease which has huge social and economical burdens for the
modern society. It is caused by accumulation of the toxic peptides, called amyloid beta, in the brain. There is
no treatment for this devastated condition. We have identified a fragment of antibody specifically recognizing
amyloid beta peptides which dissolves and remove the plaques from the brain. This project is to further test this
novel drug in mouse model of the disease.
Research achievements (from final report):
The aim of the project was to develop a novel gene therapy using a single chain Fv antibody to Aedb for AD.
We had focused two main studies: 1.
Treatment experiment: After
administration of AAV-scFv into the muscle of 9 months old animals, the animals were observed for 3months.
We found that intramuscular delivery of scFv gene was effective in reducing the brain and serum Abeta levels,
and Abeta plaque burden. We did not see any significant adverse effects such as brain microhaemorrhages or
inflammatory cells infiltration in brain. , Prevention experiment: After administration AAV-scFv into the
muscle of 3 months old animals, the animals were observed for 6 months. We found that intramuscular
delivery of scFv gene was effective in preventing the cognition from decline, reducing the brain and serum
Abeta levels, ameliorating AD-type pathologies including Abeta plaque burden, microgliosis and astrocytosis.
We also did not see any significant adverse effects such as animal death, abnormal behaviour, brain
microhemorrhages, and elevated key proinflammatory cytokines in brain and serum. ,
Expected future outcomes:
The technology can be further developed for the prevention and treatment of Alzheimer's disease. For this
purpose, its toxicity and pharcokinetics need to further study.
Name of contact:
Xin-Fu Zhou
Email/Phone no. of contact:
zhou0010@flinders.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 535093
CIA Name: Dr Yanchuang Han
Admin Inst: Flinders University
Fellowships
Main RFCD: Cellular Nervous System
Total funding: $179,848
Start Year: 2009
End Year: 2010
Grant Type: International Exchange Early Career
Title of research award:
Roles of proBDNF in adult neural precursor cells and the therapeutic implications in Alzheimeras diseaseRoles
of proBDNF in adult neural precursor cells and the therapeutic implications in Alzheimeras disease
Lay Description (from application):
Nerve growth factor, brain derived neurotrophic factor (BDNF) is the most studied neurotrophin whose roles in
the brain development have been well characterized. Understanding the functional roles of proBDNF in the
adult neurogensis will have implications not only in normal brain functions and but also in the pathological
significance of neurological diseases. This project may lead to the application of these factors for the treatment
of AD.
Research achievements (from final report):
Pluripotent stem (PS) cells can be produced by inducing somatic cells with transcription factors or miRNAs,
although the current means of producing PS cells is considerably inefficient. The use of patient-specific PS
cells in regenerative medicine would appear attractive and desirable. However, the clinical applications of these
cells are prohibited due to potential hazards of the introduction of viral transfection vectors and exogenous
oncogenic transcription factors or by the high cost of producing them. Here we describe a safer and more
efficient method to induce mouse fibroblasts into neural stem cells using only small molecules. The small
molecule-induced neural stem (SMINS) cells closely resemble neural stem (NS) cells, in morphology, gene
expression patterns, self-renewal and multipotency. Thus, we have provided a novel and safe way to efficiently
induce neural stem cells from fibroblasts for potential applications in clinical medicine.
Expected future outcomes:
One paper will be published in the high IF journal and one patent will be obtained.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 230842
Start Year: 2003
CIA Name: Prof David James
End Year: 2005
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Protein Targeting and Signal Transduction
Total funding: $440,250
Title of research award:
Mechanism of action of Sec1p-like proteins in Membrane Trafficking.Mechanism of action of Sec1p-like
proteins in Membrane Trafficking.
Lay Description (from application):
One of the most important evolutionary changes that has occurred is the development of intracellular
compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis
for intracellular specialisation. For example, in order to degrade unwanted components cells have developed
degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular
components to avoid destruction of valuable molecules. In addition, the cell has developed a complex
assembly line of modifications that are added to proteins in a specific order as they travel to their final
destination within the cell. This necessitates the accurate passage of molecules between compartments, a
process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between
all of the various intracellular compartments it is necessary to employ complex machinery to guide and check
that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of
the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies
in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple
eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly
related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in
mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with
diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that
we can apply our knowledge to understanding many different disease states.
Research achievements (from final report):
The movement of proteins within the cell is fundamental to almost all biological processes. There are now
many diseases that appear to be due to disruptions in the process of protein movement within cells, including
Parkinson's disease, Huntington's disease, as well as various kinds of cancer. Although the function of proteins
within cells is very similar across all organisms, our understanding of the molecular machinery that governs
this function is very rudimentary. In this study, we have begun to unravel the workings of one of the proteins
that is involved in this process, which we believe will provide us with important clues to fundamental questions
about the relationship between protein movement and disease. .
Expected future outcomes:
In the future we hope to be able to define the function of the protein we have identified in much greater detail.
We hope to solve the atomic structure of this molecule, and then to use this information to pinpoint exactly
how it functions in the living cell and how this may relate to different disease states.
Name of contact:
Professor David E James
Email/Phone no. of contact:
d.james@garvan.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 276401
Start Year: 2004
CIA Name: Prof Peter Schofield
End Year: 2006
Admin Inst: Garvan Institute of Medical Research Grant Type: NHMRC Project Grants
Main RFCD: Neurogenetics
Total funding: $413,250
Title of research award:
Identification and characterisation of phenotypic modifier genes in familial Alzheimer's diseaseIdentification
and characterisation of phenotypic modifier genes in familial Alzheimer's disease
Lay Description (from application):
Alzheimer's disease (AD) is the most common cause of dementia the fourth most common cause of death.
There are no effective cures for AD and those drugs currently available are of very limited value in delaying
the onset and progression of this invariably fatal disease. AD is diagnosed by two key features in the brain,
dense plaques composed of the amyloid beta peptide, and tangles composed of the tau protein. The
identification of new therapeutic targets, such as the enzymes which produce amyloid beta peptide, and the
development of drugs that interact with these targets offers the prospect of developing treatments to delay
disease onset, retard or even halt the development of this relentlessly progressive disease. Our research
focuses on the genes that are involved in variant forms of AD. One neuropathological variant form we and
others have described is characterised by large diffuse (cotton wool) amyloid plaques. Cotton wool plaque
pathology is associated with AD causing mutations in the presenilin 1 (PS-1) gene. Another clinical AD variant
that we have described is characterised by the presence of spastic paraparesis (SP). SP is associated with PS-1
mutations, but when present delays disease onset. We have identified two potential modifier genes which are
likely to be directly involved in the production of cotton wool plaques or modifying the effect of PS-1
mutations and the occurence of SP. For both genes, the goal of this project is to use a range of genetic
approaches to clone the modifier genes by and to assess their effects on the clinical and pathological
development of AD. By studying the effects of genes which act to modify the effects of the PS-1 mutations in
these variant forms of AD we hope to gain a greater understanding of how the plaques and tangles actually lead
to the clinical symptoms of the disease and to gain insights into new ways in which AD may be treated.
Research achievements (from final report):
We have investigated the hypothesis that genetic factors underlie the observed clinical and pathological
heterogeneity seen in association with variant forms of Alzheimer's disease. We have investigated this
hypothesis by examining:, A) The molecular mechanism of the formation of the pathological variant - cotton
wool plaques - and by defining the contribution of the presenilin-1 splice isoform lacking exon 8 to this variant
neuropathology. This has shown that certain presenilin-1 mutation carriers are more susceptible to deposition
of cotton wool plaques. , B) Using a cohort of early onset Alzheimer's disease pedigrees we have identified a
novel gene which alters the exon splicing of presenilin-1. This splicing factor, a regulated kinase gene, is a
candidate modifier gene for early onset Alzheimer's disease. We have also obtained genetic evidence that the
kinase gene and its homologue interact together to increase disease risk of both Parkinson's disease and
Alzheimer's disease. , C) Using a cohort of early onset Alzheimer's disease pedigrees we have identified a
genetic locus that confers the differential presentation of spastic paraparesis in a clinical variant form of
Alzheimer's disease. We have shown, by direct sequence analysis, that known candidate genes with defined
biochemical functions involved in either Alzheimer's disease or that cause spastic paraparesis do not carry any
mutations that may cause this variant form of illness. , The work conducted to date has provided evidence for
modifier genes and this new knowledge may lead to new ways in which treatments for Alzheimer's disease are
discovered.
Expected future outcomes:
The work conducted to date has provided evidence for modifier genes and is the subject of future grant
applications and will also be the subject of future patent applications. This new knowledge may lead to new
ways in which treatments for Alzheimer's disease are discovered.
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof Peter R Schofield
Email/Phone no. of contact:
p.schofield@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 481929
CIA Name: A/Pr Marie Cooke
Admin Inst: Griffith University
Main RFCD: Aged Care Nursing
Total funding: $153,635
Start Year: 2008
End Year: 2009
Grant Type: NHMRC Strategic Awards
Title of research award:
The Effect of Music on Agitated Behaviours in Older People with Dementia: A Randomised Control TrialThe
Effect of Music on Agitated Behaviours in Older People with Dementia: A Randomised Control Trial
Lay Description (from application):
This study uses a cost effective non-pharmacological intervention, that being music therapy to improve quality
of life (QOL) in people with dementia. Dementia results in a decline in mood and cognitive functioning and the
emergence of behaviour problems that include aggressive acts, agitation, and sleep-wake and rest-activity
pattern disturbance. Aggressive behaviour is a common burden for caregivers in residential and family care.
The subsequent stress that aggression places on caregivers can lead to staff and family burn out, an increase in
restraint use, and decreased quality of care. Research suggests that disruptive behaviours are recognised as a
predictor in staff resignation and carer stress, both of which add significantly to the current costs of aged care.
This project therefore has the potential to benefit both people living with dementia and their carers. The
positive outcomes of music on people of all ages and health status have been established in various clinical
settings. Recent research suggests that music therapy may be useful in the management of disruptive
behaviours in people with dementia. Music therapy for people with dementia has the potential to improve their
quality of life (QOL) through an improvement in depression, and a reduction in aggression and agitation. This
study will investigate the effect of a live music program (where participants use their voices and instruments to
perform and create music) on agitated behaviours in older people with dementia. It will provide evidence
contributing to better understandings about music therapy and its contribution to QOL and disruptive
behaviours in people with dementia that can be transferred to other settings such as the community and home
based care of people with dementia.
Research achievements (from final report):
This study found that, overall, participation in a live music intervention did not significantly affect levels of
anxiety, depression, agitation and perceived quality of life in older people with dementia. That said, however,
results did suggest that both the music and reading control group activities gave some participants a 'voice' by
improving their verbalization behaviour and offered opportunities to improve sense of belonging, self-esteem
and depressive symptoms. In addition, the music intervention actively encouraged and induced greater
participant engagement during familiar song-singing. Further research into the specific benefits of regular,
facilitation-based group engagement approaches with older people with dementia, particularly those
demonstrating greater depressive symptoms, is needed to understand these findings further and determine their
practical application. Future studies would benefit from greater participant assessment prior to study
commencement so as to mitigate the influence of low scores on the results. Similarly, it would be advantageous
to run interventions at times when the symptoms under assessment are at their most prevalent.
Expected future outcomes:
To overcome the methodological concerns of previous research we undertook a Randomized Controlled Trial
(RCT) with cross-over design. Our results should encourage future studies to consider similarly rigorous
designs in order to improve the quality of evidence regarding the potential theraputic use of music for older
people with dementia.
Name of contact:
Associate Professor Marie Cooke
Email/Phone no. of contact:
m.cooke@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 597415
CIA Name: Prof Wendy Moyle
Admin Inst: Griffith University
Main RFCD: Residential Client Care
Total funding: $286,301
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The effect of foot massage on agitation in people living with dementia in residential care settings: An RCTThe
effect of foot massage on agitation in people living with dementia in residential care settings: An RCT
Lay Description (from application):
This study investigates the effect of a 10-minute foot massage on agitated behaviours of older people living
with dementia in residential care settings. The study builds on previous complementary research and provides
further evidence to help assess whether foot massage is, indeed, a low cost, low risk, non-pharmacological and
easily applied procedure that produces tangible positive psychological and physiological effects.
Research achievements (from final report):
This is the first randomised controlled trial of foot massage for agitation in people with dementia and as such
addresses one of the key limitations of massage research to-date and offers the opportunity to consider an
alternative treatment for agitation in this population. Although the findings were equivocal - with foot massage
helping some people, but having no effect on others - the research highlights the importance of tailoring nonpharmacological approaches to individual preferences. The study also found that massage is acceptable to
residential care staff and families and can be delivered easily in an aged care setting.
Expected future outcomes:
Two findings papers are currently under review in BMC journals. A future application will review the efficacy
of foot massage for care staff.
Name of contact:
Professor Wendy Moyle
Email/Phone no. of contact:
w.moyle@griffith.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 189800
Start Year: 2002
CIA Name: Prof Roger Dean
End Year: 2004
Admin Inst: Heart Research Institute
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $406,320
Title of research award:
Mechanisms of proteolysis of proteins containing oxidised amino acidsMechanisms of proteolysis of proteins
containing oxidised amino acids
Lay Description (from application):
There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified
by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin
to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in
formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for
most heart attacks and stroke. Other important age-related diseases, such as Alzheimer s disease and other
neurological disorders, are also claimed to be associated with deranged protein oxidation, and accumulation of
oxidised products. There is clear evidence that certain defensive mechanisms, such as those acting to remove
invading organisms and clear wounds, are also associated with an enhanced production of oxidised proteins.
Perhaps the most important component of defense against oxidised proteins is their removal by complete
breakdown to constituent components, and excretion. Normally, the machinery for breakdown of proteins is in
vast excess over the required rate of degradation. However, clearly in these conditions of accumulation of
oxidised proteins, this is no longer the case, or no longer suffices. Mechanisms by which oxidised proteins are
degraded are poorly understood, and quite controversial. Therefore, the present studies bring to bear a new
approach to studying this issue, which has been developed by the applicants. The aim is to reveal mechanisms
involved in the breakdown of proteins containing oxidised amino acids, both in cellular systems, and in vivo.
Such an understanding may allow us to envisage how to remove oxidised proteins by therapeutic means and
therefore interfere with the development of age-related diseases such as Alzheimer s disease and cataract
formation and the diseases of the blood vessels associated with attack and stroke.
Research achievements (from final report):
Proteins which have been damaged by oxidation (oxidised proteins) can accumulate in cells and tissues and are
implicated in the pathology of a number of diseases associated with ageing such as the blood vessel disease,
atherosclerosis, which is responsible for most heart attacks and strokes as well as neurological disorders such
as Alzheimer's disease. , , Using a novel approach we developed we were able to identify some of the key
mechanisms used by cells to remove oxidised and damaged proteins. This allowed us to discover where this
process may fail and why these toxic proteins accumulate in certain diseases. We identified the importance of
the heat shock proteins in preventing oxidised proteins from interacting with each other and forming
aggregates. Increasing the levels of heat shock proteins in cells may provide a new approach to treat age-related
disorders., , We also discovered that oxidised proteins can increase the production of a family of enzymes
called cathepsins. Cathepsins can break down tissues and have been implicated in a range of diseases including
tumour invasion and heart disease. This important finding linking the accumulation of oxidised proteins to
levels of these enzymes could have implications in many of the diseases of ageing. , , We demonstrated that the
oxidised amino acid 3,4 dihydroxyphenylalanine (dopa) can be mistaken for the natural amino acid tyrosine
and used by cells to make proteins. The dopa-containing proteins however have the capacity to accumulate in
the cell. This has important implications for Parkinson's disease where dopa is the most commonly used and
effective therapeautic agent.
Expected future outcomes:
These studies highlighted the critical role of the heat shock proteins in protecting the cell from damaged
proteins. Studies are underway to determine if increasing the levels of these proteins in cells can protect the cell
from some of the damaging effects of oxidation and slow the ageing process.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Ken Rodgers
Email/Phone no. of contact:
k.rodgers@hri.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 487318
Start Year: 2008
CIA Name: Prof Glynda Kinsella
End Year: 2011
Admin Inst: La Trobe University
Grant Type: NHMRC Strategic Awards
Main RFCD: Neurosciences not elsewhere classified
Total funding: $577,556
Title of research award:
Early Intervention for Amnestic Mild Cognitive Impairment : A Randomised Trial of Memory
ManagementEarly Intervention for Amnestic Mild Cognitive Impairment : A Randomised Trial of Memory
Management
Lay Description (from application):
It is increasingly recognised that Alzheimer’s disease can emerge slowly over years and persons presenting
with memory impairment, or mild cognitive impairment (MCI), are at increased risk of developing Alzheimer’s
disease. Following diagnosis of MCI, active management through symptomatic drug treatment remains
equivocal, therefore, memory impairment continues to be troublesome and patients and families are seeking
interventions that offer improvement in quality of life. Cognitive interventions are low cost and, where
effective, can provide a stand-alone intervention or add value to the pharmacological approach. The primary
aim of this study is to evaluate whether an early intervention program of memory training is effective in
improving use of memory strategies in everyday life, and whether this has psychological and emotional
benefits for individuals with MCI and their families. We will evaluate through a randomised controlled trial the
efficacy of a memory-group program which will involve the family and patient, rather than just the person with
MCI, in developing increased awareness of memory issues and specific strategies to prevent memory failures.
Over successive cohorts recruited from memory clinics, families will be randomly assigned to either an
immediate intervention or a delayed intervention (waiting-list control) group. We will also recruit a sample of
healthy older adults who will be similarly randomised into early and late intervention groups. Healthy older
adults will provide a means of establishing whether any improvements in the MCI groups are (i) to the same
extent as healthy older adults and (ii) to normative levels. Evaluation will be at pre- and post-intervention and
at six months follow-up on tests of memory, questionnaires of knowledge and use of memory strategies in
everyday life, and appraisal of level of wellbeing. Information about memory and systematic training in
compensatory memory skills are expected to significantly improve the capacity of patients and families to cope
with everyday memory difficulties. Through active participation in the management of memory impairment, it
is expected that the level of wellbeing will increase, for both patient and families.
Research achievements (from final report):
Many older people seek guidance about how best to manage everyday memory challenges. This is especially
the case for older people diagnosed with mild cognitive impairment (MCI) which carries increased risk of later
development of Alzheimer's disease. In response, we investigated a six-week intervention (the LaTCH Memory
Group Program) which provides knowledge about memory strategies and how to use strategies in everyday
activities, thereby offering an alternative approach to computer-based 'brain training'. We trained
neuropsychologists to deliver the intervention through 40 memory groups throughout Victoria. In a randomised
controlled trial, 219 older adults either diagnosed with MCI or healthy older adults were randomly allocated to
receive the intervention at different study time points. Following intervention, both groups significantly
improved their knowledge about memory strategies and when to use them, and also reported increased quality
of life through greater satisfaction with their everyday memory ability. We also found that following
intervention the healthy older adult group reported using more strategies in daily activities, improved everyday
memory ability, e.g. remembering to return a missed telephone call; and were more likely to achieve their
personal memory goals e.g., learning people's names in a yoga class. The MCI group achieved small positive,
but not significant, gains in these measures. Demonstration of the benefits from memory groups is important as
it opens up opportunity for people to engage more fully in social and life activities, adding to the cycle of
improving mental health in older age, especially those at risk of cognitive decline.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
The findings from our study provide encouraging support for the efficacy of memory groups as a practical and
feasible intervention in an older age population to reduce and prevent cognitive difficulties in daily life. The
intervention is low-resource and can be easily incorporated into existing health and community services
Name of contact:
Glynda Kinsella
Email/Phone no. of contact:
g.kinsella@latrobe.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 281215
Start Year: 2004
CIA Name: Prof Steven Wesselingh
End Year: 2004
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $144,250
Grant Type:
Title of research award:
The role of HIV infection of astrocytes in the development of HIV associated dementiaThe role of HIV
infection of astrocytes in the development of HIV associated dementia
Lay Description (from application):
Dementia is an extremely common problem in the late stages of Human Immunodeficiency Virus (HIV)
infection. HIV-associated dementia is the most common cause of dementia in people under 40 years of age.
Despite the development of very good drugs to attack the virus, HIV-associaed dementia continues to be a
major clinical problem. We are looking at the reasons why some people infected with HIV become demented
and others do not. We are also looking at how best to prevent the development of dementia. We believe that
astrocytes (an important brain cell that supports neurons) play a very important role in the development of
HIV-associated dementia. With an improved understanding of the steps leading to dementia we can better plan
treatments to prevent the development of this devastating complication of HIV-AIDS.
Research achievements (from final report):
We demonstrated for the first time that HIV-1 sequences can be compartmentalized in the brain within the
different target cell populations. Predicted amino acid sequence of the V3 Env clones, were suggestive that all
strains isolated were characteristic of CCR5-using (R5) HIV-1. The major conclusion reached from this portion
of study was that there is sub-anatomical compartmentalization of R5 viral strains within different target cell
populations of the local CNS microenvironment (published in the Annals of Neurology (2004; 56:873-877).
Expected future outcomes:
This study has been expanded to include a greater number and includes patients of varying clinical states: HIV
+ve patients with HIVD, HIV+ve patients without HIV-D, further classified into categories of rapid and normal
progression to HIV-D. Characterization is ongoing.
Name of contact:
Steve Wesselingh
Email/Phone no. of contact:
Stevew@burnet.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 603708
Start Year: 2010
CIA Name: A/Pr Melissa Churchill
End Year: 2012
Admin Inst: Macfarlane Burnet Institute for Medical Research and Public Health
NHMRC Project Grants
Main RFCD: Medical Virology
Total funding: $592,661
Grant Type:
Title of research award:
Molecular studies of the astrocyte reservoir of HIV-1 in the central nervous systemMolecular studies of the
astrocyte reservoir of HIV-1 in the central nervous system
Lay Description (from application):
HIV infects the brain causing dementia in 10-20% patients. Strategies aimed at eradicating HIV infection fail
to take into account CNS infection. Understanding the way in which HIV enters, infects and replicates in the
brain is pivotal in development of drugs to prevent brain infection and dementia. Our studies have shown that
HIV infection of the brain involves mechanisms distinct to those observed for blood and other organs. This
study seeks to clarify such mechanisms.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 281505
Start Year: 2004
CIA Name: A/Pr Joanne Jamie
End Year: 2006
Admin Inst: Macquarie University
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $319,650
Title of research award:
Probing the Structure, Mechanism and Inhibition of Indoleamine 2,3-Dioxygenase Using Structure- and
Ligand-Based StudiesProbing the Structure, Mechanism and Inhibition of Indoleamine 2,3-Dioxygenase Using
Structure- and Ligand-Based Studies
Lay Description (from application):
The human enzyme indoleamine 2,3-dioxygenase (IDO) is responsible for the initiation of a major enzymatic
pathway, known as the kynurenine pathway. During certain immune and infectious diseases IDO becomes
over-active and this leads to accumulation of neurotoxic kynurenine pathway compounds (metabolites). The
elevated levels of these metabolites have been linked to severe mental deterioration associated with diseases
such as AIDS (AIDS dementia complex), malaria and Alzheimer's disease. Several kynurenine pathway
metabolites have also been linked to age-related nuclear cataract, which is the major cause of human blindness.
This project employs a multidisciplinary approach that brings together a team of expert scientists from
medicinal chemistry, protein crystallography, protein biochemistry and neurology. The overall aims of the
project are to determine the structure of IDO using the recombinant human enzyme that we have cloned and
expressed in an active form and to develop compounds that will regulate levels of the kynurenine pathway
metabolites by selectively inhibiting the action of IDO. In addition, we will begin to assess the medicinal value
of the best inhibitors. We have already synthesised several inhibitors of IDO, but wish to design more potent
inhibitors. In order to do this, computer-aided molecular modelling and X-ray crystallography (which
effectively provides a picture of the enzyme with the inhibitors attached) will be used to predict the best
molecular features needed for inhibition. This will greatly aid the design of new inhibitor compounds, which
will then be synthesised. The best inhibitors will also be examined to determine their general pharmacological
value and specifically their ability to treat AIDS dementia complex and age-related nuclear cataract. These
enzyme inhibitors also have the potential to treat other significant human diseases.
Research achievements (from final report):
The human enzyme indoleamine 2,3-dioxygenase (IDO) has become of major interest to medical researchers in
recent years due to its involvement in a range of serious human conditions. It has been shown to become
overactive during certain immune and infectious diseases, leading to the accumlation of neurotoxic compounds
(metabolites) that have been linked to severe mental deterioration associated with diseases such as AIDS
(AIDS dementia complex), malaria and Alzheimer's disease. Several of the metabolites produced from IDO
activation have also been linked to age-related nuclear cataract, which is one of the major causes of human
blindness. In addition, various tumour cells are also known to overexpress IDO. The overall aim of this project
was to gain a greater understanding of the structure and function of IDO to aid the development of compounds
(IDO inhibitors) of therapeutic value. This was to be done using a combination of synthesis, molecular biology
and molecular modeling techniques. During the course of this study we optimised production of a recombinant
version of the human enzyme and developed a sensitive assay for rapid biological assessment of IDO
inhibitors. We produced a number of mutant forms of the enzyme, which helped in identifying structural
features of the enzyme important for its biological function and stability. We also synthesised and analysed the
potential of over 40 compounds as inhibitors of IDO. This increased our understanding of the features
necessary for further inhibitor design, which is necessary for the production of inhibitors of sufficient potency
for clinical use.
Expected future outcomes:
Expected future outcomes include a detailed understanding of the structure of the active site of human IDO, i.e.
the critical region where inhibitors interact. Such an understanding is essential for rational development of
inhibitors. Following on from this, the design of inhibitors with enhanced properties is anticipated.
NHMRC Research Achievements - SUMMARY
Name of contact:
Joanne Jamie
Email/Phone no. of contact:
joanne.jamie@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334035
Start Year: 2005
CIA Name: Prof David Small
End Year: 2010
Admin Inst: Menzies Research Institute
Grant Type: Established Career Fellowships
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $811,601
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a neurochemist studying the molecular mechanisms of neurodegeneration in Alzheimer's disease and
other related brain diseases.
Research achievements (from final report):
Research conducted during the period of my research fellowship was focussed on understanding the
mechanisms which cause Alzheimer's disease with the overall aim of identify new targets for drug
development. Our research demonstrated that it may be possible to develop new drugs based on inhibition of
the production, aggregation and neurotoxicity of a brain protein known as Abeta. The fellowship has led to
many significant publications in international journals which may help to progress the field in our laboratories
both in Australia and overseas.
Expected future outcomes:
We anticipate that it may eventually be possible to develop a drug which can be used to treat Alzheimer's
disease.
Name of contact:
David Small
Email/Phone no. of contact:
d.h.small@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403000
CIA Name: Dr Velandai Srikanth
Admin Inst: Menzies Research Institute
Main RFCD: Epidemiology
Total funding: $528,331
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
A population-based study of cerebrovascular mechanisms underyling gait, balance and cognition in older
peopleA population-based study of cerebrovascular mechanisms underyling gait, balance and cognition in
older people
Lay Description (from application):
Mobility problems, falls and dementia are among the major problems affecting older Australians with
significant consequent disability. Treatment of such disorders carries an estimated annual cost of around 4
billion dollars. This study will examine the role of age-related brain changes in causing problems with walking,
balance and cognitive abilities in the general community. The clarification of the role of the ageing brain in
causing such disorders will guide efforts directed at preventing the occurrence of falls and dementia.
Research achievements (from final report):
The primary aim of this study is to examine in detail the effect of age-related brain changes termed as white
matter hyperintensities on key aspects of brain function, namely gait, balance and cognition in an older
population. A primary finding of this study has been that such changes, when present in large amounts, predict
a high risk of future falling in older people. These brain changes have also also associated with poorer gait in
older people. These initial findings suggest that we may need to find ways to treat or prevent the occurrence of
such lesions in order to prevent falling in older people.
Expected future outcomes:
Further publications are expected over the next year regarding the location-specific effects of such lesions on
gait and cognitive function.
Name of contact:
Dr. Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 490031
CIA Name: Prof David Small
Admin Inst: Menzies Research Institute
Main RFCD: Cell Neurochemistry
Total funding: $561,213
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of the beta-secretase (BACE1) by glycosaminoglycansRegulation of the beta-secretase (BACE1) by
glycosaminoglycans
Lay Description (from application):
Alzheimer's disease is the leading cause of dementia in the elderly. Because of the prolonged
institutionalisation of patients, it is a major health care burden. This project aims to develop novel drugs which
can treat Alzheimer's disease by inhibiting production of the protein which causes the neurodegeneration.
Research achievements (from final report):
Our studies have shown that compounds called glycosaminoglycans may in future be useful for the treatment
of Alzheimer's disease. We found that glycosaminoglycans can influence production of a brain component
known as the amyloid protein (Abeta). The accumulation of Abeta in the brain leads to Alzheimer's disease. By
blocking production of Abeta, it may be possible to prevent or even cure the disease.
Expected future outcomes:
We will continue our studies on glycosaminoglycans. Further work is needed to test these compounds in new
models of Alzheimer's disease. Ultimately, if our studies are successful, we aim to take lead compounds into
clinical trials with a view to obtaining approval as drugs for the treatment of Alzheimer's disease.
Name of contact:
David Small
Email/Phone no. of contact:
d.h.small@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544913
CIA Name: Prof Roger Chung
Admin Inst: Menzies Research Institute
Main RFCD: Cellular Nervous System
Total funding: $408,739
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
How does the LRP receptor megalin promote regenerative neuronal growth?How does the LRP receptor
megalin promote regenerative neuronal growth?
Lay Description (from application):
Promoting the regenerative growth of neurons to allow recovery from traumatic brain injury or Alzheimer's
disease is a major goal of neuroscientists. This project continues the Chief Investigators' work in which they
have discovered the regenerative potential of a protein and focuses on how this protein interacts with a key
neuronal receptor, megalin, which appears to drive the regenerative process. This work will identify new
targets for therapies for a range of nervous system disorders.
Research achievements (from final report):
The aim of this project was to determine the precise mechanisms through which the protein metallothionein can
promote the regeneration of injured nerves following traumatic brain injury. Through a systematic series of
experimental approaches, we determined the identity of the receptor and the precise biochemical pathway that
is activated by metallothionein to promote regenerative sprouting of injured neurons. In addition, we found that
metallothionein can also modify the behaviour of non-neuronal cells, to make them more permissive to
regeneration of injured neurons. Finally, using our experimental models we identified a new molecule that
appears to be a key driver of nerve regeneration, and we are currently evaluating this new neuroregenerative
pathway. These important discoveries will greatly benefit the scientific community towards developing
therapeutic strategies to treat traumatic brain injury.
Expected future outcomes:
These important outcomes may lead to the development of new therapeutic agents that promote the
regeneration of nerves following traumatic brain injury.
Name of contact:
Dr Roger Chung
Email/Phone no. of contact:
rschung@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 544920
CIA Name: Prof David Small
Admin Inst: Menzies Research Institute
Main RFCD: Cell Neurochemistry
Total funding: $618,950
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
How amyloid causes neurodegeneration: the role of transthyretin in familial amyloidotic polyneuropathyHow
amyloid causes neurodegeneration: the role of transthyretin in familial amyloidotic polyneuropathy
Lay Description (from application):
This project seeks to understand the biochemical basis of nerve degeneration in a disease known as familial
amyloidotic polyneuropathy. This disease is caused by a protein known as transthyretin, which is abnormally
deposited around nerves and causes nerve damage. The project is highly likely to provide clues which help us
understand some related dementia causing diseases like Alzheimer's disease and prion diseases such as scrapie
and mad cow disease.
Research achievements (from final report):
This research has helped us to understand the mechanisms that cause a rare disease known as familial
amyloidotic polyneuropathy. However, the real significance of this work is that the mechanisms which underlie
familial amyloidotic polyneuropathy may be the same as those that cause Alzheimer's disease. Understanding
these mechanisms is vital for the identification of new drug targets for the treatment of Alzheimer's disease and
related disorders.
Expected future outcomes:
This research has increased our understanding of the cause of a neurodegenerative disease. Ultimately,
therapies targetting this cause may be developed which can be used to effectively treat the disease.
Name of contact:
David Small
Email/Phone no. of contact:
d.h.small@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 143664
Start Year: 2001
CIA Name: Dr Marie Gibbs
End Year: 2003
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $241,018
Title of research award:
Investigation of the mechanisms involved in consolidation of memory by beta 3
adrenoceptoragonists.Investigation of the mechanisms involved in consolidation of memory by beta 3
adrenoceptoragonists.
Lay Description (from application):
The inability to form new memories is a major and increasingly prevalent health problem for an aging
population. In addition to aging, the inability to form new memories is associated with serious medical
conditions including Alzheimer's Disease and diabetes. Common to these conditions is the inability to
consolidate memories. Memories are intact for a short while (30 minutes) after the event to be remembered,
but memory does not pass on into permanent storage. We have been able to achieve memory consolidation in
a particular learning task, which is not normally remembered, by injection of drugs acting on novel receptors
(beta 3 adrenoceptors) in the brain of day old chicks. These drugs mimic the action of noradrenaline at beta-3
adrenoceptors. There are a number of ways in which memory consolidation can be enhanced, and we will
compare the effects of beta-3 drugs with other potential drugs acting at other types of noradrenaline receptors.
One of the actions of beta-3 agonists is related to the uptake of glucose into cells in the brain. We will
investigate whether the mechanism of beta-3 enhancement of memory involves the uptake of glucose in brain
tissue and studies in cultures of individual cell types will show us which cells are involved. Although this work
is done using young chicks, there is no reason to suppose that the basic memory mechanisms at the level of the
nerve cell should be different in birds or mammals. There are distinct advantages to using chicks in this
research as they can form a long lasting memory for an experience lasting only 10 seconds, and they will
discriminate between different colours as part of their learning. This research is aimed at understanding the
processes involved in and influencing memory formation. If we are going to develop drugs to alleviate the
cognitive problems of old age and more serious cognitive diseases, we need to understand more about the basic
mechanisms of memory formation in the normal animal.
Research achievements (from final report):
One of the two major chemical transmitters in the body is noradrenaline. Noradrenaline is ubiquitous in its
distribution in the body with particularly high concentrations occurring in the brain. It has been known for
some years that there are many different types pf receptors for noradrenaline and we have been able to establsh
a role for many of these receptors in the different stages of memory. Our recent grant has focussed on the role
of a new receptor, the beta 3-adrenoceptor and we have elucidated its role in memory and the cellular effects it
is producing in the neurons and astrocytes (specialized brain cells). We have established the role of the beta 3receptor in relation to the other noradrenergic receptors and the location of the action in the brain. Although
this work has been carried out in the young chick, the results are proving to be very similar to the limited
knowledge of the mammalian systems with respect to nnoradrenaline and the adrenergic receptors. Memory
deficits occur in many diseases such as Alzheimer's disease and Parkinsons disease and this research opens up
the exciting possibility that some adrenoceptr drugs may be able to alleviate the memory deficits seen in these.
We have extended the work into understanding the cognitive disorders that may come about through hypoxia
before birth, and have shown that stimulation of the beta 3-adrenoceptor is able to alleviate the deficits caused
by prenatal compromise.
Expected future outcomes:
we hope that we will be able to extend this work at least to rodents to demonstrate the universality of our
findings and explore the usefulness of the beta 3-adrenergic receptor drugs in alleviating cognitive problems in
both neurodevelopmental and neurodegenerative diseases.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Marie Gibbs
Email/Phone no. of contact:
marie.gibbs@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251532
CIA Name: Prof Arthur Christopoulos
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $550,750
Start Year: 2003
End Year: 2007
Grant Type: Established Career Fellowships
Title of research award:
pharmacology of central nervous system disorders such as schitzophrenia, dementia and chronic
painpharmacology of central nervous system disorders such as schitzophrenia, dementia and chronic pain
Lay Description (from application):
Not Available
Research achievements (from final report):
This Fellowship has enabled the study of novel modes of regulating a very important family of cell-surface
proteins, the "G protein-coupled receptors (GPCRs)", using small molecule chemical probes. GPCRs are
involved in virtually all physiological processes, and are the targets of the majority of drugs on the market. As
a consequence of my research, we have discovered new ways of fine-tuning the actions of these proteins, either
in a postitive or negative direction, and have developed new approaches for screening for drugs that can act on
GPCRs in this novel way.
Expected future outcomes:
Discovery of novel small molecule therapeutics acting on G protein-coupled receptors.
Name of contact:
Prof. Arthur Christopoulos
Email/Phone no. of contact:
arthur.christopoulos@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 284236
CIA Name: Prof David Small
Admin Inst: Monash University
Main RFCD: Cell Neurochemistry
Total funding: $478,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Cholinergic abnormalities in Alzheimer's disease: identification of novel therapeutic targetsCholinergic
abnormalities in Alzheimer's disease: identification of novel therapeutic targets
Lay Description (from application):
The aim of this project is to develop new drugs for the treatment of Alzheimer's disease. Alzheimer's disease
is a disease of ageing commonly associated with memory loss. The disease is caused by the build up of
amyloid protein in the brain. However, it is not known how amyloid protein causes degeneration of normal
brain function. Our previous studies have shown that amyloid protein targets two components which are
important for normal brain function. These components are 1) acetylcholinesterase and 2) nicotinic receptors,
which are known to be important for memory. The aim of this application is to identify the mechanisms by
which amyloid protein targets acetylcholinesterase and nicotinic receptors and to design inhibitors of this
interaction which may ultimately provide a platform for future drug development.
Research achievements (from final report):
This aim of this research was to understand the mechanisms that cause Alzheimer's disease. The study
demonstrated that the major culprit in the disease (a brain component known as Abeta) interacts with cell
membranes. This interaction underlies the changes that cause neurodegeneration in the brain.
Expected future outcomes:
By understanding the key mechanism causing Abeta toxicity in Alzheimer's disease, it may be possible to
identify new targets for therapeutic intervention.
Name of contact:
David Small
Email/Phone no. of contact:
david.small@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 334047
Start Year: 2005
CIA Name: Prof John McNeil
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $3,532,500
Title of research award:
Randomised double-blind placebo-controlled trial of aspirin in primary prevention of CVD events or dementia
in the aged.Randomised double-blind placebo-controlled trial of aspirin in primary prevention of CVD events
or dementia in the aged.
Lay Description (from application):
The single most important risk factor for cardiovascular disease is age. All men aged 75 years have a 10-15%
risk of having a stroke or heart attack in the next 5 years. Low dose aspirin has been shown to prevent further
strokes and heart attacks in people who have already had one. It has been also shown to protect people who
have not had a heart attack or stroke but who are at increased risk. Given that the elderly are at increased risk
why do we need to do a trial in this particular group? The reason is that relatively few elderly patients were
included in the previous prevention trials. Also while the elderly may have the most to gain from treatment,
they also have the most to lose because they are more likely to suffer from side-effects. Aspirin prevents heart
attacks by stopping clots forming in blood vessels. This also means that people taking it have an increased
tendency to bleed. Thus though it may prevent strokes due to clots it may also increase the risk of strokes
caused by bleeding. Bleeding from the gut is another major problem as aspirin tends to erode the lining of the
stomach. Minor bleeding from the gut can also lower blood oxygen carrying capacity which may exacerbate
other diseases associated with ageing, e.g. heart failure. Dementia may be caused by repeated clots in small or
large vessels. Dementia is a particular problem in the elderly affecting 10% of 85 year olds. It is a major cause
of loss of quality of life and a significant cost to the community. Aspirin may reduce the progression of such a
disease leading to a maintained quality of life (QOL) for individuals and their families. As our age increases
our years of life remaining decreases. This is self-evident. Thus the potential to add years to life reduces and
the potential of diseases to adversely affect quality of life becomes more important. Thus it may be more
important to prevent a nonfatal stroke that leads to institutionalisation than a fatal stroke. Hence QOL will be
assessed.
Research achievements (from final report):
, This NHMRC project grant initially supported the completion of the ASPREE pilot study, analysing
data from 207 participants on aspirin or placebo for 12 months. Feasibility of methods for the main study was
proven with the pilot study. The grant was primarily awarded to act as leverage to obtain funding for the main
ASPREE trial. This was outstandingly successful. On the back of this seeding grant we obtained the following:,
1)
Funding of 50 million USD (shared
with US colleagues) was awarded late in 2009 by the peak medical research funding organisation of the USA,
the National Institutes of Health., 2)
The final ASPREE grant proposal
received a ranking in the top 2.5 percentile of all grants in that review round in 2008. This was an outstanding
achievement by any standard., 3)
Leverage to obtain funding for
substudies within Australia, e.g., $1.2 million AUD for the neuroimaging substudy ENVISion from NHMRC;
$3.4 million AUD for the establishment of the ASPREE HealHealthy Ageing Biobank from the CSIRO., 4)
Leverage to obtain $1.9 million AUD
funding from the Victorian Government (Victorian Cancer Agency) to establish clinical trial centres in regional
Victoria with ASPREE as the flagship clinical trial. , 5) The capacity to establish a longitudinal study of
healthy ageing in Australia., 6) The main ASPREE primary prevention clinical trial of low dose aspirin versus
placebo in 19,000 older persons is currently being undertaken in Australia and the USA with international
funding (2010-2016). ,
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
Results from the ASPREE clinical trial will have broad implications for clinical outcomes, clinical
management and public health of older persons in Australia and internationally, particularly in the areas of
cardiovascular disease, dementia, physical disability and cancer.
Name of contact:
Dr Robyn Woods
Email/Phone no. of contact:
robyn.woods@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 334079
Start Year: 2005
CIA Name: Dr Melanie Pritchard
End Year: 2007
Admin Inst: Monash University
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $510,500
Title of research award:
The role of Intersectin-1 in endocytic anomalies: implications for Down syndrome and Alzheimer's diseaseThe
role of Intersectin-1 in endocytic anomalies: implications for Down syndrome and Alzheimer's disease
Lay Description (from application):
Individuals with Down syndrome have three copies of human chromosome 21, rather than the normal two. We
have discovered a gene called Intersectin-1, located on human chromosome 21, that is expressed at higher
levels than normal in individuals with Down syndrome. Intersectin-1 has a role in endocytosis, a process
whereby cells take up molecules from the outside. Endocytosis occurs in all cells but is highly specialised in
the brain where chemical transmitters are released and then rapidly recovered by endocytosis in a process
enabling neurones to pass signals to one another. A disturbance in endocytosis has been reported as the earliest
hallmark of Alzheimer's disease in both non-Down syndrome and Down syndrome individuals. This
disturbance is characterised by the presence of enlarged endosomes (small packages in neuronal cells
containing chemical neurotransmitters formed during endocytosis). These enlarged endosomes are present long
before the characteristic plaques of Alzheimer's disease appear. Since all individuals with Down syndrome
develop Alzheimer's-like neuropathology, there must be a common disease mechanism that can be traced to the
extra gene dosage from chromosome 21. We propose that a malfunctioning of Intersectin-1 is this common
mechanism and we aim to test our hypothesis by the generation and analysis of mouse models of disrupted
endocytosis.
Research achievements (from final report):
All individuals with Down syndrome (DS) develop pathology akin to Alzheimer's disease (AD) by the time
they are 30 years of age, therefore there must be a common disease mechanism that can be ascribed to genes on
human chromosome 21, the extra chromosome present in DS. One of the earliest pathological hallmarks of AD
and also present in DS is the appearance of enlarged cellular organelles called endosomes in brain cells,
signifying a problem with the uptake and processing of molecules inside the cell. A chromosome 21 gene
called Intersectin-1 (Itsn1) is thought to be involved in this critical cellular process of endocytosis. In this grant
our aim was to firstly prove the involvement of Itsn1 in endocytosis by generating mice in which the gene had
been ablated then investigate the effects of Itsn1-deficiency on vesicle trafficking, a specialised endocytic
process in neuronal cells. These goals were achieved. We 1) generated Itsn1 knockout mice; 2) used a
functional assay to demonstrate abnormal vesicle trafficking in primary adrenal chromaffin cells cultured from
our mice, indicating a reduction in the amount of transmitter released from vesicles; 3) found that synaptic
vesicle endocytosis was reduced in Itsn1 null mice; 4) found that endosome area was increased in our
knockouts; 5) found that an intracellular trafficking pathway was abnormal. Collectively, these data indicate
that our Itsn1 null mice display some of the endocytic and trafficking defects associated with AD.
Expected future outcomes:
An understanding of the function of a gene over-expressed in DS and involved in cellular trafficking and
signalling has the potential to provide new understanding of what is perhaps the earliest neuropathological
event in both DS and AD and ultimately, may provide candidates for drug design to target the earliest signs of
disease.
Name of contact:
Melanie Pritchard
Email/Phone no. of contact:
melanie.pritchard@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 384157
CIA Name: Prof David Small
Admin Inst: Monash University
Main RFCD: Cell Neurochemistry
Total funding: $318,268
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Lipid rafts, amyloid neurotoxicity and Alzheimer's diseaseLipid rafts, amyloid neurotoxicity and Alzheimer's
disease
Lay Description (from application):
Alzheimer's disease is the major cause of dementia in the elderly. Individuals with Alzheimer's disease exhibit
a slow decline in cognition which usually results in prolonged institutionalisation. This creates an enormous
burden on society. The project aims to identify mechanisms which cause Alzheimer's disease. Specifically, it
will examine how a component of the brain, known as the amyloid protein, contributes to nerve cell
degeneration. It is hoped that by identifying these mechanisms, new targets for drug development will be
found.
Research achievements (from final report):
We have identified a novel pathway by which the amyloid protein of Alzheimer's disease alters neurite
outgrowth. Our studies show that Abeta acts to activate RhoA, thereby increasing the activity of the RhoA
kinase which phosphorylates the collapsin-response mediator protein-2 (CRMP2). CRMP2 phosphorylation
leads to collapse of growth cones, thereby a
Expected future outcomes:
his work may provide future targets for drug development.
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 384373
CIA Name: Dr Michael Azari
Admin Inst: Monash University
Main RFCD: Central Nervous System
Total funding: $193,725
Start Year: 2006
End Year: 2009
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Lipid Rafts, Amyloid Neurotoxicity and Alzheimer's Disease.Lipid Rafts, Amyloid Neurotoxicity and
Alzheimer's Disease.
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
5 published scientific articles, 4 conference posters and a book chapter
Expected future outcomes:
A high impact article to be published in 2011
Name of contact:
Dr Michael Azari
Email/Phone no. of contact:
Michael.Azari@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 400134
CIA Name: Prof Arthur Christopoulos
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $509,018
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Allosteric regulation of G protein-coupled receptorsAllosteric regulation of G protein-coupled receptors
Lay Description (from application):
The normal function of all living cells depends on how they respond to the multitude of physical and chemical
stimuli to which they are constantly exposed. The majority of these stimuli acting on cells do so not by directly
entering the cells, but rather by acting on specific types of "receiver" proteins on the cell's surface that are
called "receptors". The most important family of cell-surface receptors transmit their message to the inside of
the cell by coupling to yet another type of protein known as a " G protein", and are therefore commonly
referred to as G protein-coupled receptors (or GPCRs). Aberrations in the normal function of these GPCRs
have been implicated in a wide variety of disorders, including neuropsychiatric conditions, endocrine disorders,
cardiovascular disease and many cancers. To date, the majority of drugs acting at GPCRs do so by binding to
specific regions on these receptors. Although many breakthroughs in disease treatment have been achieved
using this approach, there remain a number of acknowledged limitations, including lack of drug selectivity,
toxicity and reduced responsiveness with prolonged therapy. Our current proposal focuses on targeting drugs
to alternative regions of GPCRs that may overcome many of the limitations associated with current drug
therapies. An understanding of the properties of these alternative drug binding sites, which will be investigated
in our current grant, can lead to more effective treatments for a variety of diseases.
Research achievements (from final report):
This project has validated a new approach towards achieving greater selectivity in the actions of drugs, namely,
by targeting novel sites (called "allosteric sites") on the body's receptor proteins at which the majority of drugs
act. As a consequence of our studies, we have discovered novel allosteric small molecules that can lead to
superior treatments for diseases such as schizophrenia and neuropathic pain. In addition, we have developed
methods for quantifying the actions of allosteric drugs, which may find substantial utility in the pharmaceutical
industry. Finally, by combining our small molecules and analytical methods, we have also gained new insights
into basic mechanisms governing drug action at the molecular level.
Expected future outcomes:
A key outcome will be an uptake of our approaches in industry and the subsequent discovery of more selective
drugs.
Name of contact:
Prof. Arthur Christopoulos
Email/Phone no. of contact:
arthur.christopoulos@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436787
CIA Name: Prof Elsdon Storey
Admin Inst: Monash University
Main RFCD: Neurogenetics
Total funding: $411,895
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Prevalence and genetic mechanisms of neurological and gynaecological changes in women carrying small
FMR1 expansionsPrevalence and genetic mechanisms of neurological and gynaecological changes in women
carrying small FMR1 expansions
Lay Description (from application):
Fragile X syndrome is one of the commonest genetic forms of mental retardation. The abnormal gene is passed
from mothers to their sons or daughters, on their X chromosome. The gene abnormality is unstable, tending to
worsen each time it is passed on. But if this gene abnormality is passed from fathers to their daughters, it does
not worsen. Therefore, grandfathers of the affected children on their mother's side, as well as the mothers, may
carry a mildly abnormal gene (a "premutation"), insufficient to cause mental retardation. However, it has
recently been discovered that these grandfathers may develop a syndrome ("FXTAS") of tremor,
incoordination, slowness of movements and mild dementia in their later years. Women were thought to be
protected, as they carry TWO X chromosomes, one of which is normal even if the other has a premutation. But
very recent reports suggest that they may also develop the "FXTAS" syndrome, as well as early menopause.
This study aims to see how common and severe these abnormalities are in women who carry the premutation,
using clinical, MRI and electronic measurements, and to relate the abnormalities to the severity of the gene
malfunction and familial predisposition.
Research achievements (from final report):
i) To estimate prevalence and characterise neurological and cognitive changes in female carriers of fragile-X
premutations, and to see if these cluster in families. Data collected on 61 subjects. All data except MRI have
been analysed., ii) To estimate the frequency of premature ovarian failure (POF) in this group. Data collected
and analysed on POF on 61 subjects., iii) To correlate molecular measures (CGG repeat size, mRNA levels)
with findings as in i). Molecular measures and assays of FMR protein expression levels completed.
Expected future outcomes:
Further papers on 1) MRI and (lack of) neurological features in female carriers, 2) endocrinological features,
and 3) MRI + neuropsychological changes expected
Name of contact:
Professor Elsdon Storey
Email/Phone no. of contact:
elsdon.storey@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 436797
CIA Name: Dr Velandai Srikanth
Admin Inst: Monash University
Main RFCD: Epidemiology
Total funding: $510,223
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
A study of mechanisms of cognitive decline in Type 2 diabetes mellitusA study of mechanisms of cognitive
decline in Type 2 diabetes mellitus
Lay Description (from application):
Diabetes mellitus and dementia are major public health problems. Diabetes may increase the risk of dementia.
This study aims to uncover the mechanism by which diabetes may increase dementia risk. This may lead to
finding new ways to prevent or treat diabetes-related dementia and thus reduce the public health burden of
dementia.
Research achievements (from final report):
The primary aim is to study mechanisms of cognitive decline in Type 2 diabetes mellitus, postulating an
important role for cerebrovascular disease, neurodegeneration and advanced glycation endproducts
(AGEs).The recruitment of 300 people with Type 2 DM has been finally completed and measurements have all
been undertaken. Currently we are in the process of cleaning data, completing grading of carotid measurements
and beginning the analyses to answer the primary study hypotheses. The recruitment of the entire sample took
longer ~6-8 months longer than predicted. Hence the analytical phase and publication preparation will occur
this year. In the meanwhile there have been two articles published, an editorial comment and a review article
and 2 conference presentations in the final year of the grant.
Expected future outcomes:
Completion of data cleaning, analyses and publication are occurring this year (2010)
Name of contact:
A/Prof Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 436806
CIA Name: Dr Richard Burke
Admin Inst: Monash University
Main RFCD: Neurogenetics
Total funding: $381,223
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Copper Homeostasis and APP-induced Neurodegeneration in DrosophilaCopper Homeostasis and APPinduced Neurodegeneration in Drosophila
Lay Description (from application):
Alzheimer s disease, a debilitating neurodegenerative disorder suffered by many of our elderly, is characterised
by the presence of abnormal protein accumulations called plaques in the brains of affected patients. Plaques
contain amyloid protein and also have high levels of the essential metals copper and zinc. Copper is needed for
the formation of these protein aggregations and increases the toxic effects of amyloid, leading to the idea that
copper-binding chemicals could be used to treat Alzheimer s disease. However experiments in animal models
have produced conflicting results, some suggesting that increased copper levels protect against neuronal
damage while others claim the opposite effect. Comparison of these studies is hampered by the different
experimental systems used. We will clarify the role of copper in the progression of Alzheimer s disease using a
simple insect model, the fly Drosophila melanogaster. Production of amyloid in Drosophila neuronal tissues
produces a neurodegenerative effect similar to that seen in human brains, but in a matter of weeks rather than
the years required in humans. We will combine production of amyloid with production of copper uptake and
export proteins to investigate the effect of changing copper levels. We will also test the effect of increasing
copper and other metals in the diet to see whether dietary levels are an important factor in disease progression.
Finally, we will use the Drosophila model to test large numbers of metal binding compounds and drugs for
ones that slow or halt the neuronal damage caused by amyloid production, identifying potential therapeutics for
the treatment of Alzheimer s disease. This work will provide a vital and definitive clarification of the role of
copper in the progression of Alzheimer s disease and potentially lead to the development of novel treatments
for this disease that is rapidly becoming a major social and economic problem in the developed world.
Research achievements (from final report):
We have developed a model of Alzheimers disease in the vinegar fly Drosophila melanogaster to investigate
the genetic and environmental factors contributing to this disease. In particular we have tested the effect of
altered dietary metal content and found that reducing the amount of copper available in the diet leads to an
improvement in the lifespan and activity of flies affected by neurodegeneration. While this does not imply that
excess dietary copper is a risk factor in developing Alzheimers disease in humans, it does indicate that correct
metal balance is important for neuronal health and supports the development and testing of metal-binding
compounds as possible therapeutic agents in the treatment of the disease. We have also used our model to
examine the role of a key pathogenic determinant of Alzheimers disease, the amyloid beta protein which makes
up the senile plaques found in the brains of Alzheimers patients. By investigating the neuronal toxicity of
defined variants of amyloid beta in the fly, we have been able to demonstrate the importance of stability of the
protein to toxicity. Forms of the protein that are less stable or more easily removed from the brain have a
significantly weaker effect on lifespan and neuronal health.
Expected future outcomes:
Our invertebrate model of Alzheimers disease can now be used to test the efficacy of potential drugs to treat
the disease and to search for genes that may increase an individual's risk of developing the disease or act as
protective factors in slowing or preventing disease progression.
Name of contact:
Richard Burke
Email/Phone no. of contact:
richard.burke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465125
Start Year: 2007
CIA Name: Prof Daniel O'Connor
End Year: 2009
Admin Inst: Monash University
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $194,543
Title of research award:
Greek & Italian residents with dementia in aged care: Language use, psychiatric medication,quaity of life &
satisfactionGreek & Italian residents with dementia in aged care: Language use, psychiatric medication,quaity
of life & satisfaction
Lay Description (from application):
Australia has a growing older migrant population and rates of dementia in residential care are high.
Communication difficulties for older persons with limited English language proficiency and dementia provide
a particular challenge in terms of meeting care needs effectively in residential settings. The current project will
compare older Greek and Italian background persons with dementia who are residing in either mainstream or
ethno-specific residential care facilities in Melbourne. The study will extend our pilot research, which focused
on language use, and will also measure a number of factors that may influence the rate of communication,
including prescribed psychiatric medication, language proficiency, cognitive impairment and
behavioural/psychiatric symptoms. Additionally, the project will compare factors that may differ between the
facility types, to provide further understanding of services offered. Furthermore, measures of satisfaction with
the facility and quality of life will be included to provide an indication of the clinical significance of residing in
a mainstream or ethno-specific aged care facility. The expected outcome of the study is to provide additional
data in a very under researched and increasingly important field, to inform policy and practice, with the aim of
improving the quality of life for older persons from diverse backgrounds in residential care.
Research achievements (from final report):
The project compared communication of older persons from Greek and Italian background with dementia who
were residing in mainstream or ethno-specific aged care facilities. The main finding was that those in ethnospecific care communicated at a higher frequency than those in mainstream care. There was a significantly
higher rate of resident-to-resident interaction in Greek or Italian language in the ethno-specific facilities. Staffto-resident interaction rates did not differ between the facility types, demonstrating that staff were
communicating with residents, even though they often did not speak a common language. While there was no
significant difference in the overall rate of prescribed psychiatric medication, those in ethno-specific facilities
were prescribed antipsychotic medication at a lower rate than those in mainstream care. No difference was
found on the quality of life measure. Families reported higher levels of satisfaction with ethno-specific care,
compared to mainstream and offered practical suggestions for improving the care provided to residents with
dementia and limited English language proficiency. The main implication of the research is that those with
dementia and limited English language proficiency may benefit from additional opportunities to interact with
their peers in their original language.
Expected future outcomes:
We hope that our research will lead to greater awareness of the needs of older persons from culturally and
linguistically diverse background with dementia in residential care.
Name of contact:
Dr Susannah Runci
Email/Phone no. of contact:
Susannah.Runci@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 465145
CIA Name: Dr Sonia Davison
Admin Inst: Monash University
Main RFCD: Endocrinology
Total funding: $156,004
Start Year: 2007
End Year: 2010
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Randomised placebo controlled-trial of effects of transdermal testosterone admin on cognition in
postmenopausal womenRandomised placebo controlled-trial of effects of transdermal testosterone admin on
cognition in postmenopausal women
Lay Description (from application):
Not Available
Research achievements (from final report):
, The research undertaken in this fellowship explored:, 1. The effects of testosterone on cognitive performance
in healthy postmenopausal women on HRT, compared to a group of untreated women. Cognitive testing was
performed using a sensitive computerised method which is designed to minimise the effects of learning. In
addition cognitive testing was performed via functional magnetic resonance imaging (fMRI) in the treatment
group. Following 6 months of testosterone treatment improvements were seen in verbal learning and memory
in the testosterone treated group, when compared to the control group. Reduced BOLD activation was seen on
fMRI imaging for visuo-spatial and verbal fluency tasks in the testosterone treated women, with no difference
seen in test performance, potentially indicating that less neuronal activation is required to perform these tests
after testosterone treatment. The significance of these findings is that testosterone may favourably modulate
cognitive performance in postmenopausal women, and may be a future treatment option for the prevention of
cognitive decline. , 2. A questionnaire for the assessment of female sexual function was validated and
published. In addition data on female sexual function and satisfaction were published. Key findings were that
sexually dissatisfied women had lower psychological wellbeing and lower frequencies of sexual thoughts,
interest and activities; oral contraceptive and HRT use had contrasting effects on sexual function and there
were clear differences between pre- and postmenopausal women. The questionnaire has been used by other
researchers.
Expected future outcomes:
The findings for the cognitive study are currently being explored further by our group in randomised
controlled, proof of concept studies aimed at further exploring the effects of exogenous testosterone in early
and late postmenopausal women. , The sexual function questionnaire has already been used by other
researchers following its publication.
Name of contact:
Dr Sonia Davison
Email/Phone no. of contact:
sonia.davison@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491104
Start Year: 2008
CIA Name: Prof Sally Green
End Year: 2013
Admin Inst: Monash University
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,113,074
Title of research award:
Evidence-based care of people with dementiaEvidence-based care of people with dementia
Lay Description (from application):
The number of Australians with dementia is increasing and so therefore is the frequency of people with
dementia presenting to general practice. There is a recent evidence based clinical practice guideline to inform
the diagnosis and management of people with dementia and the support of their carers. Many of the
recommendations from this guideline are relevant to Australian general practitioners. Strategies to implement
guidelines into practice are needed in all areas of health care, but changing clinical practice is complex and a
body of research developing methods of identifying barriers to specific practice changes is emerging. This
project aims to support GPs in improving the general practice based care of people with dementia, and so
improve their quality of life. In addition we aim to contribute to the body of knowledge about how to bring
about practice change and implement a clinical practice guideline. We plan to design a strategy for
implementing this new guideline into practice, working with GPs to change their practice where needed. We
will test the effect of this strategy on the care of people with dementia, on their quality of life and on that of
their carers.
Research achievements (from final report):
This project 'Investigating Research Implementation Strategies (IRIS) in dementia' was conducted in three
phases and has led to i)
an understanding of the key barriers
and enablers to practice for General Practitioners in managing dementia, ii) a tailored strategy for
implementing an evidence-based clinical practice guideline (CPG) for managing people with dementia in
general practice and iii) evaluation of the effectiveness of this implementation strategy in increasing the use of
validataed methods for cognitive assessment and screening for co-morbid depression. Novel methods for
collecting practice-based data have been explored.
Expected future outcomes:
Analysis of data for the trial is underway and will inform whether a tailored implementation strategy
underpinned by theory was effective in implementing an evidence-based CPG in the general practice
management of dementia. ????
Name of contact:
Sally Green
Email/Phone no. of contact:
sally.green@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 491109
CIA Name: A/Pr Velandai Srikanth
Admin Inst: Monash University
Main RFCD: Geriatrics and Gerontology
Total funding: $1,323,362
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A population-based cohort study of brain ageing - rates of brain structural change, functional effects, and
mechanismsA population-based cohort study of brain ageing - rates of brain structural change, functional
effects, and mechanisms
Lay Description (from application):
This study will provide unique longitudinal Australian data on the effects and causes of brain aging in a
population-based sample of older people. The results may assist in preventing dementia and falls, major public
health problems in older Australians.
Research achievements (from final report):
TASCOG is a cohort study of 430 older people randomly selected from the population followed up twice after
baseline assessment, over a period of 5 years. The principal aims are as follows:In a randomly selected
population-based cohort of people aged over 60 years (n = 400) followed over 5 years, we aim to study
cerebrovascular mechanisms involved in brain ageing:1.The rates of change in key age-related brain structural
volumes [white matter hyperintensity volume (WMHV), brain parenchymal volume (BPV) and hippocampal
volume (HV)].2.The impact of changes in brain structural volumes on change in cognition, gait, and the risk of
incident falls.3.The relationship between physical activity, endothelial function and change in brain structural
volumes over time.4.The effects of novel and potentially harmful (advanced glycation endproducts, AGEs) or
potentially protective (soluble receptor for advanced glycation endproducts - sRAGE) biochemical factors on
change in brain structural volumes over time. Data collection was completed in late 2012. Overall, we have
followed up 346 people in phase 2 and 279 in phase 3. Data cleaning and MRI processing for phase 3 has
required more intensive input and was completed omplete by mid-2013. Data from the first 2 phases are being
analysed from several perspectives. the first of these papers has been accepted by the Journal of the American
Geriatrics Society. Several further manuscript are in submission on the association of white matter lesion
progression and risk of incident falls, the trajectory and predictors of decline in cognitive function and quality
of life, and the effect of lifestyle (physical activity on brain changes). These data have already been presented
at major international meetings as well as being submitted for others. In addition, these longitudinal data now
are an integral component of genome wide meta-analysis looking at novel gene variants contributing to brain
ageing - as part of the CHARGE consortium.
Expected future outcomes:
This project has provided vast dataset with rich biological measures - it will provide novel data that will reach
publication on several fronts over the next 2 years
Name of contact:
Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 545843
CIA Name: Prof Daniel O'Connor
Admin Inst: Monash University
Main RFCD: Geriatrics and Gerontology
Total funding: $211,179
Start Year: 2009
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
A controlled trial of topical lavender oil as a treatment of behavioural symptoms of dementiaA controlled trial
of topical lavender oil as a treatment of behavioural symptoms of dementia
Lay Description (from application):
Many nursing home residents with dementia have challenging behavioural symptoms. This study will test if
pure lavender oil, when massaged onto the forearms of confused nursing home residents, relieves their
agitation better than a placebo oil. Researchers will measure residents' behaviour directly and will not be aware
which oil is being applied.
Research achievements (from final report):
Four hundred and forty aged care facility (ACF) residents were screened for the study from 8 major public
psychogeriatric facilities and three large private ACFs. There were 108 persons consented into the project with
64 participants completing the study. The data collection is now compete and analyses have revealed that
lavender oil does not appear to be effective in reducing agitation in the target population.
Expected future outcomes:
Ongoing research of psychosocial interventions increase our understanding of appropriate treatments options
for people with agitated behaviour associated with their dementia. Lavender oil is used quite commonly in
ACFs and while our results did not prove scientifically the effectiveness of the oil, ACFs continue to use the oil
and anecdotally report positive results.
Name of contact:
Professor Daniel O'Connor
Email/Phone no. of contact:
daniel.oconnor@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606544
CIA Name: A/Pr Velandai Srikanth
Admin Inst: Monash University
Main RFCD: Haematological Tumours
Total funding: $394,460
Start Year: 2010
End Year: 2013
Grant Type: Career Development Fellowships
Title of research award:
Cerebrovascular Disease and Dementia in Ageing PopulationsCerebrovascular Disease and Dementia in
Ageing Populations
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This award has enabled me to be very successful in areas of research in stroke, dementia, gait and falls with an
emphasis on the interface between cerebrovascular disease and dementia. It has led to significant research
translation in the management of transient ischaemic attack (TIA) for which a novel hospital pathway was
developed and evaluated resulting in an effective and cost-saving program. In addition, several cerebrovascular
markers of future risk of falls and gait disability in older people were identified. Finally, a major program of
research examining the relation between type 2 diabetes mellitus and dementia was begun, with some key
findings relating DM to brain atrophy generated. These findings may lead to new ways to treat/prevent
dementia.
Expected future outcomes:
The above research has ste the platform for further innovation particularly in the field of diabetes and dementia
which will be a major focus for the next 5 years.
Name of contact:
Velandai Srikanth
Email/Phone no. of contact:
velandai.srikanth@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606609
CIA Name: Dr Richard Burke
Admin Inst: Monash University
Main RFCD: Cell Metabolism
Total funding: $268,329
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Intracellular trafficking of copper and platinum-based chemotherapueticsIntracellular trafficking of copper and
platinum-based chemotherapuetics
Lay Description (from application):
Platinum-based anti cancer drugs such as Cisplatin are effective against a number of cancers of the head, colon,
lungs and ovaries. Tumour resistance to these drugs has been closely associated with changes in genes that
control the movement of copper in and out of cells. We hypothesize that the same genes regulate distribution of
both copper and Cisplatin. By investigating these pathways, we aim to find ways to predict and prevent tumour
resistance to this important anti cancer treatment.
Research achievements (from final report):
Copper is an essential dietary nutrient that can also be highly toxic if not regulated correctly in the body. This
research used the vinegar fly Drosophila as a genetic model system to investigate how copper absorption,
distribution and excretion is controlled in animals. Several genes previously implicated in general cellular
protein trafficking pathways were found to play key roles in regulating the activity of known copper
transporters and thus influencing copper metabolism. In particular, localization of the uptake protein Ctr1was
found to be controlled by several different cellular processes; insufficient Ctr1 protein at the cell surface could
hinder absorption of dietary copper through the cells of the intestine, leading to copper deficiency. , Using
targeted genetic manipulation in the fly nervous system, it was also shown that both copper excess and copper
deficiency were detrimental to neuronal health, highlighting the importance of maintaining copper homeostasis
in the brain. This finding has implications for neurodegenerative disorders such as Alzheimer disease where
disturbed metal distribution may contribute to disease onset and progression., The final outcome of this
research was to establish a system for studying the pathogenic effects of disease-causing mutations. Due to the
high level of relatedness between human and Drosophila copper transport genes, mutations in the human
Menkes and Wilson disease genes can be replicated in the equivalent fly gene, allowing an in-depth analysis of
their effect on gene function. Many different mutations can be studied simultaneously and the efficacy of
potential therapeutic reagents evaluated rapidly at minimal cost.
Expected future outcomes:
The novel copper homeostasis genes discovered in this project will now be examined for roles in modifying the
onset and severity of copper-related disorders such as the inherited Menkes and Wilson disease and sporadic
Alzheimer disease. Pharmacological reagents that target these genetic risk factors can be investigated for
therapeutic potential.
Name of contact:
Richard Burke
Email/Phone no. of contact:
richard.burke@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606639
CIA Name: Prof Daniel O'Connor
Admin Inst: Monash University
Main RFCD: Geriatrics and Gerontology
Total funding: $310,078
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
A randomised controlled trial of personalised goal-directed activity to treat agitation in dementiaA randomised
controlled trial of personalised goal-directed activity to treat agitation in dementia
Lay Description (from application):
We will test by means of a randomised controlled trial the effectiveness of personalised, goal-directed activities
in reducing agitated behaviour in aged care residents with dementia. Evidence suggests that treatments work
best when adapted to people's interest, skills and backgrounds. Our activities require no special equipment and
there is no need to exclude people with limited language skills. The study will be controlled to ensure that
benefits are not due just to social interaction.
Research achievements (from final report):
For nursing home residents who have severe dementia and marked, persistent agitation, activities that are
tailored to their interests and level of ability proved immensely helpful in reducing agitated behaviours,
engaging their interest and lifting their mood.
Expected future outcomes:
This study demonstrates that many severely disabled people, who are typically excluded from actvities, can
benefit greatly from them provided that care is taken to tailor the activities to their interests and level of ability.
This finding has real implications for Australian aged care providers.
Name of contact:
Daniel O'connor
Email/Phone no. of contact:
daniel.oconnor@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 606967
CIA Name: Dr Lachlan Gray
Admin Inst: Monash University
Main RFCD: Medical Virology
Total funding: $297,808
Start Year: 2010
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Mechanisms involved in the development of HIV-associated dementiaMechanisms involved in the
development of HIV-associated dementia
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This project aimed to identify how HIV invades brain cells, and how it causes damage resulting in dementia.
The project also sought to identify the mechanisms of viral persistence in the brain and the establishment of a
viral reservoir. These studies revealed that HIV is able to infect brain cells via a non-classical pathway.
Identifying this unique entry route paves the way for the development of novel entry inhibitors to block this
process. Preventing HIV infection of brain cells will lower the frequency of HIV-associated neurocognitive
disorders (HAND), including HIV dementia, while also assisting to reduce the size of the persistent viral
reservoir within the brain, aiding HIV 'cure' research. Further studies identified that select antiretrovirals
routinely used to treat patients suspected of having pronounced HIV brain infections, have no/limited activity
in select brain cells, thereby potentially exacerbating their infection and leading to worse clinical outcomes.
Optimising antiretroviral regimens to include drugs which act in all HIV infected brain cells has the potential to
result in better viral control, lower incidence of neurocognitive impairment and improved quality of life.
Finally, the mechanisms governing viral persistence were found to involve several factors encompassing both
the cell (altered levels of transcription proteins) and the virus (mutations in the viral promoter). Together, these
findings will enable the development of novel interventions to either 'switch on' viral production to purge
latently infected cells, leading to a sterilising cure, or lock the virus into a permanently 'switched off' state,
leading to a functional cure.
Expected future outcomes:
This work will inform the development of new entry inhibitors designed to prevent HIV infection of brain
cells, which has benefits for neurocognitive health and in preventing HIV persistence. Additionally, it will
assist in designing optimal antiretroviral regimens for complete viral suppression in the brain, and improved
quality of life.
Name of contact:
Dr Lachlan R Gray
Email/Phone no. of contact:
lachlan.gray@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1007907
CIA Name: A/Pr Siew Yeen Chai
Admin Inst: Monash University
Main RFCD: Central Nervous System
Total funding: $517,897
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms of IRAP inhibitors action on memoryMechanisms of IRAP inhibitors action on memory
Lay Description (from application):
IRAP inhibitors are currently being developed as a new class of drugs for treating dementia and other forms of
memory deficits. However, there are still gaps in our knowledge about how these drugs act to improve
memory. The experiments outlined in this proposal will provide important insights into the drug action in
different mouse models of memory deficit.
Research achievements (from final report):
This NHMRC project investigated the role of the enzyme insulin-regulated aminopeptidase (IRAP) in the
brain, in particular, its role in memory processing and involves the use of newly developed drugs that block
IRAP activity (IRAP inhibitors) as well as transgenic mice that has the IRAP gene deleted (the IRAP knockout
mice). Our experiments on the IRAP knockout mice revealed that these mice are protected against
experimentally-induced epileptic seizures and stroke damage. These findings provide evidence that IRAP plays
a role in seizure development as well as causing brain damage following ischemic stroke. We propose that the
drugs that block IRAP activity that we have developed in our laboratory may be potentially useful in the
treatment of epilepsy and stroke. We are currently investigating the effects of these drugs in our experimental
models of epilepsy and stroke. The outcome of these studies is that we have uncovered previously unexpected
roles for IRAP in the brain in addition to its known role in memory processing.
Expected future outcomes:
The IRAP inhibitors that were developed by the laboratory have demonstrated memory-enhancing properties
and may have potential therapeutic use in the treatment of memory disoders.
Name of contact:
Siew Yeen Chai
Email/Phone no. of contact:
siew.chai@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1011796
CIA Name: Dr Meritxell Canals
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $334,054
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Understanding new drug paradigms at M1 muscarinic receptors.Understanding new drug paradigms at M1
muscarinic receptors.
Lay Description (from application):
The M1 muscarinic receptor is a brain protein that plays vital roles in memory, and has been implicated in
Alzheimer’s and schizophrenia. However, this protein remains poorly targeted by current medications. The
current proposal will investigate the mechanisms of action of a new class of more selective M1 receptor drugs.
Our studies will generate valuable information that is directly relevant to the pharmaceutical industry and
academic drug discovery.
Research achievements (from final report):
The current research award has provided further understanding of the signalling and regulation mechanisms of
novel muscarinic receptor ligands. Such ligands offer the potential of selective targeting of specific receptor
subtypes, limiting the off-target effects of the current muscarinic drugs. We have provided valuable
information that can now be exploited in drug development programs for M1 muscarinic acetylcholine
receptor-related neuropsychiatric disorders. Our initial studies provided a new pharmacological framework to
evaluate the action novel M1 -targeting ligands (Canals et al. TiBS 2011; Canals et al. JBC 2012; Abdul-Ridha
et al. Mol Pharmacol 2012). Subsequently, our structure-function studies elucidated the site where BQCA, a
prototypical allosteric ligand, binds to the M1 mAChR (Abdul-Ridha JBC 2014). These studies will have an
important impact in M1-related drug discovery programs. Additionally, since many drug therapies are chronic
in nature our studies investigating the cellular consequences of prolonged administration of these drugs will
undoubtedly inform in the progression of these ligands as therapies (Yeatman et al. JBC 2014, Lane et al. ACS
Chem Neurosci. 2013). Finally, during the progress of the current project we have developed novel methods to
assess the trafficking of G protein-coupled receptors to different compartments of the cell, a technological
approach that will allow further understanding of receptor function. Collectivelly this project has resulted in 5
directly related publications and 3 publication that inderectly have benefited from the advances made by our
studies.
Expected future outcomes:
Our studies have provided detailed understanding about the mechanism of action of novel drugs targeting the
M1 muscarinic acetylcholine receptors. In particular, the structural and mechanistic information provided by
our work is currently guiding the development of new drugs with improved characteristics in the context of
cognition-related drug discovery.
Name of contact:
Meritxell Canals
Email/Phone no. of contact:
meri.canals@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 1011920
CIA Name: Dr Jonathan Lane
Admin Inst: Monash University
Main RFCD: Basic Pharmacology
Total funding: $540,357
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Bitopic ligands as a novel approach to G-protein-coupled receptor selectivityBitopic ligands as a novel
approach to G-protein-coupled receptor selectivity
Lay Description (from application):
This project will focus on two important types of brain proteins that have been implicated in various symptoms
associated with schizophrenia. The aim is to exploit a new paradigm of drug action that we have discovered,
whereby novel compounds can be utilized to simultaneously target multiples sites on these brain proteins, in an
effort to discover new mechanisms that can promote more selective signalling and, ultimately, can be used to
design safer and more effective medicines.
Research achievements (from final report):
This research project has focused on two brain proteins that have been implicated as drug targets in treating the
various symptoms of schizophrenia. We have expoited new paradigms of drug action to characterise drugs that
bind to different sites on these proteins and demonstrated that by targeting these sites we can achieve greater
selectivity. This greater selectivity may translate into the development of safer more efficaceous drugs.
Moreover, we have been able to gain mechanistic insight into how these novel drugs work. This research will
enable the design of more efective drugs that target these proteins. The results from this project have been
published in peer-reveiwed best-in-discipline journals and presented at both national and international
conferences. At one of these brain proteins, the dopamine D2 receptor, we have demonstrated that one ligand
can target multiple sites on this protein simultaneously. Through this novel mechanism of action this drug acts
like a molecular dimmer switch to tune down the effect of the neurotransmitter dopamine. This research has
been accepted for publication in the leading journal Nature Chemical Biology.The dopamine D2 receptor is an
important therapeutic target for schizophrenia with all current treatments exerting their effect through this
receptor. Our research demonstrates a diferent approach to designing drugs to target this therapeutically
important protein and this approach may also be used for other therapeutically relevant proteins within the
same family.
Expected future outcomes:
Our results from this research has given us unprecedented insight into the mechanism of action of drugs that
selectively target two brain proteins, the muscarinic M1 receptor and the dopamine D2 receptor. This will
provide a the basis for the development of new more effective therapies for the treatment of schizophrenia.
Name of contact:
Robert Lane
Email/Phone no. of contact:
rob.lane@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 447709
Start Year: 2007
CIA Name: A/Pr David Scott
End Year: 2010
Admin Inst: St Vincent's Health
Grant Type: NHMRC Strategic Awards
Main RFCD: Neurosciences not elsewhere classified
Total funding: $392,105
Title of research award:
Cognitive outcome and therapeutic interventions for coronary artery disease.Cognitive outcome and therapeutic
interventions for coronary artery disease.
Lay Description (from application):
Dementia is recognized as an increasingly important factor affecting quality of life as people age. Deaths from
heart disease are declining, in part due to improved surgical techniques and to the use of less invasive methods
to keep arteries open such as coronary stenting. It is now well known that 20 to 60% of patients experience
some degree of impairment in thinking ability (cognitive impairment) after cardiac surgery, that this will persist
in some of these individuals for years and may increase the risk of long-term problems. Cognitive impairment
affects people in many ways. While it is not yet known whether the occurrence of cognitive impairment
predisposes to dementia, it is thought that Mild Cognitive Impairment (MCI) may do so. We propose to explore
the link between MCI and Post Procedural Cognitive Deficit (PPCD) in patients with coronary disease from
before the first point of objective diagnosis, i.e. prior to the coronary angiogram, and over a 12-month period,
through and subsequent to further treatment interventions such as stenting or cardiac surgery. Our Pilot data
suggest that PPCD does indeed occur after angiography, and we propose to identify how long this lasts,
whether MCI predisposes to it and whether it is better to wait until it resolves before further interventions are
undertaken. In this way we hope to identify the safest treatment strategy for patients with coronary disease that
will minimize the occurrence of Cognitive Deficit and possibly longer-term cognitive changes after
investigation and treatment for their symptoms.
Research achievements (from final report):
The seeding study for this award (the CISCO study, NHMRC # 454622) provides evidence that the incidence
of cognitive decline 3 months after invasive procedures is equivalent following cardiac surgery, non-cardiac
surgery and sedation for coronary angiography in individuals aged 55 years or more., This study has recruited
over 285 patients and is stably recruiting over 100 per year. Thus we have already achieved the milestone of
being the largest prospective investigation into the impact of anaesthesia on cognitive function and new onset
dementia. Especially important is the comprehensive study-entry baseline cognitive function evaluation. We
seek the opportunity to provide full results of this study when complete.
Expected future outcomes:
This work, when complete, will inform the rate of conversion to dementia in patients aged 55 years or more in
the 2 years following coronary angiography and subsequent interventions for cardiac disease. This will include
any association between pre-existing cognitive impairment, mild cognitive impairment, post-procedural
cognitive decline and subsequent symptoms of early dementia.
Name of contact:
A/Prof David Scott
Email/Phone no. of contact:
david.scott@svhm.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 296201
Start Year: 2004
CIA Name: Prof Michael Parker
End Year: 2006
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $481,500
Title of research award:
Structural studies of amyloid precursor proteinStructural studies of amyloid precursor protein
Lay Description (from application):
In Australia, one in four school-aged children is currently overweight and childhood obesity rates are
continuing to rise. In the last five years it has become clear that rates of overweight and obesity are also rapidly
increasing in pre-school age children. These are issues that are of concern to health officials as well as to
parents. We understand that these rising rates in fatness relate to children's diet and activity patterns, and that
these patterns, once established are likely to be patterns for life. To date, there has been relatively little
research regarding the chance to support parents to establish the eating and activity patterns that will protect
their children from the very beginning of life. This project seeks to support first-time parents to establish
healthy eating and activity behaviours in their children using the highly utilised Maternal and Child Health
Centres first time parents' groups. We believe that these groups will provide a strongly supportive environment
in which to provide parents with strategies and knowledge for promoting healthy eating and activity patterns
for their children, and in turn, promote healthy weight gain. This project will assess the effectiveness of this
intervention.
Research achievements (from final report):
We determined the three-dimensional structure of part of a protein centrally involved in Alzheimer's disease.
This protein domain binds copper and in doing so greatly reduces the generation of a toxic protein fragment
that is thought to cause the disease.
Expected future outcomes:
The structural data obtained in this project provides the basis for the development of novel therapeutics against
Alzhiemer's disease. This work is proceeding in partnership with the local biotechnology company Prana
Biotech.
Name of contact:
Professor Michael Parker
Email/Phone no. of contact:
mparker@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 502602
Start Year: 2008
CIA Name: Prof Michael Parker
End Year: 2010
Admin Inst: St Vincent's Institute of Medical Research
Grant Type: NHMRC Project Grants
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $526,703
Title of research award:
Structure-function studies of insulin-regulated membrane aminopeptidaseStructure-function studies of insulinregulated membrane aminopeptidase
Lay Description (from application):
Memory loss can occur as a result of injuries or disease such as Alzheimer's disease, the fourth biggest killer in
developed countries. Currently there is no effective treatment for memory loss. This proposal concerns the
biochemical investigation of a protein involved in memory and possibly diabetes. This work is expected to
provide an understanding of how this protein functions in the body and will form the basis for the design of
drugs for the treatment of memory loss.
Research achievements (from final report):
We constructed a three-dimensional model of a brain protein called insulin-regulated aminopeptidase and then
computationally screened the model against a database of 2 million potential drug-like molecules. The most
promising molecule was tested in animals and shown to enhance memory. We plan to develop these molecules
into drugs that could be used to treat a range of cognitive impairments such as Alzheimer's disease.
Expected future outcomes:
To maximise the drug development opportunities both Institutes involved in the discovery have enlisted a
commercial partner, Bio-Link, to seek out international biopharmaceutical companies to help develop our
molecules into drugs that can used to treat cognitive impairment such as Alzheimer's disease
Name of contact:
Professor Michael W Parker
Email/Phone no. of contact:
mparker@svi.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219195
CIA Name: A/Pr Jane Chalmers
Admin Inst: University of Adelaide
Main RFCD: Residential Client Care
Total funding: $58,900
Start Year: 2003
End Year: 2003
Grant Type: SRDC - Research
Title of research award:
A best practice oral health model for australian residential careA best practice oral health model for australian
residential care
Lay Description (from application):
Carers are essential to the delivery of oral hygiene care and maintenance of residents’ oral health in residential
care faclities. This research will investigate the role that carers can play to maintain adequate oral health for
residents, and improving their timely referral and access to dental professionals. It will also assist with the
development of appropriate policies and procedures for oral and dental care, in accordance with
Commonwealth Residential Aged Care Standards
Research achievements (from final report):
This research project tested the use of an Oral Health Assessment Tool (OHAT) and a related Oral Hygiene
Care Plan (OHCP) in residential care settings in SA, Vic and NSW. A total of 23 residential care settings were
selected., Each facility was assisted through a process of drawing a sample and obtaining consent of residents
to participate in the research, the use of the OHAT and tasks associated with the OHCP. Each resident was
assessed at baseline by carers using the OHAT. The validity of the OHAT was assessed against the
observations of a gold standard, Dr Chalmers, at facilities in SA. The OHAT assessment linked to an OHCP for
each resident. The OHAT was reassessed at 3 and 6 months and again linked to potentially revised OHCPs. At
3 months considerable emphasis was placed on the reliability of OHATs by having the OHAT repeated several
days later by the same and a different carer. Focus group sessions were held with carers at each facility to
receive carer feedback on the OHATs and OHCPs at baseline, 3 and 6 months. Further, facilities have
maintained records of referral for dental treatment after an OHAT., A total of 534 older adults in residential
care were recruited at baseline and 454 held through to the 6 month follow-up., All collected data were
prepared at The University of Adelaide., The OHAT was evaluated as being a reliable and valid screening
assessment tool for use in residential care facilities, including the cognitively impaired residents. The OHCP
was evaluated as being a user-friendly adjunct to residents' care-planning. The OHAT and the OHCP improved
carers' involvement in maintenance of residents' oral health and the delivery of oral hygiene care.
Expected future outcomes:
Several facilities have adopted the OHAT and OHCP approach on an ongoing basis. , Results of the research
have been provided to the Commonwealth Depatment of Health and Ageing. The Oral Health Assessmrnt Tool
and the Oral Health Care Plans are under consideration for inclusion in the electronic documentation
recommendations for Australian Residential Aged Care Services.
Name of contact:
Professor John Spencer
Email/Phone no. of contact:
john.spencer@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 453622
CIA Name: Dr Michael Lardelli
Admin Inst: University of Adelaide
Main RFCD: Neurogenetics
Total funding: $414,006
Start Year: 2007
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
Truncating presenilin mutations and their effects on gamma-secretase activity, tau and beta-cateninTruncating
presenilin mutations and their effects on gamma-secretase activity, tau and beta-catenin
Lay Description (from application):
Alzheimer's disease (AD) and cancer are increasingly important both in terms of human suffering and the
burden of care it imposes on society and the economy. Sporadic (non-inherited) AD is the most common form
of dementia but is poorly understood. The PRESENILIN genes, PSEN1 and PSEN2, are the major sites for
mutations causing inherited AD and are also implicated in cancer. Using the zebrafish embryo model we have
discovered that, contrary to current thought, mutations that truncate presenilin proteins potently suppress
normal presenilin activity. (They are so called, "dominant negatives"). This means that they are lethal for
embryo development and explains why such mutations have never been found in inherited AD. Notably, this
discovery could only be made using a subtle form of gene manipulation that is possible in zebrafish embryos.
Our work has also established the first assay for the non-apoptotic (non-cell death) function of PSEN2 and has
shown that PSEN2 activity is inhibited by truncated PSEN1. This is the first indication of possible interaction
between PSEN1 and PSEN2 proteins at normal physiological expression levels. Loss of presenilin activity
promotes cancer. Truncated presenilin proteins could be produced by errors in gene transcription (aberrant
transcript splicing) common in cancerous cells. This suggests that truncated, dominant negative forms of
presenilin produced through aberrant splicing (or mutation in precancerous cells) might be common in tumour
formation. The proposed research will define the region of PSEN1 in which truncation leads to dominant
negative activity. This will allow further examination of the role of presenilins in the cell signalling pathways
involved in AD and cancer. We will also investigate the role that age-related truncation of presenilins in human
cells can play in the formation of sporadic AD. This may reveal a common molecular link between the
inherited and sporadic forms of this disease.
Research achievements (from final report):
We made a number of fundamental discoveries about genes important for the inherited (familial), early onset
form of Alzheimer's disease. Uniquely, our discoveries were greatly facilitated by applying a relatively "new"
model organism, the zebrafish, in our research. PRESENILIN1 is the gene most commonly mutated in early
onset, familial Alzheimer's disease. However, unusually, no mutations that truncate the protein produced by
this gene have ever been found. We discovered that truncations occurring in a particular, limited region of the
PRESENILIN1 protein potently suppress the "gamma secretase" activity of both PRESENILIN1 and
PRESENILIN2 proteins. Recently, another research group discovered the first purely truncating mutation
within the same limited region of PRESENILIN1 in a human family and saw that it caused a skin condition but
not Alzheimer's disease. Together with our data this surprisingly suggests that PRESENILIN1 activities
independent of gamma-secretase may play a major role in Alzheimer's disease pathology, such as another
recently discovered function of PRESENILIN1 - in "autophagy" which is a pathway that recycles large
aggregates and structures in cells. Our research also uncovered PRESENILIN protein truncations that can boost
gamma-secretase activity and identified the zebrafish equivalents of the Tau protein that is thought to be
important for development of Alzheimer's disease. Our research results have greatly enhanced the utility of
zebrafish in studies of Alzheimer's disease and this, together with our insights into gamma-secretase activity, is
bringing us closer to the understanding of the mysterious molecular mechanism(s) underlying this disease that
will be necessary to prevent and, maybe, even treat it effectively.
Expected future outcomes:
Our research results should lead to an increased focus on understanding the autophagy function of
PRESENILIN1 and also on the naturally occurring "PS2V" truncation of the PRESENILIN2 protein that we
NHMRC Research Achievements - SUMMARY
have now shown is conserved in most mammals and that greatly boosts gamma-secretase activity by an
unknown mechanism.
Name of contact:
Michael Lardelli
Email/Phone no. of contact:
michael.lardelli@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003788
CIA Name: Prof Bernhard Baune
Admin Inst: University of Adelaide
Main RFCD: Central Nervous System
Total funding: $444,461
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
REVERSIBLE AND IRREVERSIBLE TNF-MEDIATED COGNITIVE DECLINEREVERSIBLE AND
IRREVERSIBLE TNF-MEDIATED COGNITIVE DECLINE
Lay Description (from application):
This proposal seeks to clarify the neuronal mechanisms underlying the inflammatory processing leading to
cognitive decline. Furthermore, the research project identifies anti-inflammatory treatment options aiming at
improved cognitive performance in people at risk for or suffering from cognitive impairment of
neuropsychiatric disorders such as dementia and depression.
Research achievements (from final report):
This study substantially unraveled the mechanisms underlying neurodegenerative and neuroprotective effects
of TNF on cognitive function in a mouse model. Equally important, this study clarified and found for the first
time in the literature that the treatment effects of anti-TNF interventions not necessarily restrict to cognitive
dysfunction or depression as previously believed, but also to anxiety-like behaviours in mice. Our research
identified TNF receptor specific pathway effects on behaviour and neurotrophins in the hippocampus and the
prefrontal cortex. This basic research has implications for further research in animals and humans by
stimulating 1) the initiation of similar receptor and pathway specific research involving other pro-inflammatory
cytokines, such as IL-1 and IL-6 in animals and 2) the development of anti-TNF / TNF modifying treatment
options to improve cognitive dysfunction and emotiona regulation in various human disorders (i.e. depression,
dementia, anxiety). Our research stimulates the development of receptor specific TNF-targeting treatment
options aimed to improve cognitive dysfunction, depression and anxiety-like behaviours. In translational
research, various patient groups sharing the pathophysiology of systemic inflammation with raised TNF levels
(i.e. patients with vascular diseases, neurodegeneration such as dementia, major depression, and multiple
sclerosis) and exhibiting cognitive dysfunction might benefit from our findings of receptor specific anti-TNF
and TNF modifying drug interventions.
Expected future outcomes:
The grant has closed now and no further outcomes are expected form this grant. However, a future outcome in
translational research inspired by this grants outcomes is the exploration of anti-TNF on brain disorders in
humans.
Name of contact:
Bernhard Baune
Email/Phone no. of contact:
bernhard.baune@adelaide.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145655
CIA Name: Prof Ashley Bush
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $461,443
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
NOVEL THERAPIES FOR ALZHEIMER'S DISEASE BASED ON A-BETA - METAL
INTERACTIONSNOVEL THERAPIES FOR ALZHEIMER'S DISEASE BASED ON A-BETA - METAL
INTERACTIONS
Lay Description (from application):
The genetic data clearly show that the amyloid protein (A-beta) is central to the brain damage which occurs in
Alzheimer's disease (AD). However exogenous or environmental factors involved in regulating its toxic actions
are not understood. We have shown that the metals zinc and copper have dramatic effects on the properties of
A-beta and that chemicals which alter the amounts of these metals in the brain may be useful in treating the
disease. In this project we are investigating the ability of one such compound to affect the metabolism of Abeta in a mouse model of AD.
Research achievements (from final report):
One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (A-beta) protein in the
brain. These protein deposits are termed 'amyloid plaques'. Our research has been pivotal in ascertaining that
particular metals (i.e., copper and zinc) are involved in the architecture or assembly of these plaques. We have
demonstrated that A-beta reacts with excess metals (i.e., copper and iron) to produce abnormal amounts of
toxic chemicals (e.g., hydrogen peroxide). In addition, in the presence of copper, A-beta participates in a
reaction with cholesterol to generate elevated levels of another toxin called cholestenone. The brain is
particularly vulnerable to these toxic products, which can damage surrounding nerve cells leading to the typical
symptoms of AD such as memory loss., Arising from these research discoveries, we proposed an innovative
and promising therapeutic strategy for the treatment of AD, i.e., to use compounds that target the abnormal
interaction between A-beta and copper/zinc. In the process of interacting with specific amyloid plaque metals,
these compounds were effective in disassembling brain plaques and reducing the production of associated
deleterious chemicals (as was demonstrated in our studies with animal models of AD). In addition, this novel
mechanistic approach, using the retired antibiotic, clioquinol, has shown promising results in a small human
clinical trial (e.g., reduced mental decline in severely affected AD patients). On the basis of these trials, we
have designed other compounds with similar structure and mechanism which are currently being tested for
improved efficacy in subsequent clinical trials.
Expected future outcomes:
Future outcomes include a treatment for the cause of AD. Based on our theory that metals partake in the
degeneration of nerve cells, we anticipate the exciting prospect that our therapeutic strategy may be applied in
the treatment of other age-related diseases (e.g., Parkinson's).
Name of contact:
Ashley Bush
Email/Phone no. of contact:
abush@mhri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 145761
CIA Name: A/Pr Roberto Cappai
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $160,475
Start Year: 2001
End Year: 2001
Grant Type: NHMRC Project Grants
Title of research award:
Functional studies on a neuroprotective activity of the amyloid precursor protein of Alzheimer s
disease.Functional studies on a neuroprotective activity of the amyloid precursor protein of Alzheimer s
disease.
Lay Description (from application):
Alzheimer's disease is a major health problem of the elderly. With our aging population living longer, this
presents enormous economic and social pressures. Research into the mechanism of Alzheimer's disease is
therefore of immediate importance. In this study we are trying to determine the relationship between proteins
involved in the disease process. In particular we are studying the amyloid precursor protein (APP). APP has
both therapeutic as well as disease causing actions. It gives rise to the toxic amyloid peptide Abeta which is
responsible for disease. However APP can also inhibit Abeta toxicity thus controlling cell death. We are
studying how APP is able to modulate the neurotoxic activity of Abeta. These studies will identify key aspects
of the disease pathway and hopefully lead to treatment strategies.
Research achievements (from final report):
We have better defined the physiological function of the amyloid precursor protein of Alzheimer's disease. We
investigated its role in the vivo survival of mice and showed it regulates glucose metabolism, which has
implications for the disease causing pathway in Alzheimer's disease.
Expected future outcomes:
This grant was rolled into an NHMRC Program grant in 2002.
Name of contact:
Roberto Cappai
Email/Phone no. of contact:
r.cappai@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 157610
CIA Name: A/Pr Zeinab Khalil
Admin Inst: University of Melbourne
Main RFCD: Geriatrics and Gerontology
Total funding: $285,000
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Developing a skin test for early diagnosis of Alzheimer's disease and for monitoring effectiveness of
treatmentDeveloping a skin test for early diagnosis of Alzheimer's disease and for monitoring effectiveness of
treatment
Lay Description (from application):
Approximately 140,000 Australians suffer from Alzheimer's disease (AD). As the ageing population continues
to grow, this number will double by the middle of the next century unless a cure or prevention is found.
Scientists are continuously seeking new, more effective diagnostic tests in an effort to make it easier to
diagnose AD in its early stages. Being able to recognize symptoms early and obtain an accurate diagnosis
would give affected individuals a greater chance of benefiting from putative treatments. However, there is no
single, comprehensive diagnostic test for AD. Diagnostic tests (including peripheral markers) that can help to
reliably diagnose AD at an early stage are needed as are tests that can help in monitoring the progression of
AD, including response to therapy. The accuracy and clinical utility of previously proposed peripheral markers
(platelets and pupil dilation test) is questionable. The only way to confirm a diagnosis of AD is through
autopsy. We have obtained a provisional patent application for the use of a skin test for early diagnosis of AD
(Patent No: PQ2881/99). This test is based on our extensive research over the past decade to understand the
biochemical mechanisms underlying the txic vascular actions of beta amyloid protein. This protein has been
implicated in the pathology of AD and it accumulates in the brain, peripheral tissues and is present in
circulating blood of AD patients. The test is based on our discovery that vascular effects of Ab could be
detected in the peripheral microcirculation .We now wish to further examine the utility of this novel skin test. If
the test is sensitive, it could be used for screening; if it is specific it would be useful for confirmation of
suspected AD. If the test is sensitive to change in clinical status it would help select treatments that might cure
or improve the symptoms of AD.
Research achievements (from final report):
We investigated the utility of a simple non-invasive skin test for early diagnosis of Alzheimer's disease (AD).
To validate the test, we examined the ratio of the skin microvascular response to an endothelial provocative
agent compared to saline (ratio E/S) in patients with clinically confirmed AD and in patients with cognitive
impairment due to other dementia (a sample of 169 patients). This data was compared to that of 168
cognitively intact healthy volunteers. In addition, we studied a small sample of normal elderly people at risk of
developing AD, to establish the predictive value of the test. Mean + SEM of ratios E/S were 8.8+0.9 for
controls (n=168), 1.4+0.1 for AD patients (n=76) and 2.9+0.5 for other dementia (n=94). The other dementia
group was then classified according to clinical diagnosis. This yielded 6 subjects identified to have pure
vascular dementia (E/S ratio of 2.4+0.8), 9 subjects identified to have both vascular and AD dementia (E/S
ratio of 1.7+0.4), 7 subjects identified to have FTD (E/S ratio of 2.1+1.2), and 6 subjects identified to have
DLBD (E/S ratio of 1.3+0.3).Using the optimal cut-off point of E/S ratio of 1.9 determined by Receiver
Operating Characteristic Curves, an 80% diagnostic sensitivity and specificity for AD have been observed. The
interrater and retest reliability was 0.89. Furthermore, 15 subjects were randomly drawn from a longitudinal
healthy ageing study initially recruited in 1996. Five of those subjects met the criteria for MCI after eight years
of follow up using a battery of cognitive tests. When tested for their E/S ratio in a blind fashion, the skin test
successfully identified those subjects. We suggest that this simple skin test could potentially be applied as
diagnostic adjunct in-patients with mild cognitive symptoms or those with clinical evidence of AD.
Expected future outcomes:
The E/S ratio was abnormal in individuals even with very mild MCI (identified from a subtle decline memory
function over the eight years prior to assessment). This suggests that the test is also sensitive to differentiating
NHMRC Research Achievements - SUMMARY
normal from abnormal ageing. With further refinement the E/S ratio may also be useful as a preclinical
biomarker of AD and for monitoring the effectiveness of treatment.
Name of contact:
Zinab Khalil
Email/Phone no. of contact:
z.khalil@nari.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208913
Start Year: 2002
CIA Name: A/Pr Geoffrey Howlett
End Year: 2004
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $210,990
Title of research award:
The structural basis for amyloid formation by human apolipoproteinsThe structural basis for amyloid formation
by human apolipoproteins
Lay Description (from application):
Amyloid formation is considered an abnormal state of protein aggregation that accompanies numerous medical
conditions, notably Alzheimer disease, Parkinson's disease, the transmissible spongiform encephalopathies
(e.g. scrapie, Creutzfeldt-Jakob disease) and metabolic diseases such as diabetes. These diseases involve a
variety of normally non-fibrillar proteins with at least 20 human proteins identified as components of different
types of amyloid. The current wide publicity given to bovine spongiform encephalopathy (BSE) disease and
the potential impact on human health highlights the importance of developing strategies for treating these
conditions. The prevalence of apolipoproteins in atherosclerotic amyloid deposits and senile plaques suggests
a general propensity for human apolipoproteins to form pathogenic amyloid fibrils. Our recent observations
that lipid-free human apolipoprotein C-II (apoC-II) forms ribbon-like fibrils in vitro provides an experimental
system to explore this phenomenon. We propose to determine the structural requirements for the formation of
amyloid fibrils human apoC-II and whether lipid-free human apolipoproteins form mixed-amyloid fibrils.
Future strategies for treatment require better information on amyloid structure, the potential for mixed amyloid
formation and the role of in vivo factors such as lipids and macromolecular crowding in regulating amyloid
growth.
Research achievements (from final report):
Protein aggregation and amyloid formation accompanies numerous medical conditions, notably Alzheimer's
disease and Parkinson's disease. These diseases involve a variety of normally non-fibrillar proteins with at least
20 human proteins identified as components of different types of amyloid. The prevalence of apolipoproteins in
atherosclerotic plaques suggests a general propensity for human apolipoproteins to form pathogenic amyloid
fibrils. We set out to explore the factors that affect amyloid fibril formation by lipid-free human apolipoprotein
C-II (apoC-II). We identified several conditions likely to affect the in vivo rate of amyloid fibril formation. We
showed that apoC-II amyloid fibrils activate the scavenger receptor of macrophages, an early event in the
development of atherosclerosis and heart disease. Our studies provide new insight into the structure and
mechanism of formation of amyloid fibrils and the role of in vivo factors such as lipids and macromolecular
crowding in regulating amyloid growth. These observations will form the basis for new strategies for the
treatment of amyloid related diseases.
Expected future outcomes:
Our work has established the importance of non-fibrillar components, such as lipids and fibril-binding proteins,
in amyloid deposition within the body. Our finding that amyloid fibrils activate macrophages is highly
significant since this process is an acknowledged early event in the development of heart disease.
Name of contact:
Geoffrey Howlett
Email/Phone no. of contact:
ghowlett@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 208978
CIA Name: Prof Colin Masters
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $5,248,710
Start Year: 2002
End Year: 2005
Grant Type: Programs
Title of research award:
Neurodegenerative diseases of the ageing brain: diagnosis & therapy based on the study of aggregated protein
depositionNeurodegenerative diseases of the ageing brain: diagnosis & therapy based on the study of
aggregated protein deposition
Lay Description (from application):
Not Available
Research achievements (from final report):
The major achievements of this program was that we made significant progress in (a) understanding the how
the key proteins involved in Alzheimer's disease, Parkinson's disease, Prion diseases and poly-glutamine
expansion diseases are metabolised by the brain; (b) the factors that control the neurotoxic activity of these
proteins; (c) understanding the structure of these proteins. These discoveries have placed us in a strong position
to develop agents and assays for the treatment and diagnosis of these major age-related disorders.
Expected future outcomes:
It is expected that our future work will involve the development of in vitro and cell based and animal based
models to study these diseases. Moreover, the will be significant progress made in isolating and characterizing
the toxic species.
Name of contact:
Prof Colin L Masters
Email/Phone no. of contact:
c.masters@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219291
CIA Name: Prof Stephen Gibson
Admin Inst: University of Melbourne
Main RFCD: Geriatrics and Gerontology
Total funding: $120,000
Start Year: 2003
End Year: 2005
Grant Type: SRDC - Research
Title of research award:
Pain sensitivity and fMRI Pain-related cortical activity in persons with Alzheimer's diseasePain sensitivity and
fMRI Pain-related cortical activity in persons with Alzheimer's disease
Lay Description (from application):
Not Available
Research achievements (from final report):
People with Alzheimer's disease (AD) report less pain and receive fewer analgesics than cognitively intact
peers with similar painful disorders. It has been unclear whether these differences result from inadequate
clinical diagnosis of pain or from neuropathological deficits in central nervous system (CNS) pain transmission
pathways. This study used psychophysical methods to determine whether pain sensitivity and unpleasantness
were compromised in AD. Thresholds for just noticeable pain, weak pain and moderate pain were established
in response to noxious electrical and pressure stimuli using a random staircase design. In a subsequent session
these individually determined threshold levels were applied to participants in a random series of pressure
stimuli (innocuous pressure, weak pain, moderate pain) while magnetic resonance images of the CNS were
collected. Analysis of these images was undertaken to identify regions of the CNS where significant increases
in blood-oxygenation-level-dependent signals occurred during painful stimulation compared to innocuous
stimulation. Results showed a significant difference in pain threshold and unpleasantness of AD patients when
compared to controls, suggesting that pain sensitivity is somewhat decreased at threshold in AD. However,
pain ratings at more clinically relevant levels (mild-moderate) were simlar in both groups. Further, AD patients
responded to painful stimuli with significant activation in medial and lateral pain pathways including the
primary and secondary somatosensory cortices, medial and lateral thalamus, posterior cingulate, insula and
superior frontal gyrus. Given that AD patients showed apparently intact patterns of pain-related brain
activation, the use of lower levels of analgesics for the treatment of painful conditions in this group would
seem inappropriate. These results have serious implications for clinical practice and support the view that pain
in this group is currently being undertreated.
Expected future outcomes:
The routine prescription of fewer analgesics to treat pain in AD patients compared to cognitively intact peers
can no longer be attributed to the idea that AD patients are less sensitive to pain or that they suffer less.
Consequently, management of pain in AD patients must be supported by the development of reliable and
validated new pain assessment methods for use with this population.
Name of contact:
Associate Professor Stephen Gibson
Email/Phone no. of contact:
s.gibson@nari.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219294
CIA Name: Dr Dina Logiudice
Admin Inst: University of Melbourne
Main RFCD: Geriatrics and Gerontology
Total funding: $200,000
Start Year: 2003
End Year: 2005
Grant Type: SRDC - Research
Title of research award:
The Assessment & pervalence of dementia in Aboriginal & Torres Strait Islander people in the Kimberley
RegionThe Assessment & pervalence of dementia in Aboriginal & Torres Strait Islander people in the
Kimberley Region
Lay Description (from application):
Not Available
Research achievements (from final report):
Dementia is a significant issue for older people, yet little research has been performed on the impact of
dementia in older Indigenous people especially from rural and remote areas. To address this issue, a culturally
appropriate cognitive assessment tool was developed called the Kimberley Indigenous Cognitive Assessment
Tool (KICA). This tool was tested and validated on a group of 70 older Indigenous people living in different
rural and remote areas of the Kimberley. The KICA was found to be acceptable by the communities and
accurate is assessing cognitive function for this group. A study of the magnitude or prevalence of dementia and
cognitive impairment is currently being undertaken in the Kimberley, where the KICA is utilised to assess a
representative sample of the Indigenous population over the age of 50 years. Other issues such as general
health status (e.g. falls, incontinence) and depression are also assessed. This study will improve knowledge on
health care needs of older Indigenous people and assist with planning of adequate and appropriate health care
and accommodation. The study has assisted in raising awareness of aged care issues in the region.
Expected future outcomes:
The magnitude of health care needs of older Indigenous people in the Kimberley will provide information
required for future policy and planning needs for this group of people.The KICA tool will be tested in Northern
Territory to determine its suitability in this region of Australia.An abridged version will be developed for use
by GPs and health workers in the area.
Name of contact:
Dina Logiudice
Email/Phone no. of contact:
dina.logiudice@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 236801
CIA Name: Dr Christopher Reid
Admin Inst: University of Melbourne
Main RFCD: Cellular Nervous System
Total funding: $272,750
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Mechanisms underlying short- and long-term plasticity at the mossy fibre -> CA3 synapse in the
hippocampusMechanisms underlying short- and long-term plasticity at the mossy fibre -> CA3 synapse in the
hippocampus
Lay Description (from application):
Synapses, the contacts between brain cells, are extremely plastic. They can become stronger and weaker
depending on the activity they experience. The hippocampus, a structure in the brain, is known to be critical to
the formation of conscious memories. The plastic nature of the synapse in this structure is thought to underlie
learning and memory. Understanding the mechanisms that are responsible for the changes in synaptic strength
in the hippocampus are therefore important to our understanding of learning and memory. This proposal
describes a series of experiments that are designed to determine the mechanisms of plastic changes . We hope,
that by understanding these mechanisms, we can start to understand how we learn and remember.
Research achievements (from final report):
This grant proposal set out to determine the role of a receptor (the kainate receptor) at a particular synapse in
the brain (the mossy fibre->CA3 synapse). This synapse has been implicated in processes of learning and
memory (the teacher synapse) and in pathogenic states such as epilepsy. The experimental work completed as
part of this project discovered a novel interaction between kainate receptors and another channel, the voltage
gated calcium channel. This interaction alters excitability of nerve cells and may provide a novel biological
target for drugs designed to reduce nerve cell excitability. Beyond the scope of the original plan this project
grant also supported projects looking at other ion channels and their relationship to brain excitability in
epilepsy.
Expected future outcomes:
Based on results from this study we have completed experiments that investigate brain excitability in an animal
model of epilepsy. Preliminary results suggetst that we can use this interaction to reduce brain excitability.
Name of contact:
Christopher Reid
Email/Phone no. of contact:
careid@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251538
CIA Name: Prof Arthur Christopoulos
Admin Inst: University of Melbourne
Main RFCD: Basic Pharmacology
Total funding: $363,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Allosteric Modulation of G Protein-Coupled ReceptorsAllosteric Modulation of G Protein-Coupled Receptors
Lay Description (from application):
The normal function of all living cells depends on how they respond to the multitude of physical and chemical
stimuli to which they are constantly exposed. The majority of chemical stimuli acting on cells do so not by
directly entering the cell, but rather by acting on specific types of "receiver" proteins on the cell's surface called
"receptors". One important family of receptors transmit their message to the inside of the cell by coupling to
yet another type of protein known as the "G protein". Aberrations in the normal function of these "G proteincoupled receptors" have been implicated in a wide variety of disorders, including neuropsychiatric conditions,
endocrine disorders, cardiovascular disease and many cancers. To date, the majority of drugs acting at G
protein-coupled receptors do so by binding to specific regions on these receptors. Although many
breakthroughs in disease treatment have been achieved using this approach, there remain a number of
acknowledged limitations, including lack of drug selectivity, toxicity and reduced responsiveness with
prolonged therapy. Our current proposal focuses on targeting drugs to alternative regions of G protein-coupled
receptors that may overcome many of the limitations associated with current drug therapies. An understanding
of the properties of these alternative drug binding sites, which will be investigated in our current grant, can lead
to more effective treatments for a variety of diseases.
Research achievements (from final report):
This project identified a number of novel modes for regulating one of the most important families of signaling
proteins in the human genome, the "G protein coupled receptors" (GPCRs). These modes involved the binding
of drugs and other test molecules to special sites on the GPCRs that are not normally utilized by the body's own
chemicals. Depending on the type of protein and the type of molecule tested, binding to these novel sites was
found to lead to more selective modulation of the activity of the protein relative to traditional drugs currently
on the market that act at GPCRs, thus opening the possibility of designing more selective drugs for the
treatment of disorders mediated by GPCRs.
Expected future outcomes:
The results of this study are expected to lead to the design of more selective and effective medicines to target
one of the most therapeutically relevant protein families in the human genome.
Name of contact:
Prof. Arthur Christopoulos
Email/Phone no. of contact:
arthur.christopoulos@med.monash.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 251685
CIA Name: A/Pr Graham Barrett
Admin Inst: University of Melbourne
Main RFCD: Cellular Nervous System
Total funding: $265,500
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
How does the p75 neurotrophin receptor transmit both pro-survival and pro-apoptotic signals in neurons?How
does the p75 neurotrophin receptor transmit both pro-survival and pro-apoptotic signals in neurons?
Lay Description (from application):
Signaling by the two NGF receptors, TrkA and p75, determines the survival or death of sensory neurons and of
certain brain neurons involved in memory and learning. The most baffling aspect of these receptors is that in
most circumstances they cooperate with each other to maximise the survival of neurons when NGF is present,
but in some situations they are opposed to each other. In the latter case, NGF treatment can lead to death, rather
than rescue, of neurons. In the last three years we have developed novel antisense oligonucleotides which can
be used to switch off each receptor separately. These have been, and will continue to be, particularly valuable
tools for our research. We have also uncovered a novel way in which the two receptors interact (via a signal
transduction molecule known as SHC), which provides us with a competitive edge in this area. We have the
expertise and equipment to identify and clone the missing factors that account for the paradoxical interactions
between p75 and TrkA. A successful outcome from this project will have important benefits by improving our
understanding of the factors controlling neuronal fate, and will help to develop treatments for
neurodegenerative diseases.
Research achievements (from final report):
We investigated and solved a riddle surrounding the p75 nerve growth factor receptor - how it promotes nerve
cell survival in some contexts, and nerve cell death in others. It does so by selectively combining with key
intracellular proteins.
Expected future outcomes:
More targetted research into treatments for neurodegenerative disorders
Name of contact:
Graham Barrett
Email/Phone no. of contact:
grahamlb@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 285103
CIA Name: Prof Stephen Gibson
Admin Inst: University of Melbourne
Main RFCD: Residential Client Care
Total funding: $306,000
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
New methods of pain assessment in demented older personsNew methods of pain assessment in demented
older persons
Lay Description (from application):
There are substantial risks of inadequate pain assessment and management in persons with cognitive
impairment and particularly in those with communication problems. Undetected or under-treated pain can have
serious adverse effects on frail older adults including poorer cognitive performance, increased levels of
depression, anxiety and disruptive behaviours, a reduced quality of life and higher levels of functional
disability. These adverse effects contribute to greater demands for daily nursing care and a corresponding
increase in health care costs. The present proposal aims to develop more sensitive, reliable and valid
questionnaire and non-verbal measures of pain in older adults with cognitive impairment and particularly in
those with verbal communication problems. By completion, the present studies should provide much needed
information on the reliability and validity of several different types of verbal and non-verbal indicators of
possible pain. This research should lead to improved pain assessment and management for the growing
segment of the population who suffer from pain and impaired cognitive function.
Research achievements (from final report):
There is growing international concern over the apparent inadequacy of current pain assessment methods for
persons with dementia and particularly in those who have lost verbal communication skills. Undetected or
untreated pain can have serious adverse effects on frail older persons and contribute to greater demands for
daily nursing care with a corresponding increase in health care costs. While self-report has become the de facto
gold standard for pain assessment, other non-verbal methods (ie. behavioural measures, observational tools)
also provide important and clinically relevant information, and may be the preferred assessment choice in cases
of moderate-severe dementia. The present studies examined the comparative reliability and validity of several
new behavioural pain assessment tools and facial expressions of pain in non-verbal, demented older adults.
Most of the selected scales measure combinations of behaviours such as, facial grimace or wince, negative
vocalisation, changes in body language (rubbing, guarding, restlessness etc), altered breathing or physiologic
signs (heart rate, blood pressure etc) in order to provide an index of likely pain intensity. Staff rated measures
that quantify facial expressions, behavioural actions (ie. rubbing the affected part), physical changes (ie.
bruises, arthritis), vocalisation (ie. moaning) and ability to console the person, were shown to be the best
indicators of likely bothersome pain. The best set of individual items indicative of a high likelihood of pain
were tested on a new sample of persons in residential aged care facilities and shown to have an 84% correct
classification of demented older persons with pain. This research is expected to lead to much improved pain
assessment methods for this highly vulnerable and dependent group.
Expected future outcomes:
The identification of valid and reliable behavioural markers of pain and pain-related facial expressions in nonverbal demented older persons has immediate application for future clinical trials (ie. analgesic trials in
demented persons with pain) and more simple, user friendly, pain assessment tools are expected to follow.
Name of contact:
A/Prof Stephen Gibson
Email/Phone no. of contact:
s.gibson@nari.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299891
CIA Name: A/Pr Anthony Hannan
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $249,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Gene-environment interactions and experience-dependent plasticity in the healthy and diseased cerebral
cortexGene-environment interactions and experience-dependent plasticity in the healthy and diseased cerebral
cortex
Lay Description (from application):
Huntington's disease (HD) is a devastating illness in which movement disorders (including chorea) and mental
problems progress for 10-20 years after onset, and inevitably lead to death. HD is caused by an expansion in a
repeating segment of DNA in a single gene and is inherited by 50% of the offspring of sufferers. Despite this
strong genetic factor, we have recent evidence from a mouse model, in which the human HD gene mutation has
been inserted into the mouse genome, supporting a role for environmental factors in disease onset and
progression. Following on from our work showing that environmental enrichment delays disease and
progression in this mouse model of HD, we are using experimental manipulations of the environment to
examine effects on brain degeneration and behaviour. This project aims to investigate gene-environment
interactions in HD, focusing on dysfunction of neurons in the cerebral cortex. The combination of behavioural,
physiological, anatomical and molecular analysis of HD mice will bring us closer to a comprehensive
understanding of HD. This will have implications for the development of new therapies for HD. Our
environmental enrichment paradigm may also lead to development of occupational therapy strategies for HD
and other neurological disorders. There are at least ten other fatal brain disorders which are caused by the same
DNA repeat expansion in other genes. New insights into HD will therefore have implications for the
understanding and development of therapeutics for these other DNA repeat expansion brain diseases.
Furthermore, another devastating brain disorder which, like HD, involves abnormal protein interactions and
dysfunction of the cortex, is Alzheimer's disease. Understanding HD may therefore also have implications for
our understanding of Alzheimer's disease. Additionally, analysing control mice in this project will provide new
information on mechanisms of plasticity in the normal cortex, which may underlie learning and memory.
Research achievements (from final report):
Huntington's disease (HD) is an inherited brain disorder that involves progressive problems with movement
(e.g. chorea), cognition (dementia) and also psychiatric symptoms (e.g. depression). While disease onset is
usually in midlife (30's or 40's) it can occur as a juvenile-onset form in approximately 5% of cases, and
progresses relentelessly before killing HD sufferers. We have previously established that in mice, the disease's
onset and progression can be delayed with enhanced mental and physical exercise - putting running wheels in
their cages, plus interesting items to smell, see and touch. The findings have been recently supported by clinical
evidence in humans, and now open up exciting opportunities to establish whether other illnesses, such as
depression and Alzheimer's disease, can be delayed with mental and physical stimulation - and if so, exactly
how this works. Over the past few years, with NHMRC funding, we have been able to show that environmental
enrichment, enhancing mental and physical activity, delays onset of cognitive deficits (dementia) in the HD
mice. We have also identified changes at the level of synapses (connections between neurons) that are altered
by HD and environmental stimulation. We have also discovered specific molecules in the brains of the HD
mice that are severely affected by the disease, but rescued by environmental stimulation. This will have
implications not only for HD, but for other brain disorders such as dementia and depression which are also
associated with this disease.
Expected future outcomes:
Our aim is to ultimately use these molecules to facilitate development of a new class of therapeutic drugs
(taken in combination with exercise and mental stimulation that enhance a person's ability to stave off a brain
disease.
NHMRC Research Achievements - SUMMARY
Name of contact:
Dr Anthony Hannan
Email/Phone no. of contact:
ajh@hfi.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 299980
CIA Name: A/Pr Roberto Cappai
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $637,000
Start Year: 2004
End Year: 2008
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I have been successful in studying the cellular processes and the biophysical and structural properties of
proteins and peptides involved in the neurological disorders of Alzheimer's disease, Parkinson's disease and
Prion disease. I have published over 44 publications specific to this area during my fellowship term. These
studies have been published in top tier biochemical journals PNAS, J Neuroscience, FASEB J, J Mol Biol and J
Biol Chemistry. These studies have provided key insights into the factors that modulate the neurotoxic activity
of the Abeta peptide that is centrally involved in Alzheimer's disease. I have identified key aspects of the
structure and function of the Alzheimer's disease Amyloid Precursor Protein (APP) and how its activity and
metabolism is modulated by APP binding proteins. In relation to Parkinson's disease I have studied how the
aggregation of the alpha-synuclein protein is affected by the chaperone αB-crystallin and the major
neurotransmitter dopamine. The interaction between dopamine and alpha-synuclein is particularly relevant to
Parkinson's disease since it is the dopamine containing neurons that are affected in Parkinson's diseases. My
studies have led to the identification of novel pathways and molecular targets upon which to base therapeutic
and diagnostic strategies for these diseases. Significant progress in these areas have been achieved during my
fellowship.
Expected future outcomes:
It is expected that the work will continue by providing a more detailed understanding of the molecular and
structural hallamarks of neurotoxicity in Alzheimer's and Parkinson's disease. It will also pursue developing
therapeutic and diagnostic agents for the treatment and diagnosis of these disorders.
Name of contact:
Kevin Barnham
Email/Phone no. of contact:
kbarnham@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400073
Start Year: 2006
CIA Name: Dr Genevieve Evin
End Year: 2008
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $526,518
Title of research award:
Gamma-secretase complex: molecular characterization, and moduation of enzymatic activityGamma-secretase
complex: molecular characterization, and moduation of enzymatic activity
Lay Description (from application):
A small protein fragment terned A-beta accumulates as amyloid plaques in the brain of patients with
Alzheimer's disease. A-beta is toxic, it causes degeneration of brain cells, and it is believed to be the primary
cause of Alzheimer's disease. Therefore, developing strategies to reduce the amounts of A-beta in the brain
constitutes a rational therapeutic approach. A-beta is produced from a precursor protein by two cleaving
enzymes that operate in a sequential order: these are termed beta and gamma-secretases. Gamma-secretase
carries out the second and final step in the release of A-beta peptide, and it is a determining factor since it can
create A-beta fragments of different lengths and with different toxic properties. Our group studies the
biochemical characteristics of gamma-secretase, and the factors that regulate its activity to uncover novel
therapeutic leads. In this project we will 1) investigate the molecular composition of gamma-secretase using
biochemical methods 2) study the importance of the two components of gamma-secretase, termed APH-1 and
nicastrin, for the enzymatic activity 3) analyse the mechanism of mutations in the A-beta precursor protein
that occur at or near the gamma-secretase site of cleavage and cause familial Alzheimer's disease 4) search
for factors that regulate gamma-secretase activity using a genetic screen approach. The results of the proposed
experiments will provide information to help design new therapeutic strategies for Alzheimer's disease, an
illness that afflicts a large proportion of the ageing population and places a major socio-economic burden upon
our society.
Research achievements (from final report):
Gamma-secretase is an important enzyme involved in the production of Abeta amyloid peptides. The
accumulation of Abeta in the brain causes the death of neurons and is believed to be the initial event that
triggers a cascade leading to Alzheimer's disease. Therefore inhibiting gamma-secretase represents a rational
therapeutic approach to treat Alzheimer's disease. Gamma-secretase is also implicated in normal physiological
functions, therefore it is important to understand its mechanism and properties to develop specific drugs with
little side-effects. The major achievement of this project was the finding that there exists different forms of
gamma-secretase that respond to alternative drugs. Futher research is needed to fully chracterize these enzymes
and pinpoint their differences at the molecular level. This may lead to developing gamma-secretase inhibitors
with greater selectivity.
Another achievement was the discovery of new inhibitors of BACE, the other enzyme involved in Abeta
production. In collaboration with our colleagues at WEHI we have identified four new compounds that can
inhibit BACE in vitro and that will constitute leads for drug development. This finding is still very preliminary
but is encouraging because these compounds are small molecules with drug properties.
Expected future outcomes:
The immediate outcome of this award is the exploitation of the results we obtained in our current and future
research. Further expected outcomes are the potential development of new treatments for Alzheimer's disease.
Name of contact:
Dr Genevieve Evin
Email/Phone no. of contact:
gmevin@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400191
CIA Name: A/Pr Kevin Barnham
Admin Inst: University of Melbourne
Main RFCD: Cell Neurochemistry
Total funding: $548,878
Start Year: 2006
End Year: 2010
Grant Type: Established Career Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
New therapeutic and strategies for the neurodegenerative diseases such Alzheimer's and Parkinson's disease
have been developed
Expected future outcomes:
The further development of therapeutic and diagnostic strategies for the neurodegenerative diseases.
Name of contact:
Kevin Barnham
Email/Phone no. of contact:
kbarnham@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400202
Start Year: 2006
CIA Name: Prof Colin Masters
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: Programs
Main RFCD: Medical and Health Sciences not elsewhere classified
Total funding: $12,322,838
Title of research award:
Neurodegeneration in the ageing brain: how the pathways leading to aggregated protein cause
diseaseNeurodegeneration in the ageing brain: how the pathways leading to aggregated protein cause disease
Lay Description (from application):
The team consists of eight highly experienced research scientists who are dedicated to solving the question of
how the brain degenerates in the elderly when associated with the
accumulation of certain proteins: e.g. Aß amyloid (Alzheimer’s disease) and PrP (Creutzfeldt-Jakob disease).
Understanding the molecular pathways leading to the degeneration (loss of neuronal synapses) will permit the
development of rational diagnostic and therapeutic interventions. Over the past five years the program has
identified several diagnostic and therapeutic avenues which are now being developed by the Pharmaceutical
and Biotechnology industries. Much more research is still required for maximizing the chances of success
using these approaches.
Research achievements (from final report):
During the funding period 2006-2010, major advances were made in understanding the basic mechanisms of
neurodegeneration in the ageing brain. These have been detailed in the regular annual reports. The Alzheimer's
Disease Program has successfully taken fundamental research on the structure of the Abeta protein into clinical
application for diagnosis and therapeutic interventions. The Creutzfeldt-Jakob Disease Program has begun the
process of separating infectivity from the toxic degeneration. And the Parkinson's Disease Program has
successfully developed animal models which are now being used for drug discovery.
Expected future outcomes:
The continued advancement of clinical applications arising from our basic research.
Name of contact:
Colin Masters
Email/Phone no. of contact:
c.masters@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400401
CIA Name: Dr Paul Adlard
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $173,750
Start Year: 2006
End Year: 2007
Grant Type: Early Career Fellowships (Australia)
Title of research award:
Effect of dietary copper on evolution of Alzheimer's disease (AD)-like neuropathological & neurochemical
alterations...Effect of dietary copper on evolution of Alzheimer's disease (AD)-like neuropathological &
neurochemical alterations...
Lay Description (from application):
Not Available
Research achievements (from final report):
We have continued to define the role of metals in the progression of both the pathological and the symptomatic
features of Alzheimer's disease (AD). We have developed a greater understanding of the many different aspects
of the AD brain that are affected by altered metal levels and have also advanced our understanding of how the
modulation of these metal species is sufficient to alter the course of the disease. These advances will enhance
our ability to develop novel drug targets that are truly disease modifying and will also provide insight into the
pathogenesis of AD.
Expected future outcomes:
As these studies continue we will further define the effect of dietary metals in the evolution and progression of
Alzheimer's disease and associated memory deficits. We will also further define the normal role of metals in
learning and memory functions.
Name of contact:
Paul Adlard
Email/Phone no. of contact:
padlard@mhri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 400437
Start Year: 2006
CIA Name: Dr Vi Pham
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Neurosciences not elsewhere classified
Total funding: $308,769
Title of research award:
Investigating the role of apolipoprotein E, low-density lipoprotein receptor, and amyloid- in Alzheimer
diseaseInvestigating the role of apolipoprotein E, low-density lipoprotein receptor, and amyloid- in Alzheimer
disease
Lay Description (from application):
Not Available
Research achievements (from final report):
The past four years awarded as an NHMRC Postdoctoral Fellowship to train with Prof David Holtzman at
Washington University School of Medicine in St Louis (in 2006) and Dr Siew Yeen Chai at Howard Florey
Institute (2007-2010) have been a rewarding and productive period as I was given the opportunity to participate
in a number of exciting projects. , The first achievement was to generate a construct using the mouse prion
promoter vector and create several transgenic mice that overexpress LDLR (low density lipoprotein receptor)
in the brain. This led to the important finding that increasing the LDLR levels have beneficial effects on
pathogenic amyloid aggregation and neuroinflammatory responses. , The second achievement was to
demonstrate that deletion of the IRAP (insulin-regulated aminopeptidase) gene protects the brain from
ischemic damage in the mouse model of stroke. Moreover the early exciting data have also shown that the
newly developed small molecule IRAP inhibitor significantly reduced size of cerebral infarct, providing an
avenue to explore a novel use for the drug in the treatment of stroke.
Expected future outcomes:
LDLR and IRAP may be a potential therapeutic target for Alzheimer's disease and ischemic stroke,
respectively.
Name of contact:
Siew Yeen Chai
Email/Phone no. of contact:
siew.chai@monash.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 454386
Start Year: 2007
CIA Name: Prof James Camakaris
End Year: 2009
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $454,692
Title of research award:
Functional copper deficiency models of Alzheimer's diseaseFunctional copper deficiency models of
Alzheimer's disease
Lay Description (from application):
Alzheimer's disease is a serious neurodegenerative disease which increases in incidence with age. It affects the
quality of life and care required for approximately 160,000 Australians and costs the national economy 6.6
billion dollars per annum. Current therapy is of limited efficacy. Our studies are directed towards testing the
hypothesis that a functional deficiency of the essential trace element, copper, occurs in the brain with ageing,
and this leads to oxidative stress and death of neurons associated with Alzheimer's disease. We will use animal
and cell culture models to test this hypothesis which is based on promising preliminary data from such models.
We believe that beta amyloid, which accumulates in Alzheimer's brains and is believed to be a major part of the
pathological mechanism, has a normal role in maintaining copper balance and that this balance is disturbed by
ageing or particular mutations. This research should lead to better treatments using drugs which mobilise
copper entry into cells.
Research achievements (from final report):
Alzheimer's disease (AD) is the most common form of dementia and is characterised by the accumulation of
toxic amyloid beta peptide (Abeta) and neurofibrillary tangles in certain regions of the brain. Moreover, the
trace metals copper, iron and zinc are enriched in amyloid plaques and have been reported to contribute to the
pathogenesis of AD. Therapeutics which restore copper balance in the brain have been tested both in animal
and human trials with promising results. The general aim of this project was to further characterize the
relationship between brain copper levels, amyloid burden and functional copper deficiency in a various AD
transgenic mouse models. In addition, we have investigated the role copper plays in the regulation of the
Amyloid Precursor Protein (APP; from which Abeta is derived) and how APP impacts copper homeostasis
using cultured cell models. We have found that at 12 months of age, there is a functional copper deficiency in
female transgenic mice in two animal models analysed, as shown by the decrease in enzymatic activity of the
cuproenzyme cytochrome C-oxidase. At the cellular level, we have made the exciting discovery that copper
can promote a change in the cellular localization of APP, which is a novel mechanism by which copper
regulates the function of APP. These findings have provided important insight into the relationship between
copper, APP and amyloidogenesis, which is relevant to the development of therapeutics that aim to restore the
balance in copper levels in the brain.
Expected future outcomes:
Our research has generated exciting data on the role of copper in the normal and Alzheimer's disease brain. The
outcomes will be explored in further research that will inform on the use of copper-complexing agents as
therapeutics in Alzheimer's disease.
Name of contact:
Prof. James Camakaris
Email/Phone no. of contact:
j.camakaris@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 454714
Start Year: 2007
CIA Name: Dr Siew Yeen Chai
End Year: 2007
Admin Inst: University of Melbourne
Grant Type: NHMRC Development Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $195,450
Title of research award:
Development of small molecule inhibitors of IRAP - potential use for the treatment of memory
disordersDevelopment of small molecule inhibitors of IRAP - potential use for the treatment of memory
disorders
Lay Description (from application):
This research project provides proof of concept that IRAP is a suitable target for use in the development of a
new class of clinically valuable cognitive-enhancing agents. We have recently identified a family of small
molecule compounds that inhibited the catalytic activity of the enzyme using a molecule model of IRAP to
screen virtual libraries. This research proposal aims to validate that this family of compounds have memoryenhancing properties by acting specifically on IRAP. At the conclusion of this project, we will have elucidated
important information on the specificity of the memory effects and the structure activity relationship of this
family of compounds. We will have identified and characterised a lead compound for development into a new
class of cognitive enhancers.
Research achievements (from final report):
A family of new drug-like compounds suitable for development into drugs for treating memory loss has been
developed based on their ability to bind to and inhibit a protein in the brain known as insulin-regulated
aminopeptidase (IRAP). A computer model of IRAP was used to screen 1.5 million compounds on different
chemical databases for their ability to fit into the active site of IRAP. These compounds were then tested in the
laboratory for their ability bind to and alter the activity of IRAP. Then their chemical structures were then
modified to improve their 'drug-like' properties and the most effective compound was found to improve
performance in normal rats in two different memory tasks. Therefore a family of drug-like compounds that
specifically target IRAP (named HFI 142 analogues) that have memory-enhancing properties have been
identified at the conclusion of the project. We propose that these analogues will serve as potential lead
compounds that can be developed into therapeutically effective agents that will be used to treat the cognitive
decline in Alzheimer's disease.
Expected future outcomes:
The expected future outcome would be the identification of families of IRAP inhibitors with memoryenhancing properties that will form the "lead series" for a drug development program for a new class of
cognitive-enhancing agents.
Name of contact:
Siew Yeen Chai
Email/Phone no. of contact:
sychai@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 508974
Start Year: 2008
CIA Name: Prof Colin Masters
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $604,734
Title of research award:
Novel therpeutic approaches for Alzheimers diseaseNovel therpeutic approaches for Alzheimers disease
Lay Description (from application):
There are currently no effective treatments for Alzheimer's disease. In this application we will develop a novel
class of compound to assess their potential as AD therapeutics. These compounds will be tested in vitro and in
vivo models of Alzheimer's disease. The successful conclusion of the work described here would provide new
leads suitable for further development as therapeutics for Alzheimer's disease.
Research achievements (from final report):
Alzheimer's disease (AD is the most common cause of progressive dementia in the elderly population.
Currently there are ~20 million AD patients worldwide, and it is predicted that this figure will reach 70 million
by 2050 unless a treatment to delay onset the disease becomes available soon. The effects of AD are
devastating on both economic and social perspectives due to the ageing of the population world wide., AD is a
neurodegenrative disorder characterised by deposition of extracellular amyloid plaques, the major constituent
being the amyloid-beta peptide (Aβ). Hence, the Ab is the primary target for a large percentage of current
therapeutic developments in AD. The inhibition of its aggregation to a toxic spieces (plaques) was considered
as a valuble potential therapeutic approach (anti-amyloid appraoch)., During 2008-2010, we have undertaken
the following research activities under this grant., Synthesize a diverse array of novel organic ligands. ,
Synthesize their Platinum (II) species for in vitro studies. , Preparation of their Platinum (IV) counter species
for in vivo studies (to improve bioavailability). , Screen compounds through a series of in vitro assays
including Aβ affinity studies (NMR). Inhibition of Aβ aggregation (amyloid formation). Inhibition of
neurotoxicity caused by Aβ. Inhibition of Aβ toxicity (Long Term Potentiation studies) . , Cell permeability
and bioavailability., Screen lead chemical entities in a transgenic mouse model., Results: A lead compound,
VK-12 was identified as a lead compound form in vitro experiments and it was further modified to improve its
bioavailabilty and blood brain barrier permeability (BBB) for in vivo studies. Currently testing of these
compounds are under way to test the proof of concept.
Expected future outcomes:
These compounds are expected to decrease the number of amyloid plaques and the size of plaques in mice and
ultimately improve the coginition in mice. This experiment should prove not only the involvement of amyloid
plaques in pathogenises of AD but also open a platform for therapeutic drug discover for AD
Name of contact:
Colin Masters
Email/Phone no. of contact:
c.masters@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509031
CIA Name: A/Pr Anthony Hannan
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $550,387
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Molecular mechanisms mediating experience-dependent cellular plasticity and cognitive deficits in
Huntingtons diseaseMolecular mechanisms mediating experience-dependent cellular plasticity and cognitive
deficits in Huntingtons disease
Lay Description (from application):
We will use a genetic mouse model of Huntington's disease (HD), to understand how cognitive disorders
(dementia) are caused, focusing on cells and molecules within the brain. We will investigate how the HD gene
mutation disrupts communication between brain cells (neurons), as well as disrupting production of new cells
(via adult neural stem cells). The results of this project will not only have implications for treating HD but also
for other diseases involving dementia, such as Alzheimer's.
Research achievements (from final report):
Huntington's disease (HD) is a fatal brain disorder that strikes in early to mid life, leading to psychiatric,
cognitive and motor symptoms. We have been using a mouse model of HD to understand disease mechanisms
and pave the way for development of a treatment for this currently incurable disease. We have discovered
specific changes to molecules and cells in the brains of HD mice that may explain the early onset of cognitive
and affective abnormalities. We have also followed up our previous discovery, that envrionmental enrichment
delays disease onset in these HD mice, to further understand how increased cognitive stimualtion and physical
activity can act at the level of molecules and cells.
Expected future outcomes:
Some of the specific molecules we have identified have the potential to be used as targets for new drug
development. We hope that these findings in this model of HD can be translated into clinical trials, via our
interactions with clinician scientists within Australia and internationally.
Name of contact:
A/Prof. Anthony Hannan
Email/Phone no. of contact:
anthony.hannan@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509040
Start Year: 2008
CIA Name: Prof Roberto Cappai
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $749,022
Title of research award:
Delineating the interaction between the Amyloid Precursor Protein family and sorLA-LR11Delineating the
interaction between the Amyloid Precursor Protein family and sorLA-LR11
Lay Description (from application):
The Alzheimer's disease Amyloid Precursor Protein (APP) is central to the cause of Alzheimer's disease (AD).
It's metabolised into the neurotoxic amyloid beta (Abeta) peptide that is deposited in AD brains. The sorLA
protein is a neuronal protein that interacts with APP and alters its metabolism into Abeta. This grant will study
the interaction between APP and sorLA and define the APP binding site for sorLA which represents a potential
drug target.
Research achievements (from final report):
The interaction between the Amyloid Precursor Protein (APP) and the sorLA proteins are important in
Alzheimer's disease. In order to delineate how these molecules interact we generated a large number of
mutations in APP based on the proposed sorLA binding site in APP, D6a. We used Surface Plasmon
Resonance (SPR) technique to measure the binding of the D6a mutant proteins to sorLA CR protein on an SPR
chip. Three different residues have been identified that affected binding. The hydrophobic residue V364A and
the two heparin binding/charged residues of R424A and K428A affected binding. The 424,428 double mutant
shows significantly less heparin binding and this correlated with reduced sorLA CR binding. These binding
mutants have been incorporated into mammalian expression vectors pCEP4-APP695 and expressed in
mammalian cells to determine their effect on APP processing/metabolism and transport. These findings have
identified a novel site that modulates APP metabolism into Abeta. Since Abeta is a key toxic agent responsible
for Alzheimer's disease then these findings provide a therapeutic target upon which t devise drugs that can
stablise the APP;sorLA interaction in order to reduce Abeta levels.
Expected future outcomes:
It is expected that these studies will form the basis for a crystal structure based drug design project. The aim
will be to solve the structure of the APP:sorLA binding site and use that to develop compounds that can bind to
this site and alter APP processsing into Abeta.
Name of contact:
Robeto Cappai
Email/Phone no. of contact:
r.cappai@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509166
Start Year: 2008
CIA Name: A/Pr Victor Villemagne
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $1,084,267
Title of research award:
Abeta amyloid imaging in neurodegenerative disorders with a novel 18F radiotracerAbeta amyloid imaging in
neurodegenerative disorders with a novel 18F radiotracer
Lay Description (from application):
Alzheimer's disease is the most common age-related neurodegenerative disease, and the most common cause of
dementia. It is estimated that 212,000 Australians suffer from dementia and this will rise to approximately
730,000 by 2050. Currently there are no definitive diagnostic methods for AD. The research proposed in this
application describes the evaluation of a new imaging radiotracer that would be suitable for widespread noninvasive diagnosis of AD.
Research achievements (from final report):
β-amyloid (Aβ) imaging with positron emission tomography (PET) permits in-vivo assessment of Aβ
deposition in the brain, providing an important new tool for the evaluation of the causes, diagnosis and future
treatment of dementias, where Aβ may play a role. Aβ imaging is allowing earlier diagnosis of Alzheimer's
disease (AD) pathology and accurate differential diagnosis of the dementias. As the criteria for the diagnosis of
AD evolve, Aβ imaging is likely to have an increasingly important role in clinical practice provided it is
accessible and affordable. Unfortunately, the 20-minute radioactive decay half-life of carbon-11 (11C) limits
the use of 11C-PiB to centers with an on-site cyclotron and 11C radiochemistry expertise. Consequently,
access to 11C-PiB PET is restricted and the high cost of studies is prohibitive for routine clinical use. To
overcome these limitations, several tracers labeled with fluorine-18 (18F; half-life of 110 minutes) that permits
centralized production and regional distribution were synthesized and tested. We compared cortical amyloid
deposition using 18F-Florbetaben and PET in healthy control (HC) and subjects with mild cognitive
impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular
dementia (VaD), Parkinson's disease (PD) and AD. 18F-Florbetaben had high sensitivity for AD, clearly
distinguished subjects with FTLD from AD, and provided results comparable to those reported with 11C-PiB
in a variety of neurodegenerative diseases.
Expected future outcomes:
Our results demonstrate that 18F-Florbetaben can reliably detect Aβ deposition in the brain and is thereby
useful in the early and differential diagnosis of AD from other dementing or non-dementing neurodegenerative
conditions. 18F-Florbetaben provides images similar to 11C-PiB without the limitation of the short decay halflife that precludes its application in clinical practice.
Name of contact:
Victor L Villemagne
Email/Phone no. of contact:
villemagne@petnm.unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509246
CIA Name: A/Pr Andrew Gundlach
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $537,579
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Relaxin-3 systems in brain: validation of neural targets and functional rolesRelaxin-3 systems in brain:
validation of neural targets and functional roles
Lay Description (from application):
Our laboratory recently discovered the brain 'transmitter' called 'relaxin-3', and are researching how it affects
brain activity and animal physiology and behaviour. Findings suggest that relaxin-3 can modulate memory,
responses to stress and other complex behaviours. Identifying the various actions of relaxin-3 in the brain
could provide potential new treatments for conditions such as anxiety/depression, cognitive deficits (dementia)
and schizophrenia.
Research achievements (from final report):
Our research has begun to establish the physiological importance of a recently identified, highly-conserved
neurotransmission system in brain that comprises a neuropeptide 'ligand' or messenger known as 'relaxin-3' and
its specific neural membrane receptor, 'RXFP3', which translates the relaxin-3 'message' to its target nerve
cells. The distribution of this system within a number of neural networks in mammalian brain and our 'proofof-principle' studies, strongly implicate it in control of basic functions including behavioural arousal and levels
of sleep and wakefulness, and related complex behaviours. This in turn suggests a modulatory influence of this
brain signalling system on mental health and a possible efficacy in treating symptoms of stress-associated
psychiatric illnesses., Specifically, our research has established a role for relaxin-3/RXFP3 signalling in a
prominent nerve pathway from a small nucleus (cell group) in the brainstem to forebrain areas important in
controlling the rhythmic, synchronised activity of the brain during behaviour. This activity in areas such as
'septum' and 'hippocampus' is critical for optimal spatial, working memory in animals (and humans); and we
have demonstrated that reducing RXFP3 signalling in the septum of rats reduces their spatial 'working'
memory. We have also identified the types of neurons affected by relaxin-3/RXFP3 signalling in the septum
and this suggests that stimulation of RXFP3 might improve cognitive performance associated with dementia.
Furthermore, the circadian 'hypoactivity' and increased sleep identified in mice that lack relaxin-3 in brain is
consistent with an important biological role in control of arousal, with implications for understanding and
treating clinical depression.
Expected future outcomes:
In the future, the extension of these ground-breaking studies on the brain relaxin-3/RXFP3 system could lead to
the development of novel treatments for a range of psychiatric illnesses, including affective disorders (anxiety
disorders, depression, addiction), complex neurodevelopmental conditions (autism spectrum disorders and
schizophrenia) and associated cognitive deficits.
Name of contact:
Andrew L. Gundlach
Email/Phone no. of contact:
andrewlg@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509276
CIA Name: A/Pr Paul Adlard
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $333,314
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
The effect of metals on neurofibrillary tangle formationThe effect of metals on neurofibrillary tangle formation
Lay Description (from application):
The majority of studies into Alzheimer's disease (AD) have focussed on two brain lesions- the "plaque" and
"neurofibrillary tangle" (NFT), which are believed to have a causative role in AD. Our lab has made several
seminal discoveries about the role that metals play in the development of "plaques". We are now extending this
work to evaluate the role of metals in NFT formation. These studies will provide insight into the formation and
possible treatments for this primary brain lesion in AD.
Research achievements (from final report):
This project has generated experimental evidence for the effectiveness of a novel treatment for common brain
disorders, including Alzheimer's disease and fronto-temporal dementia. The concepts developed in this grant
may lead to a new direction in the search for therapies for neurodegenerative diseases and indeed, may lead to
human clinical trials that ultimately improve patient outcome.
Expected future outcomes:
In addition to further publications and a new focus for our laboratory, this work may result in a new direction
in the treatment of neurodegenerative disorders.
Name of contact:
Paul Adlard
Email/Phone no. of contact:
p.adlard@mhri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 509400
Start Year: 2008
CIA Name: Prof Andrew Hill
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: Career Development Fellowships
Main RFCD: Medical Infection Agents (incl. Prions)
Total funding: $312,730
Title of research award:
Cellular pathogenesis of key proteins involved in neurodegenerative disordersCellular pathogenesis of key
proteins involved in neurodegenerative disorders
Lay Description (from application):
Prion proteins are involved in neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and Bovine
Spongiform Encephalopathy (BSE). The aim of this research proposal is to investigate factors which can
change the prion protein from a normal, benign, form into an abnormal shape which can cause disease. The
outcomes of this work will provide further insight into the role of prion proteins in these diseases and also for
other neurodegenerative disorders such as Alzheimer's disease.
Research achievements (from final report):
I developed an active research program studying the cellular and molecular biology of Neurodegenerative
Diseases. This includes the development of novel systems for investigating the processing of infectious prions
within and between cells, the amyloid-beta peptide involved in Alzheimer's disease and collaborator work on
Parkinson's disease. I completed 4 PhD supervisions as primary supervisor and 2 as secondary, gained
international recognition for my research work through invitations to meetings, was awarded several young
investigator awards and the 2010 Merck Medal for Research Excellence from the ASBMB.
Expected future outcomes:
My research into the role of exosomes in neurodegenerative diseases is now moving into using these as targets
for biomarker discovery for these hard to diagnose disorders as well as increasing our understanding of the
pathogenesis of neurodegeneration.
Name of contact:
Andrew Hill
Email/Phone no. of contact:
a.hill@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 520345
Start Year: 2008
CIA Name: Dr Michael Cater
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Biochemistry and Cell Biology not elsewhere classified
Total funding: $287,321
Title of research award:
Neuronal copper homeostasis and the role of the Alzheimer Amyloid-Beta Precursor Protein (APP)Neuronal
copper homeostasis and the role of the Alzheimer Amyloid-Beta Precursor Protein (APP)
Lay Description (from application):
Alzheimer’s disease (AD) is creating a growing burden upon Australian medical resources. Copper plays an
important role in the development of AD and drugs designed to adjust brain copper levels are being tested for
AD treatment and show therapeutic benefits. This project will determine how copper is involved in AD so that
more effective drugs can be developed. Focus will primarily be on copper-binding proteins central to AD and
establishing their role in AD development and progression.
Research achievements (from final report):
My fellowship focus on 'metallomics' expanded into the fields of neuroscience and cancer research. The
decision to research metals in Alzheimer's disease (AD) at the Mental Health Research Institute (MHRI)
proved productive, with numerous publications resulting, including a landmark Cell paper that described the βamyloid precursor protein (APP) as an iron-export ferroxidase (Duce et al Cell 2010). I further identified that
the state of neuronal copper-deficiency, as found in neurons of AD brains, increases the production of βamyloid, the peptide found in senile plaques (Cater et al 2008, Biochem J). The worked described in these
publications formed the basis of ongoing research into therapeutic intervention of AD, through correction of
metals imbalance in the brain. Working in at MHRI (Professor Ashley Bush's group) further gave invaluable
exposure to pharmacological studies testing copper-ionophores as an intervention for AD. I switched research
focus to the cancer field and relocated to the Peter MacCallum Cancer Centre at the beginning of 2010. This
followed the realization that copper-ionophores have enormous potential for cancer therapy. While working at
MHRI I gained invaluable experience with pharmacological studies, testing copper-ionophores as intervention
for AD (mouse models). I quickly made the transition to cancer research as evidenced by my recent
publications in Biochemical Journal (2011) and PNAS (2012) and podium presentation at the international
Metallomics conference (June 2011). Another first-author paper is in preparation and will be submitted by
October 2012 to the Journal of Clinical investigation. During the period of 2008 to 2012, I published a total of
eight articles on metallomics related research undertaken during my fellowship.
Expected future outcomes:
My goal is to provide an effective pharmaceutical-based therapy for prostate cancer as an alternative to radical
prostatectomy. I was recently awarded funding (NHMRC project) to investigate the role of metals in cancer
development and to furhter investigate targeting metals as a therapy for cancer (to 2015).
Name of contact:
Michael Cater
Email/Phone no. of contact:
michael.cater@petermac.org
NHMRC Research Achievements - SUMMARY
Grant ID: 520695
Start Year: 2008
CIA Name: Dr Siew Yeen Chai
End Year: 2010
Admin Inst: University of Melbourne
Grant Type: NHMRC Development Grants
Main RFCD: Clinical Pharmacology and Therapeutics
Total funding: $369,899
Title of research award:
Development of small molecule IRAP inhibitors for treating memory deficitsDevelopment of small molecule
IRAP inhibitors for treating memory deficits
Lay Description (from application):
We have identified a series of small molecule compounds based on their ability to inhibit the catalytic activity
of a protein, IRAP using a computer model of IRAP to screen chemical libraries. This research proposal aims
to investigate the properties of these compounds and their ability to treat Alzheimer's dementia. At the
conclusion of this project, we will have 2 families of "lead" compounds suitable for development into a new
class of therapeutic agents for treating Alzheimer's disease.
Research achievements (from final report):
IRAP inhibitors were initially developed for the symptomatic treatment of Alzheimer's disease (AD) based on
earlier reports that peptides that inhibit IRAP activity significantly facilitate memory in rat deficit models.
However, we have recent exciting data that chronic delivery of HFI419 markedly decreased amyloid plaque
accumulation, a pathological hallmark of AD, in a mouse model of the disease. This early data is consistent
with a role for IRAP inhibitors in AD modification, alleviating and/or preventing disease progression as well as
treating the cognitive symptoms. We are currently investigating the disease-modifying effects of HFI419 in
two mouse models (familial and late onset) of the disease.
Expected future outcomes:
We hope to obtain important proof-of-concept that IRAP inhibitors are strong candidates to be developed into a
clinically effective treatment for AD based on their effects in treating the memory symptoms as well as
arresting the progression of the disease.
Name of contact:
Siew Yeen Chai
Email/Phone no. of contact:
sychai@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566520
CIA Name: Dr Genevieve Evin
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $641,541
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The influence of gamma-secretase complex subunits on the production of Alzheimer amyloid peptidesThe
influence of gamma-secretase complex subunits on the production of Alzheimer amyloid peptides
Lay Description (from application):
Alzheimer's disease is a devastating illness of the aged population and represents a major socio-economic
problem in Australia. There is no cure or effective treatment for the illness. A toxic protein fragment known as
Abeta amyloid accumulates in the brain of the diseased patients. This is produced by an enzyme called gammasecretase. This project will investigate different forms of gamma-secretase to gain information useful for
developing Alzheimer-specific drugs with little side-effects.
Research achievements (from final report):
The aim of this project was to investigate the properties and expression of an enzyme that plays an important
role in the pathology of Alzheimer's disease. Gamma-secretase is responsible for the production of Aβ protein
fragments that accumulate in the brain of patients with Alzheimer's disease to form toxic aggregates
responsible for neuronal cell death. Gamma-secretase is also involved in many cellular signalling functions and
is implicated in some forms of cancer. Our work demonstrates that gamma-secretase expressed in the brain and
peripheral tissues, such as lung and liver respond differently to inhibitory drugs, suggesting it may be possible
to design tissue-targeted therapies. In particular, we found that the brain and peripheral tissues express different
forms of the gamma-secretase subunit critical for substrate recognition and placement for cleavage. Study of
temporal expression showed that the Aph1a subunit is elevated at 24 month. This may have implications for the
regulation of the gamma-secretase complex and may increase the cellular life of a toxic fragment precursor to
Aβ. We also showed that gamma-secretase and BACE1 (beta-secretase) are elevated in the brain at the postnatal age compared to the adult age. This stresses the importance of these enzymes during brain development.
Because both enzymes are also implicated in the processing neuregulin 1, a protein important for brain
development and a major susceptibility gene for schizophrenia, we began investigating the expression of the
secretases and the cleavage of neuregulin 1 in relation to this psychiatric illness. We found a decrease in a
cleavage product of neuregulin and increased expression of alternative variants of BACE1 in association with
schizophrenia. These studies are being pursued.
Expected future outcomes:
Taken together, our data provide novel information that may help design drugs that target specifically brain
gamma-secretase. They also help understand the biology of gamma-secretase and its complex role in the brain.
Furthermore, they open new leads to investigate the molecular mechanism of schizophrenia, a psychiatric
disorder that remains poorly understood.
Name of contact:
Dr Genevieve Evin
Email/Phone no. of contact:
gmevin@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566614
CIA Name: A/Pr Kevin Barnham
Admin Inst: University of Melbourne
Main RFCD: Analytical Biochemistry
Total funding: $607,489
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Identification of Biomarkers for Alzheimers diseaseIdentification of Biomarkers for Alzheimers disease
Lay Description (from application):
Alzheimer's disease is the most common age-related neurodegenerative disease, and the most common cause of
dementia. It is estimated that 212,000 Australians suffer from dementia and this will rise to approximately
730,000 by 2050. Currently there are no definitive diagnostic methods for AD. The research described in this
application seeks to identify and validate a range of biomarkers identified in the blood of patients that would be
suitable to use for diagnostic purposes.
Research achievements (from final report):
We identified new new peptides and proteins in the blood that have the potential to be developed as biomarkers
to aid in the diagnosis of Alzheimer's disease. New protocols for blood collection and processing were devised.
Expected future outcomes:
The continued development of methods to detect Alzheimer's disease associated biomarkers in blood
Name of contact:
Kevin Barnham
Email/Phone no. of contact:
kbarnham@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566618
CIA Name: A/Pr Anthony Hannan
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $384,200
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Experience-dependent maturation and plasticity of the cerebral cortex mediating schizophrenia-like
endophenotypesExperience-dependent maturation and plasticity of the cerebral cortex mediating
schizophrenia-like endophenotypes
Lay Description (from application):
We will use genetic mouse models of schizophrenia to understand how specific abnormal behaviours are
caused, focusing on cells and molecules within the brain. We will investigate how the gene mutations disrupts
communication between, and production of, brain cells (neurons), and the role of mental and physical activity.
The results of this project will not only have implications for understanding schizophrenia, but also for other
brain disorders involving cognitive problems, such as dementia.
Research achievements (from final report):
Schizophrenia is a devastating brain disorder, caused by an unknown combination of genetic and
environmental factors, that affects at least 1% of Australians. Our group, funded by a previous NHMRC grant,
was able to demonstrate that environmental enrichment (enhanced mental and physical activity) has significant
beneficial effects in a mouse model of schizophrenia, a major brain disorder affecting cognition, emotions and
behaviour. In our new work funded by this latest NHMRC grant, we have discovered changes that occur in the
brains of these mice, at the level of molecules and cells, which may contribute to the development of
schizophrenia like cognitive deficits and behavioural abnormalities.
Expected future outcomes:
This research, providing mechanistic insights into the cause of these abnormalities of brain development and
function, can be used to inform the future development of new treatments for schizophrenia, which will benefit
not only those suffering from this major mental illness, but also their families.
Name of contact:
A/Prof. Anthony Hannan
Email/Phone no. of contact:
anthony.hannan@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566743
CIA Name: Dr Janetta Culvenor
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $699,456
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation and substrate identification of Parkinsons disease causative Leucine-rich Repeat Kinase 2
(LRRK2)Regulation and substrate identification of Parkinsons disease causative Leucine-rich Repeat Kinase 2
(LRRK2)
Lay Description (from application):
Parkinson's disease afflicts 100,000 Australians. Mutations in the recently identified enzyme Leucine-rich
Repeat Kinase-2 are a common cause of Parkinson's disease. This project will use biochemical methods to
understand how this brain enzyme causes disease by investigating its enzymology, modes of regulation, and
target substrates that it modifies by addition of phosphate groups. Characterization of this enzyme will facilitate
design of inhibitors to slow the course of Parkinson's disease.
Research achievements (from final report):
We have investigated structural and regulatory aspects of the Leucine-rich repeat kinase 2 which is a key
enzyme important in the development of Parkinson's disease. To assist in identifying the major
autophosphorylation sites we generated and tested rabbit antibodies to predicted phosphorylation sites in the
major kinase activation loop of the protein. We have also undertaken significant production and purification of
truncated over-expressed LRRK2 from bacteria and insect cell culture systems. This has enabled analysis of
potential substrates using radioactive kinase assays. Some of the predicted substrates were investigated for
potential interaction with LRRK2 isolated from mouse brain membrane extracts. In addition we have
investigated the GTPase activity of LRRK2 using purified protein generated from GTPase LRRK2 constructs
after production in insect cells. Metal binding analysis and nucleotide binding studies assisted in the
biochemical characterization of the GTPase activity. Extensive bioinformatic analysis of LRRK2 amino acid
sequence has revealed details of predicted secondary structure for LRRK2 protein domains, prediction of
critical interaction surfaces, and information on the likely effects of particular Parkinson's associated mutations.
Expected future outcomes:
We have generated unique research reagents for further study of this key protein kinase. These products will be
further utilized in ongoing studies by research colleagues. Two major publications of these findings are close to
completion. Our basic biochemical investigations have contributed to understanding the action of this large and
complex protein kinase.
Name of contact:
Dr Janetta Culvenor
Email/Phone no. of contact:
j.culvenor@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566764
Start Year: 2009
CIA Name: A/Pr Anthony White
End Year: 2012
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Therapies and Therapeutic Technology
Total funding: $653,113
Title of research award:
Modulation of neurotherapeutic cell signalling pathways by metallo-complexes as a treatment for Alzheimers
disease.Modulation of neurotherapeutic cell signalling pathways by metallo-complexes as a treatment for
Alzheimers disease.
Lay Description (from application):
Alzheimer's disease (AD) is an enormous burden on the Australian health care system . We have begun to
investigate therapeutic treatments based on triggering protective cell signalling pathways with metal-based
compounds. These compounds trigger the activation of a signalling cascade resulting in inhibition of ADassociated symptoms. In this proposal we will further investigate how these compounds modulate specific
receptors and cellular kinase activity to protect neurons in the AD brain.
Research achievements (from final report):
This project involved the further development of small, lipid soluble metal complexes that are capable of
entering the brain and delivering limited levels of metals to neurons. This triggers activation of specific cell
signaling pathways that lead to neuroprotective outcomes in models of Alzheimer's disease. Our research in
this project further identified new compounds (bis(thiosemicarbazones) that have increased efficacy at metal
delivery and activation of key signaling pathways such as the glycogen synthase kinase (GSK3) pathway. We
also obtained a greater understanding of how neurons took up, trafficked and effluxed these compounds and
how this is related to modulation of specific neuroprotective outcomes. The significance of this work has been
the improved understanding of the pathways associated with action of our neuroprotective complexes. In
addition, our work has expanded quickly to successful development in models of several additional forms of
neurodegeneration. This has led to a strong potential for pre-clinical development of metal-complexes as
therapeutic treatments for neurodegeneration.
Expected future outcomes:
We are continuing to develop a greater understanding of how these complexes induce broad neuroprotective
action and working with the commercial development arm of University of Melbourne to obtain funding for
pre-clinical studies.
Name of contact:
Anthony Robert White
Email/Phone no. of contact:
arwhite@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566827
CIA Name: Prof Ashley Bush
Admin Inst: University of Melbourne
Main RFCD: Cellular Nervous System
Total funding: $949,667
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Amyloid precursor proteins novel role in Alzheimers disease through regulating neuronal iron
homeostasis.Amyloid precursor proteins novel role in Alzheimers disease through regulating neuronal iron
homeostasis.
Lay Description (from application):
Our group has discovered a novel role of amyloid precursor protein (APP) in cellular iron balance. The
smallest form of APP, prevalently found in the brain, is able to convert a damaging iron variety (Fe2+) into the
safer Fe3+. Alternative, larger, forms of APP are found to inhibit this effect. This project will establish how
APP controls iron homeostasis within brain neuronal cells and how this activity is impaired in disease, thus
development a mechanism for diagnostic tests and therapeutics.
Research achievements (from final report):
The aim of this project was to examine a novel role of APP in its ability to regulate iron homeostasis through
facilitating iron efflux from the cell and to determine if by altering its function, APP was responsible for the
iron accumulation known to be present in Alzheimer's disease (AD) and similar neurodegenerative disorders.
Our efforts have demonstrated that through a similar mechanism proposed for a previous protein called
ceruloplasmin, APP is able to facilitate the export of iron from neurons through its interaction with other
members of the iron export pathway. As neurons do not express ceruloplasmin, APP may be the predominant
way in which iron is released from neurons and therefore this work begins to explain why neurodegenerative
diseases in which APP expression is altered, such as in AD, have an increase in toxic iron within the cell that
raises the susceptibility of neuronal death caused by iron-associated oxidative stress. This work has also
demonstrated that zinc, another metal known to be altered in AD, may impair APP-associated iron efflux and
has highlighted the potential suitability of utilizing metal binding therapeutic compounds in the treatment of
AD and other neurological disorders such as Parkinson's disease in which neuron iron is also known to be
altered.
Expected future outcomes:
Data generated has added momentum into understanding the involvement of APP in iron dyshomeostasis
associated with AD. It also provided the foundation of future successful grants aimed at exploring the cellular
trafficking of APP to the cell surface, the location required for its ability to export iron, and to determine the
relationship of APP and iron in other neurodegenerative diseases.
Name of contact:
Ashley Bush
Email/Phone no. of contact:
ashleyib@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566851
CIA Name: A/Pr John Drago
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $385,007
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a practicing neurologist with a clinical interest in movement disorders and dementia with an international
reputation in neurosciences in the fields of neural stem cells, transgenic animal models of movement disorders
and epilepsy. In line with my cl
Research achievements (from final report):
Research has been undertaken in the field of movement disorders of which Huntington's disease and
Parkinson's disease are examples. Cures and novel treatments will only follow a detailed understanding of the
deranged brain circuitry involved in these conditions. The research undertaken during this fellowship has
shown definitively that one population of brain cells expressing a receptor called the D1 dopamine receptor are
absolutely pivotal in mediating important clinical deficits including problems with balance, speed of
movement, orofacial function and abnormal limb positioning referred to as limb dystonia. Involuntary shocklike body movements are also seen in animal models where these cells are destroyed in the deep structures of
the brain called the striatum. Impairments in socialization are seen when these cells are selectively destroyed in
the surface of the brain called the cortex of genetically engineered mice. The next step is to design
experimental stategies in which D1 dopamine receptor bearing cells are replaced in specific brain regions so as
to repair the pathological defect and thereby ameliorate the clinical deficit. In addition to this core research into
movement disorders I was also involved in exploring the effects of destroying or augmenting signalling
through the brain nicotine receptor system. This research clarified the role of this important receptor in
mediating facets of addiction.
Expected future outcomes:
There is now a rational basis for designing cell based therapies in which D1 dopamine receptor expressing cells
are specifically replaced in designated brain region depending on the clinical deficits displayed by the patient.
Nicotine receptor interacting drug design would be expanded for treating addiction.
Name of contact:
John Drago
Email/Phone no. of contact:
john.drago@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566853
Start Year: 2009
CIA Name: A/Pr Paul Adlard
End Year: 2011
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $436,238
Title of research award:
The modulation of metals to improve the cognitive and pathological features of Alzheimers diseaseThe
modulation of metals to improve the cognitive and pathological features of Alzheimers disease
Lay Description (from application):
This proposal will characterise the effects of a novel therapy for the treatment of Alzheimer's disease. Our
preliminary data show that this approach can affect both the onset and progression of the disease, as well as
the symptoms that characterise it. Thus, a thorough assessment of these effects and this drug target provides a
tangible movement towards a truly effective treatment for Alzheimer's disease.
Research achievements (from final report):
The aim of this project was the examine the effect of a novel class of compound in a mouse model of
Alzheimer's disease. Our efforts have demonstrated that this class of compound has significant positive benefits
in preventing the development of abnormal brain pathology in this mouse model, in addition to restoring the
function of a number of cellular pathways that are crucial to the maintenance of normal cognitive function.
This work has also demonstrated that one of the primary ways that the compounds achieve this biological
effect is by promoting the maintenance of normal metal (eg. zinc) levels within the brain. This work has
highlighted the potential utility of this class of compound in treating Alzheimer's disease, and has also opened
up the possibility that the compounds may be useful for the treatment of a diverse range of neurological
disorders that are characterised by metal-dependent cognitive deficits.
Expected future outcomes:
The data generated in this grant has added momentum to the transition of these compounds into human clinical
trial. It was also the foundation for future successful grant applications which aim to explore the more generic
effect of this class of compound on age-related cognitive decline.
Name of contact:
Paul Adlard
Email/Phone no. of contact:
padlard@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 566980
CIA Name: Dr Giuseppe Ciccotosto
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $553,236
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Characterization ol a novel covalently cross -linked Abeta peptide dimer and its role in Alzheimers
Disease.Characterization ol a novel covalently cross -linked Abeta peptide dimer and its role in Alzheimers
Disease.
Lay Description (from application):
Currently there are limited therapeutic treatments and no cure for Alzheimer's disease (AD). The key protein
causing AD is called Abeta. Abeta peptides form dityrosine cross-linked dimers (when 2 peptides join together)
and this is thought to be responsible for killing brain cells in AD. Therefore, this proposal will determine the
role of Abeta dimers in relation to killing brain cells and the progression of AD through analysis of their
biological and biochemical properties.
Research achievements (from final report):
We investigated a novel molecular form of the Abeta peptide which is responsible for neuronal cell death in the
brains of Alzhiemer Disease (AD) patients. We were able to determine the neurotoxic, biochemical,
biophysical and binding properties of the novel molecular form, the dityrosine crosslinked Abeta peptides,
compared to the monomeric equivalents. We were able to demonstrate that the dimer peptide required at least
40 amino acids to induce toxicity and that it was significantly more toxic than the monomeric equivalent.
Shorter peptides were examined including a 16 and 28 amino acid length variants but both peptides were not
toxic in our cell culture models. In addition, the dimer peptide bound to neuronal cells more strongly compared
to the monomeric version. The significance of these results imply that the dimer species rather than the
monomeric species of Abeta is a better model for investigating AD pathogenesis. We now believe we have a
better model to investigate the mechanisms of Abeta toxicity. Potentatial benefits of these results include
demonstrating that a specific molecular species of Abeta is most likely causing the neuronal cell death
associated with AD and we should begin designing therapeutic strategies to inhibit the binding of the dimer
peptide from neurons to prevent AD progression.
Expected future outcomes:
We will now use the dityrosine cross linked Abeta peptide to as a new tool to determine the key protein/lipid
target on neuronal membrane surfaces which is essential for mediating the neurotoxic properties of this peptide.
Name of contact:
Giuseppe Ciccotosto
Email/Phone no. of contact:
jcicco@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 567018
Start Year: 2009
CIA Name: Dr Noel Faux
End Year: 2012
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Medical Biochemistry: Proteins and Peptides
Total funding: $292,639
Title of research award:
Blood biomarker discovery for the diagnosis of Alzheimers DiseaseBlood biomarker discovery for the
diagnosis of Alzheimers Disease
Lay Description (from application):
Alzheimer's disease (AD) currently affects approximately 24 million people world wide, with >200,000 people
within Australia currently affected, by 2050 an estimated 730,000+ people will be affected. The discovery of
blood based biomarkers for AD will enable earlier diagnosis of AD, allowing early preventative treatments to
be given. Thus, reduce the rate of disease progression and the cost of care and, gain significant improvement in
the quality of life for the patients and their families.
Research achievements (from final report):
This project has identifed two blood signatures for the diagnosis and prognosis of Alzheimer's disease (AD).
The first blood signature comprises of 8 analytes, in conjunction with age and ApoE genotype, is able to
distinguish health congnativly normal subjects from those subjects with AD with high specificity and senitivity
(Doecke JD, Laws, SM, Faux NG, et al. Arch Neurol, 2012). The second blood signature comprises of 5
analytes, in conjunction with age and ApoE genotype, which is able to predict the amount of ?-amyloid in the
brain with high accuracy, as measured but a Pitsburge compound B Pisitron Emisson Tomography (PiB-PET)
scan (Burham SC, Faux NG, et al. Mol Mol Psychiatry 2013 doi: 10.1038/mp.2013.40.). This is a very
important finding, as a PET scan is expensive and the only other way to determine the amlyoid burden in the
brain is via a lumber puncture to measure two key proteins, amyloid ? and Tau, which is highly invasive. The
cost of a PET scan and the invasive nature of a lumber puncture, prohibit these techiques being used as front
line screening tools. The minimal invasive nature of a blood collection and the cheap cost of measuring these
analytes, allow it to be developed into a cheap population screening tool.
Expected future outcomes:
The development of a chaep assay to measure these blood analyes for its ustisation as a population screening
tool; to identify subjects with high brain amalyoid.
Name of contact:
Noel Faux
Email/Phone no. of contact:
nfaux@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 567046
Start Year: 2009
CIA Name: Dr Shayne Bellingham
End Year: 2013
Admin Inst: University of Melbourne
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Neurosciences not elsewhere classified
Total funding: $292,639
Title of research award:
Investigating the Role of Exosomal Shuttle RNA in Mediating Pathogenesis of Neurodegenerative
DisordersInvestigating the Role of Exosomal Shuttle RNA in Mediating Pathogenesis of Neurodegenerative
Disorders
Lay Description (from application):
The risk for dementia increases with age and is placing a growing burden upon Australian medical resources.
Novel genetic signals can be communicated between cells. This process may contribute to the development of
dementia related disorders, such as Alzheimer's and Prion diseases. We hope to identify the genetic signals
communicated between cells that may contribute to dementia. This will help us develop novel treatments that
delay the onset or ultimately prevent Alzheimer's and Prion disease.
Research achievements (from final report):
Novel genetic signals can be communicated between cells in small vesicular bubbles known as exosomes. We
discovered that exosomes contribute to the transmission of prion disease and contain unique small genes called
miRNA. This was the first study in the world to sequnce small genes in exosomes and identifed a genetic
signature that has potential benefits in th early diagnosis of Prion diseases. This study also has the potential to
screen blood donors who resided in the United Kingdom that are currently preveted from donating blood in
Australia.
Expected future outcomes:
The utility of small genes present in exosomes as a non-invasive marker of pre-clinical prion disease will be
tested to determine their clinical applications in early diagnosis, screeing of donated blood and has the potential
to reduce the public health burden associated with the risk of prion disease transmission through surgical
transmission.
Name of contact:
Prof Andrew Hill
Email/Phone no. of contact:
a.hill@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572563
CIA Name: Prof Nicola Lautenschlager
Admin Inst: University of Melbourne
Main RFCD: Geriatrics and Gerontology
Total funding: $773,753
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
A multicentre randomised clinical trial of physical activity for the treatment of patients with Alzheimers
DiseaseA multicentre randomised clinical trial of physical activity for the treatment of patients with
Alzheimers Disease
Lay Description (from application):
The number of older adults living with Alzheimer's disease (AD) will increase from 26.6 million to 106.2
million by 2050. In the absence of curative treatment options it is important to focus on non-pharmacological
interventions such as physical activity. We propose to investigate whether a home-based physical activity
program of 24 weeks for patients with AD can successfully decrease the rate of cognitive and functional
declince and improve quality of life and psychological well-being.
Research achievements (from final report):
The final number of participants enrolled in the FABS II is 132 (55 in Perth, 70 in Melbourne and 7 in
Brisbane). Follow-up visits were completed in June 2013. A total of 124 participants completed the trial (51 in
Perth, 66 in Melbourne and 7 in Brisbane). Only 8 participants withdrew after rendomisation. The overall
adherence was very good. So far FABS II was able to demonstrate that patients with mild to moderate
Alzheimer's Diseas (AD) can successfully participate in a home-besed physical activity (PA) program with the
support of their carers. 4 peer-reviewed publications have been published so far.
Expected future outcomes:
Analysis on the overall trial outcome has started and the aim is to submit the main trial outcome paper for
publication in 2014. It is planned that subsequent secondary analyses will lead to further publications. All these
results will then be dessiminated to the scientific community, clinicians, policy makers, consumer
organisations, participants and the public.
Name of contact:
Nicola Lautenschlager
Email/Phone no. of contact:
nicolatl@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628480
CIA Name: Prof Malcolm Horne
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $561,558
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Repair of the nigrostriatal pathway by phenotype shift of dopamine neuronesRepair of the nigrostriatal pathway
by phenotype shift of dopamine neurones
Lay Description (from application):
Repairing the injured brain will depend on developing new cells that can form the correct cell type, make the
right connections and be incorporated into normal brain circuitry. We have found that dopamine cells, which
are lost in Parkinson's Disease, are being renewed in the adult rodent brain. This study is directed at finding
factors that control this process and to exploit these factors therapeutically. We provide evidence that this can
be used to treat Parkinson's Disease.
Research achievements (from final report):
We showed that dopaminergic cells can be induced to change phenotype and that this is reversable. We showed
that it can be induced by changing the excitability of these neurones by directly infusing drugs into the brain to
either change their resting membrane potential or to activate the neurones synaptically. We showed that other
pathwasy could effect these dopamine cells and then went on to show that this can occur in ordinary behaviourin particaulr when the environment is enriched by novelty or during sexual activity. We also show that the most
important way that this occurs is by changing phenotype, although recruitment of newly born cells (ie
neurogenesis is also possible). It also appears that it is unleikely to be usefull in Parkinsons although findings
form this study may help in stem cell transplantation.
Expected future outcomes:
We are now wishing to show that these mechansims also occur in humans and to understand which behaviours
in humans are relavant. We also intend to better understand how phenotype change occurs so it can be used in
therpay.
Name of contact:
Malcolm Horne
Email/Phone no. of contact:
malcolm.horne@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628491
CIA Name: Dr Mark Murphy
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $542,890
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Amelioration of the cognitive deficits in a model of Alzheimers diseaseAmelioration of the cognitive deficits in
a model of Alzheimers disease
Lay Description (from application):
The project investigates a brain molecule called p75, and the part it plays inmemory impairment in Alzheimer's
Disease (AD). We predict that p75 is a vital link in the disease processes affecting memory.This research has
the potential to lead to an effective treatment for AD, by stimulating work on compounds with the ability to
blockthe damaging functions of p75.
Research achievements (from final report):
Alzheimer's disease (AD) is an extremely prevalent cause of dementia. It is characterized by progressive
memory loss, confusion and other behavioural and physiological problems. The Amyloid-? (A?) protein is
thought to be involved in the pathogenesis of AD and there is evidence that A? may act through the p75
neurotrophin receptor (p75) to mediate its pathogenic effects. This raises the possibility that reducing levels of
p75 could be a treatment for AD by preventing the effects of A?. In this study we have crossed the transgenic
AD model mice, Tg2576, with p75-/- mice to generate Tg2576/p75+/- mice with reduced levels of p75. These
mice are rescued from the deficits in learning and memory and hippocampal function which were found in the
Tg2576 mice. These findings suggest that reduction of p75 can ameliorate some of the primary symptoms of
AD.
Expected future outcomes:
We hope that our findings will lead to a potential new treatment for Alzheimer's disease. This would involve
finding methods to reduce the level or block the function of p75 in the brains of Alzheimer's patients.
Name of contact:
Mark Murphy
Email/Phone no. of contact:
m.murphy@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 628868
CIA Name: Dr Mark Ransome
Admin Inst: University of Melbourne
Main RFCD: Cellular Nervous System
Total funding: $297,808
Start Year: 2010
End Year: 2013
Grant Type: Early Career Fellowships (Australia)
Title of research award:
A synergistic approach to treating Huntingtons diseaseA synergistic approach to treating Huntingtons disease
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
This research furthered our understanding of how Huntington's disease effects brain function. The research
revealed sex-specific aspects of Huntington's disease and demostrated evidence that sex-specific hormone
treatment could be an effective intervention for Huntington's disease patients.
Expected future outcomes:
Development of hormone-based therapeutic interventions for Huntington's disease
Name of contact:
Mark Ransome
Email/Phone no. of contact:
mransome@florey.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1006077
CIA Name: Prof Terence O'Brien
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $524,820
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Targeting Tau phosphorylation to treat and prevent acquired epilepsy, neurodegeneration and neuropsychiatric
disease following a brain injuryTargeting Tau phosphorylation to treat and prevent acquired epilepsy,
neurodegeneration and neuropsychiatric disease following a brain injury
Lay Description (from application):
This project will explore a new approach to the prevention and treatment of epilepsy and the associated mental
health disorders following a brain injury. This involves inhibiting pathological forms of the Tau protein, which
has been implicated in the development of epilepsy and neurodegeneration. The drug that will be tested in this
study has already been demonstrated to be safe and well tolerated in humans, meaning that a positive result
from these studies could be expediently translated into clinical studies.
Research achievements (from final report):
Epilepsy is a common and disabling consequence of a brain injury, and is often associated with significant
mental health, cognitive and degenerative brain changes. There is currently no available treatment that is
effective in protecting against the development of epilepsy and its associated problems. This project
investigated the efficacy of an entirely novel intervention, sodium selenate, which inhibits the pathological
accumulation of the a toxic form of the brain protein, tau., The study aimed to establish: (i) Whether sodium
selenate is effective at suppressing spontaneous seizures in animals with acquired epilepsy; (ii) Whether
treatment with sodium selenate is effective at inhibiting epileptogenesis, neurodegeneration, and behavioural
disturbances following a range of acquired brain insults in rat models; (iii) To examine whether epilepsy
inducing brain insults results in altered levels of expression of Tau, its neurotoxic form, phospho-tau, and
PP2A in transgenic mouse strains, and whether treatment with selenate mitigates these changes., The results
demonstrated that treatment with sodium selenate was effective in suppressing spontaneous seizures in animals
with established acquired epilepsy. We further demonstrated that treatment with sodium selenate was effective
at inhibiting the development of epilepsy and the associated behavioural, cognitive and degenerative brain
changes when administered following a brain injury. In addition we found that treatment with sodium selenate
administered following a brain injury was effective in preventing the brain molecular changes related to the
neurotoxic form of tau that occur in animals that have developed epilepsy following a brain injury., This study
provides strong preclinical evidence for the efficacy of a novel approach to prevent the development of
epilepsy and the associated mental health, cognitive and degenerative brain changes following a brain insult.
Expected future outcomes:
This study established a new paradigm for assessing the effectiveness of an intervention on the development of
epilepsy, and also its associated neurodegeneration, neurobehavioural and neurocognitive deficits, following a
brain injury by performing serial in-vivo assessments complimented by terminal tissue level analysis.
Name of contact:
Terence O'brien
Email/Phone no. of contact:
obrientj@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1006428
CIA Name: Dr Yuekang Xu
Admin Inst: University of Melbourne
Main RFCD: Enzymes
Total funding: $498,505
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of the Cardiovascular Disease-Associated Protease Inhibitor Cystatin C for Therapeutic
ApplicationRegulation of the Cardiovascular Disease-Associated Protease Inhibitor Cystatin C for Therapeutic
Application
Lay Description (from application):
Proteases can contribute to atherosclerosis, so they are normally controlled by the endogenous inhibitor,
Cystatin C (Cst C). Some conditions cause reduction in Cst C levels and hence disease. On the other hand,
excess Cst C can form toxic aggregates. In this project, we will identify mechanisms controlling Cst C
expression and aggregation to find therapeutic strategies to treat cardiovascular diseases associated with Cst C.
Research achievements (from final report):
Some extracellular proteases can be destructive to vascular system if not properly controlled by their
endogenous inhibitor, Cystatin C (CstC), whose level is often reduced under inflammatory condition as in the
case of atherosclerosis. CstC can also directly damage the vessel wall by aggregating to form fibrils in patients
with neurodegenerative disorders. Therefore, regulation of CstC synthesis and dimerisation is of major clinical
significance. Dendritic cells (DC) and macrophages are found in these disease lesions and can secrete large
amounts of CstC, indicating a possible source of pathogenic CstC. In this project, we verified our hypothesis
that DCs and their related macrophages possess mechanisms to regulate CstC production and dimerisation that
similarly operated in other cells in the lesions. We found that inflammation-induced CstC down-regulation in
DC requires transcriptional factor IRF8, which was suppressed by IL-10, an inflammation-induced cytokine
that also represses circulating CstC levels in this condition. Furthermore, we identified that Reactive Oxygen
Species regulate CstC dimerization in the DCs and macrophage of the haematopoietic system, which are major
contributors to the total pool of circulating CstC. Collectively, these data suggest that the synthesis and
dimerization of CstC in haematopoietic cells might be manipulated for therapeutic gain.
Expected future outcomes:
Cytokines or drugs that interfere with the pathways controlling CstC gene expression might be useful to
increase CstC expression in atherosclerotic lesions, or to reduce CstC fibril formation. Bone marrow
transplantation might be useful for the treatment of diseases associated with formation of CstC amyloid.
Name of contact:
Yuekang Xu
Email/Phone no. of contact:
Yuekang.Xu@hotmail.com
NHMRC Research Achievements - SUMMARY
Grant ID: 1008044
Start Year: 2011
CIA Name: A/Pr Robert Hester
End Year: 2013
Admin Inst: University of Melbourne
Grant Type: NHMRC Project Grants
Main RFCD: Neurocognitive Patterns and Neural Networks
Total funding: $359,504
Title of research award:
Performance monitoring dysfunction in ageingPerformance monitoring dysfunction in ageing
Lay Description (from application):
The ability to monitor one's cognitive performance deteriorates with normal ageing, and is particularly affected
in a range of clinical conditions of older age, such as Parkinson's Disease, where it is a predictor of a poor
prognostic outcome. This project aims to clarify the effects of age on cognitive and neural processes
underlying performance monitoring, as an important first step to improving interventions for age-related
impairments, including those accompanying neurodegenerative diseases.
Research achievements (from final report):
The current research demonstrated that normal ageing results in a decline in the detection, correction and
learning from errors. Functional neuroimaging of healthy older adults demonstrated that failures of
performance monitoring in older age resulted from a deterioration in the magnitude of the neural response to
errors. In particular, the dopaminergically mediated error-related response in key cortical sites was diminished
in older adults, and was linked with deteriorations in key cognitive functions such as conscious awarenss of
errors. The loss of awareness was associated with everyday failures of cognition, such as greater difficulty with
activities of daily living (e.g., finances, medication adherence).
Expected future outcomes:
The sensitivity of performance monitoring to age-related changes, and in turn its prediction of difficulties of
daily living, suggest it is a viable biomarker for future research aiming to intervene with this population.
Name of contact:
Rob Hester
Email/Phone no. of contact:
hesterr@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011689
CIA Name: Prof Christopher Rowe
Admin Inst: University of Melbourne
Main RFCD: Central Nervous System
Total funding: $661,164
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
AIBL II - Neuroimaging StreamAIBL II - Neuroimaging Stream
Lay Description (from application):
A new scan called PiB PET shows the build up of amyloid protein deposits in the brain in all patients with
Alzheimer's disease (AD) but also in 30% of normal elderly persons. This study will track the build up of
amyloid and clinical progress in 280 elderly Australians to confirm that this scan can detect AD before
symptoms and investigate factors that influence this build up and its damaging effects on memory and thinking.
Early detection of Alzheimer's disease will assist accurate diagnosis and the development of treatment.
Research achievements (from final report):
Post mortem studies show that patients with Alzheimer's disease (AD) have abnormal microscopic clumps of
beta amyloid protein throughout their brain. These are called amyloid plaques and they can be measured with a
new brain scan using positron emission tomography called PiB-PET. This study is the first to show that
amyloid plaques build up slowly in the brain over a 30 year period and can be detected with brain PiB-PET 15
years before the development of dementia. This was achieved by performing scans every 18 months over 3-6
years in over 200 participants in the AIBL study of aging in Melbourne and Perth. The study also showed that
normal older persons with high brain amyloid levels have a slow decline in memory that can be detected with
repeat testing over 3 years while those with negative amyloid scans do not decline. This work was published in
the top clinical neuroscience journal, Lancet Neurology, and won the US Alzheimer's Association prize for best
research paper on imaging in AD in 2013. The work also showed that genetic make up influences the rate of
memory decline. It also showed that in individuals with moderate memory loss, those with a positive PiB-PET
scan had an 80% chance of dementia in 3 years compared to 20% is those with a negative scan. These findings
have led to new criteria for earlier diagnosis of Alzheimer's disease and to treatment trials in individuals with
brain amyloid but no or minimal symptoms to prevent dementia.?????
Expected future outcomes:
The AIBL study continues to follow the participants with regular scans and cognitive assessments. More genes
and lifestyle factors that alter the risk of Alzheimer's disease are expected to emerge along with blood tests to
help identify those at highest risk for future AD.
Name of contact:
Prof. Christopher Rowe
Email/Phone no. of contact:
christopher.rowe@austin.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 151620
CIA Name: Prof Des Richardson
Admin Inst: University of New South Wales
Main RFCD: Cell Metabolism
Total funding: $227,485
Start Year: 2002
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
The Physiological and Pathophysiological Roles of MelanotransferrinThe Physiological and
Pathophysiological Roles of Melanotransferrin
Lay Description (from application):
Melanotransferrin (MTf) is a membrane bound molecule that was originally identified in the malignant
melanoma skin cancer and other tumours. Interestingly, MTf has many similarities to the serum iron-binding
protein, transferrin, and initially MTf was thought to play a role in iron uptake by these cells. However, a series
of studies by the applicant demonstrated that MTf did not play a major role in iron uptake by melanoma cells
(Richardson et al. 1990, 1991a,b). In fact, most iron taken up by these cells was via the binding of transferrin to
the transferrin receptor. More recently, under the current NHMRC grant, we have been able to confirm and
signficantly extend our previous studies to convincingly show that MTf is not involved in iron uptake by
melanoma cells where it is expressed at very high levels (Richardson 2000 Eur. J. Biochem. 267 (in press). In
addition, we showed that the expression of MTf in 50 human tissues was very different to transferrin and the
transferrin receptor (TfR) that are well known to be involved in iron transport. For example, the TfR is
expressed at high levels in tissues that require large amounts of iron eg. the placenta and bone marrow. In
contrast, MTf was not expressed at high levels in these tissues, but was found in large amounts in unexpected
locations such as the salivary gland. Furthermore, the expression of MTf was widespread through a variety of
tissues, and in contrast to expectations, was found at higher levels in normal rather than fetal tissues. It is also
intesting that MTf is found in the blood and brain of Alzheimer's disease patients. Our results suggest that
MTf may play other unexpected roles apart from iron uptake. The present proposal will assess the roles of
MTf in cellular functioning. This information will be very important in understanding the function of MTf in
cancer cells, Alzheimer's disease and also in other tissues (eg. the salivary gland) where it is expressed at very
high levels.
Research achievements (from final report):
We have generated a melanotransferrin knockout mouse. Beginning by engineering a deletion of part of the
mouse melanotransferrin gene outside the genome, we have successfully replaced the mouse natural MTf gene
with our engineered defective gene. This in effect knocks out the gene and thus its function from the mouse
genome.
Expected future outcomes:
By studying the effect the absence of the MTf gene has on mouse growth we are able to determine the
functional role of MTf
Name of contact:
Prof. Des Richardson
Email/Phone no. of contact:
DRichardson@ccia.unsw.edu
NHMRC Research Achievements - SUMMARY
Grant ID: 157034
CIA Name: Prof Gary Halliday
Admin Inst: University of New South Wales
Main RFCD: Central Nervous System
Total funding: $605,152
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
GENETIC FACTORS AND REGIONAL BRAIN ATROPHY IN THE DIAGNOSIS OF DEMENTIA WITH
LEWY BODIESGENETIC FACTORS AND REGIONAL BRAIN ATROPHY IN THE DIAGNOSIS OF
DEMENTIA WITH LEWY BODIES
Lay Description (from application):
The number of people with dementia is increasing in Australia as people live longer. Dementia sometimes has
a genetic basis and identification of such cases has improved our understanding of the events leading to the
destruction of the brain tissue. In the vast majority of people, the degenerative changes were previously thought
to be as a result of Alzheimer's disease. However, our recent research, funded by the NHMRC, confirms
international findings showing more than 25% of people with dementia have a different disease called
"Dementia with Lewy bodies" or DLB. Of course identifying these patients occurs at death when the cells in
the brain can be examined for Lewy bodies. We now know that the brain degeneration differs significantly in
patients with this disease. However, it is still not possible to identify DLB in life with any certainty. This
project aims to develop objective methods to clinically differentiate dementia patients. We will seek out
families in which genetic influences may underly the disease and determine whether these factors differ from
those found in other dementing illnesses. Also, our preliminary studies have observed volume loss in a
particular brain region in pathologically confirmed DLB patients. We wish to do further measurements to
determine if tissue loss in this region can clinically differentiate DLB patients. In addition, we will determine
the reasons for the tissue loss by careful pathological studies.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 157125
CIA Name: Prof Perminder Sachdev
Admin Inst: University of New South Wales
Main RFCD: Geriatrics and Gerontology
Total funding: $153,021
Start Year: 2001
End Year: 2002
Grant Type: NHMRC Project Grants
Title of research award:
RISK AND PROTECTION FACTORS FOR NORMAL AND ABNORMAL BRAIN AGEING: A
LONGITUDINAL EPIDEMIOLOGICAL MRI STUDYRISK AND PROTECTION FACTORS FOR
NORMAL AND ABNORMAL BRAIN AGEING: A LONGITUDINAL EPIDEMIOLOGICAL MRI STUDY
Lay Description (from application):
Brain is considered the last frontier of medicine, and ageing the major challenge to health care in the 21st
century. In this proposal, we bring these two challenges together in a major new longitudinal study of ageing
in Canberra that has recently been initiated. This is a longitudinal study of a random community sample
covering 3 age groups - 20-24 years, 40-44 years and 60-64 years, with at least 2000 participants in each age
group - who are being assessed in 1999-2001, and will be followed up at 4-yearly intervals for 20 years. The
focus of the study is on neuropsychiatric disorders (anxiety, depression, substance use and cognitive disorders).
In this application, we propose to perform MRI scans and blood tests on a quarter (n=500) of the 60-64 sample
to obtain an epidemiological sample for brain morphology. Not only will we be able to study changes in brain
morphology over time, and relate it with cognitive function and psychiatric disorder, we will also be able to
assess the role of risk and protection factors. We are particularly interested in brain reserve, dietary factors
(anti-oxidants, omega 3, wine and folate) and drugs (anti-inflammatory drugs, hormone replacement and
vitamin supplements) as protection factors, and hypertension, homocysteine levels, white matter lesions on
MRI and low hippocampal volumes as risk factors for cognitive impairment and dementia. We also want to
study the brain morphological correlates of Depression in a community sample. The study will enhance our
understanding of the ageing brain, both in health and disease, and identify factors that increase or decrease the
risk of cognitive impairment and psychiatric disorder in old age.
Research achievements (from final report):
This grant was awarded to perform MRI scans on a random sample of 500 individuals in the age range 60-64
years who are participating in a longitudinal study of ageing (Path Through Life Project) being carried out by
Prof Tony Jorm and his colleagues in Canberra. It served as a baseline examination for future repeat scans, to
be performed in 4 years' time. Cross-sectional analyses were also planned to examine MRI parameters in a
community sample, and to relate them to cognitive function. The sampling began in March 2001 and MRI
scans commenced in May 2001, and was completed in August 2002. Of 637 participants so approached, 478
(75%) (men = 252, women = 226) agreed to undergo an MRI brain scan. A further 35 subjects had MRI scans
as they were diagnosed with Mild Cognitive Impairment as part of the larger cohort (n = 2551). Data collection
was completed in 2002, and the data have been analysed and many publications have emanated from this study.
Further publications are planned. There were a number of other positive outcomes from this grant: i) A
neuroimaging lab has been set up in Canberrra at the Centre for Mental Health Research so that analysis can
occur concurrently in Canberra and Sydney. This lab has supported two PhD students who are nearing the
completion of their work; ii) The study was enhanced by obtaining blood samples from this cohort, which are
being analysed in various laboratories for neurochemistry, genetics and proteomics. A number of significant
publications have emerged from these analyses; iii) A collaboration has developed between our centres and the
NICTA for the development of image analysis software for advanced image analysis. iv) Many salient
publications have emerged from the study
Expected future outcomes:
This is the second largest community-based MRI study in the world and has a wealth of information. Wave 2
of this study will occur in 2005-06 and will be funded from the Program Grant awarded to Professors Sachdev,
Brodaty & Andrews, and to Prof Jorm's group at the CMHR.
Name of contact:
NHMRC Research Achievements - SUMMARY
Prof Perminder Sachdev
Email/Phone no. of contact:
p.sachdev@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 209548
CIA Name: Prof Bruce Brew
Admin Inst: University of New South Wales
Main RFCD: Central Nervous System
Total funding: $241,980
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
The kynurenine pathway chemokines and MIC-1 in the pathogenesis of AIDS dementia complex.The
kynurenine pathway chemokines and MIC-1 in the pathogenesis of AIDS dementia complex.
Lay Description (from application):
This proposal will examine the mechanisms by which HIV and other brain disorders such as encephalitis
damage the brain. Further understanding of the biochemical pathway involved will lead to the possibility of
novel drug therapy for these disorders.
Research achievements (from final report):
This project discovered that quinolinic acid, a neurotoxin produced by human immune cells, can increase HIV
brain infection. This is mediated by increasing the production of chemokines and increasing the expression of
their receptors on a variety of brain cells. This mechanism probably has wider importance in the generation and
amplification of brain damage in inflammatory brain diseases in general. Inhibitors of quinolinic acid are being
developed and may be of benefit in HIV therapy and more generally in inflammatory brain diseases.
Expected future outcomes:
The next step is to inhibit quinolinic acid production in animal models of HIV disease to prove that there is
significant reduction in brain disease.
Name of contact:
Prof Bruce James Brew
Email/Phone no. of contact:
B.Brew@UNSW.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 222842
CIA Name: Prof Perminder Sachdev
Admin Inst: University of New South Wales
Main RFCD: Psychiatry
Total funding: $321,800
Start Year: 2003
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
An extended follow-up of stroke patients for cognitive impairment and neuropsychiatric disorders: Sydney
Stroke StudyAn extended follow-up of stroke patients for cognitive impairment and neuropsychiatric disorders:
Sydney Stroke Study
Lay Description (from application):
Vascular Dementia (VaD) is the second most common cause of dementia after Alzheimer's disease. In fact, it
may be a preventable cause of dementia. Yet it has been relatively neglected by researchers until the last
decade, which has seen an upsurge of interest in this disorder. There is no consensus on the criteria for
dementia. The profile of early cognitive impairment due to vascular factors is still poorly understood, and the
longitudinal course of VaD as defined by modern criteria has not been studied. There have been few studies of
the progressive changes in MRI in patients with cerebrovascular disease. The overlap of VaD and Alzheimer's
disease (AD) remains a problem for taxonomists and clinicians. One approach to the study of VaD is to
examine a high risk group of subjects longitudinally to determine the early features, the risk factors and
progressive changes. With this in mind, we began studying a cohort of stroke patients who are at high risk of
VaD, in 1997-1999, and are following them longitudinally. The follow-up is now in its third year, and three
neuropsychological assessments and two MRI/MRS scans have been performed. We propose to extend the
follow-up to 5 years, with repeat neuropsychiatric, neuropsychological and MRI/MRS investigations, and
wherever possible to necropsy, to determine the nature of vascular pathology that underlies cognitive
impairment. Our cohort of stroke patients is arguably the most comprehensively assessed such cohorts
internationally, and presents an excellent opportunity for a long-term follow-up study.
Research achievements (from final report):
This grant enabled us to follow up a cohort of stroke pateints for 5 years after the index stroke. In the earlier
stages of this study, funded by prevous NHMRC grants, we demonstrated that vascular dementia (VaD) and
vascular mild congitive impairment (VaMCI) are common in this cohort. In the extended follow up, we
demonstrated that a significant proportion of these subjects show progressive decline in their cognitive
function, even in the absence of further strokes. One of the factors that may account for this worsening is an
increase in small vessel disease, as shown by white matter hyperintensities (WMHs) on MRI. Some of the risk
factors of WMHs are hypertension, diabetes, low lung capacity and high homocysteine, all of which are
partially correctable. Stroke pateints do not have smaller hippocampi than control subjects, and the volume
decreases over 3 years of follow-up, at about the same rate as controls. The occurrence of further stroke or TIA
leads to greater cognitive worsening. High lifetime mental activity is protective against such worsening.
Individuals with high lifetime mental activity have less decline in hippocampal volumes. Magnetic resonance
spectroscopy (MRS.) can be used to distinguish between stroke patients with and without cognitive
imapirment. MRS. at baseline is also a predictor of decline in the future. Depression and apathy are common in
patients with stroke, with rates of depression peaking at the 1 year follow-up.
Expected future outcomes:
This cohort is now being followed up by telephone contact and mailouts. A significant proportion has signed in
for brain donation. This will help confirm the neuropahtology, especially to determine what proportion of those
with dementia have Alzheimer pathology.
Name of contact:
Perminder Sachdev
Email/Phone no. of contact:
p.sachdev@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 222909
Start Year: 2003
CIA Name: Dr Olivier Piguet
End Year: 2007
Admin Inst: University of New South Wales
Grant Type: Early Career Fellowships (Overseas)
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $333,591
Title of research award:
Structural, functional and neuropathological correlates of normal and patholgical cognitive ageingStructural,
functional and neuropathological correlates of normal and patholgical cognitive ageing
Lay Description (from application):
Not Available
Research achievements (from final report):
To date, this research has shown that healthy ageing is accompanied by changes in emotion processing.
Deficits in emotion processing are also present in many dementia types but require careful characterisation.
Future research will identify the early manifestation of deficits in emotion processing that are disease specific
and monitor their progression as the disease worsens. , , Using neuroimaging and postmortem investigations,
this research has also shown that age-related brain changes affect the connections between brain regions (i.e.,
the brain white matter) rather than the nerve cells (i.e., the brain grey matter). , , In a next phase, we will apply
these tools to patients with early frontotemporal dementia and early Alzheimer's disease in order to define the
progression of the neuropathological brain changes over time.,
Expected future outcomes:
This research will contribute to a more accurate clinical detection of the early signs of dementia and to a better
understanding of their associated brain changes. Ultimately, this knowledge is essential to the success of future
treatments and management interventions.
Name of contact:
Olivier Piguet
Email/Phone no. of contact:
o.piguet@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 230862
CIA Name: Dr John Kwok
Admin Inst: University of New South Wales
Main RFCD: Not Allocated
Total funding: $435,500
Start Year: 2003
End Year: 2007
Grant Type: Career Development Fellowships
Title of research award:
Identification and Characterisation of Causative and Modifier Genes Involved in Variant Forms of Alzheimer's
DiseaseIdentification and Characterisation of Causative and Modifier Genes Involved in Variant Forms of
Alzheimer's Disease
Lay Description (from application):
Media Summary not available
Research achievements (from final report):
During my fellowship, my research team have identified the causative gene in a pedigree with frontotemporal
dementia with amyotrophic lateral sclerosis (ALS). Our experiments have confirmed that altered expression of
the dementia gene can lead to perturbations in key molecular markers of neurodegenerative diseases . We have
also been able to demonstrate that commercially available and therapeutically relevant drugs are able to
modulate the biological activity of the same molecular markers. This project has the potential to revolutionise
the diagnosis and treatment of two neurodegenerative disorders.
Expected future outcomes:
We will initiate clinical trials based on these class of drugs for hitherto untreatable neurodegenerative diseases
Name of contact:
John BJ Kwok
Email/Phone no. of contact:
j.kwok@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300400
CIA Name: Prof Glenda Halliday
Admin Inst: University of New South Wales
Main RFCD: Central Nervous System
Total funding: $565,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Alzheimer's disease and Dementia with Lewy bodies: How different are they?Alzheimer's disease and
Dementia with Lewy bodies: How different are they?
Lay Description (from application):
Dementia is a devastating disorder, taking the individuals mind. As the population ages, a significant
proportion become demented, impacting on these individuals, their families and the community as a whole
(Federal and State budgets for this disorder are costed in the billions). There are many cellular causes of
dementia, the most frequent being considered Alzheimer's disease. However, many people currently thought to
have Alzheimer's disease have another dementia cause - dementia with Lewy bodies. This study aims to
determine 1) how common these two types of dementias are (currently unknown) 2) how better to diagnose
them and tell them apart 3) how badly the brain is affected by each disorder and 4) whether the same genes are
involved in both disorders. The knowledge we will gain will allow better diagnosis of the cellular causes of
dementia, knowledge necessary for rational treatment.
Research achievements (from final report):
Difficulties in clinically separating the different cellular causes of neurodegenerative dementias prompted our
research studies. We identified limited tissue atrophy in dementia with Lewy bodies (a particular cellular
pathology different from Alzheimer's disease) and determined the overlapping regions of atrophy responsible
for clinical similarities and differences to Alzheimer's disease. Despite significant differences in tissue loss
with time, abnormalities with brain protein solubility overlap in these dementia syndromes, although metabolic
regulation appears to differ. Our work contributed to the new international consensus criteria for the diagnosis
and management of dementia with Lewy bodies, and dementia in the context of the movement disorder
Parkinson's disease.
Expected future outcomes:
Identification of the cellular causes for fluctuations in cognition, one of the dominant symptoms of dementia
with Lewy bodies. Identification of cellular triggers for the region selective nature of the pathological processes
observed.
Name of contact:
Glenda Halliday
Email/Phone no. of contact:
g.halliday@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300467
CIA Name: Dr Claire Shepherd
Admin Inst: University of New South Wales
Main RFCD: Central Nervous System
Total funding: $392,750
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Targeting inflammatory mechanisms in Alzheimer's disease.Targeting inflammatory mechanisms in
Alzheimer's disease.
Lay Description (from application):
Alzheimer s disease accounts for the majority of dementia cases and is the most common cause for nursing
home requirements in Australia. It is not a disease that is confined to old age as it can also affect individuals in
their 20s and 30s. There is currently no cure for Alzheimer's disease, largely because the underlying cause is
unknown. Deposition of the amyloid-beta protein within the brain of Alzheimer's disease patients is thought
to be responsible for the neuronal cell loss which underlies the dementia. However, amyloid-beta protein
deposition can occur in the absence of dementia and in the asbence of significant neuronal cell loss, suggesting
that an alternative mechanism of neurotoxicity exists. Inflammation is a consistent feature of the Alzheimer's
disease brain. We have preliminary evidence to suggest that inflammation is responsible for the neurotoxicity
in Alzheimer's disease. We have recently observed a significant inflammatory response surrounding an
unidentified protein in the brains of individuals with a familial form of Alzheimer's disease due to a genetic
mutation. This inflammatory response is not associated with the significant amyloid-beta protein deposition
seen in these cases suggesting that a novel potent inflammatory stimulus exists. Furthermore, these cases have
greater neuronal cell loss and a shorter disease duration, both indicators of increased neurotoxicity. The
present study is designed to determine the toxicity of inflammation and the stimulus driving this response in the
Alzheimer's disease brain using tools for protein and gene analysis, as well as determining the extent of
inflammation-mediated toxicity on neuronal cells grown in culture. Only by addressing these aims can we
concentrate on developing safe and effective therapeutic strategies to prevent or treat the disease process.
Research achievements (from final report):
We identified a ~6 fold increase in an individual inflammatory mediator, monocyte chemoattractant protein-1
(MCP-1), that drives the inflammatory response in familial and sporadic forms of Alzheimer's disease. This
mediator also showed a trend towards higher levels in familial forms of Alzheimer's disease that have a more
severe and aggressive disease and greater neuronal loss. In addition, these familial forms of Alzheimer's
disease have increases in additional inflammatory mediators that may also contribute to the more severe
disease process. We have also identified proinflammatory S100 proteins in the pathological hallmarks of
sporadic and familial Alzheimer's disease that appear to contribute to the inflammatory process. Identifying the
major mediators of the chronic damaging inflammatory response in Alzheimer's disease will enable the
development of potential therapeutic strategies to halt the neuronal cell loss that underlies this dementia
syndrome.
Expected future outcomes:
Further characterisation of the major mediators of inflammation in Alzhemer's disease for the future
development of potential therapies.
Name of contact:
Claire Shepherd
Email/Phone no. of contact:
c.shepherd@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300584
Start Year: 2004
CIA Name: Dr Gilles GUILLEMIN
End Year: 2008
Admin Inst: University of New South Wales
Grant Type: Career Development Fellowships
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $444,500
Title of research award:
Involvement of the Kyurenine pathway in the neuropathogenesis of the Alzheimer's diseaseInvolvement of the
Kyurenine pathway in the neuropathogenesis of the Alzheimer's disease
Lay Description (from application):
Not Available
Research achievements (from final report):
Dr Guillemin has built an new research group, an international reputation in his fiels and made major finding
for the neuropathology of Alzheimer's disease and other neurodegenerative diseases.
Expected future outcomes:
Develop the research group and develop new drugs targeting neurodegenerative diseases.
Name of contact:
Prof Bruce Brew
Email/Phone no. of contact:
bbrew@stvincents.com.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350827
Start Year: 2005
CIA Name: Prof Glenda Halliday
End Year: 2009
Admin Inst: University of New South Wales
Grant Type: Established Career Fellowships
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $651,750
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
Not Available
Research achievements (from final report):
I am a neuroscientist with a major reputation in the area of pathology of neurodegenerative diseases not only
for my research in basic mechanisms, but also for my involvement in neurological diagnoses. My research
group is recognized as one of the top research groups in Parkinson's disease and Lewy body pathology
worldwide. I have published over 225 papers which appear in the top neurological and neuropathological
journals. In Parkinson's disease I have identified early intra- and extra-cellular events important in its
pathogenesis. In addition I have started to determine the impact of genetic variation on both Parkinson's and
Alzheimer's diseases. Patients with presenilin-1 gene mutations differ significantly in a number of pathologies
from sporadic Alzheimer's disease. This has implications for transgenic models using these mutations. My
group is also internationally recognized for work on frontotemporal dementia in association with the
international Frontotemporal Dementia Research Group (FRONTIER) at POWMRI., My work has been
directly translated into clinical practice and incorporated into both national and international consensus
diagnostic criteria for dementia syndromes, and international consensus criteria for dementia with Lewy bodies
and frontotemporal lobar degeneration. I have been involved in the development of clinical tools to both aid
diagnosis and predict prognosis for neurodegenerative disorders, including simple atrophy staging, a diagnostic
GeneChip for Parkinson's disease, and a patent application for a genetic test for predicting progression of
Parkinson's disease. Several current research contracts have significant potential for future industry interactions
(developing novel α-synuclein imaging ligands).
Expected future outcomes:
In Parkinson's disease, determine critical proteins in pathogenesis and develop research on adult stem cells to
develop diagnostic tools for patients., In Alzheimer's disease, determine inflammatory pathways and
characterise the role of ABC transporters., In non-Alzheimer dementias, determine pathogenic mechanisms in
frontotemporal dementia subtypes to develop tools for in vivo differentiation.
Name of contact:
Glenda Margaret Halliday
Email/Phone no. of contact:
g.halliday@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 350833
CIA Name: Prof Perminder Sachdev
Admin Inst: University of New South Wales
Main RFCD: Psychiatry
Total funding: $4,929,015
Start Year: 2005
End Year: 2009
Grant Type: Programs
Title of research award:
The prevention, early detection, & effective management of neurocognitive disorders in the elderlyThe
prevention, early detection, & effective management of neurocognitive disorders in the elderly
Lay Description (from application):
The unprecedented greying of the world population is posing a major challenge to health care in meeting the
needs of older individuals with cognitive disorders such as Alzheimer’s disease. At the same time, drugs are
being developed to prevent these disorders, or to treat them effectively. Our proposal is a comprehensive
attempt at dealing with the neuropsychiatric aspects of these neurocognitive disorders. Our group is
endeavouring to better define the early stages of these disorders, and studying methods of detecting them at an
early stage, using the latest neuropsychological and neuroimaging techniques. We wish to investigate new
drugs for the prevention of dementia. Much of dementia is not treated early because of lack of training of
primary care physicians in identifying dementia, and we are developing methods to deal with this problem. We
are also examining the role of cognitive disorders in accidents and suicides in the elderly, and the development
of depression. We are determining the role of psychiatric disorders in the care of these patients, and the
methods of alleviating the burden of disease. We expect that this research will make a major impact on health
policy for these disorders in Australia. We also hope to make our Program the premier centre for training in
geriatric neuropsychiatry.
Research achievements (from final report):
The program grant enabled the establishment of large longitudinal cohorts to examine risk and protective
factors in ageing, in particular the Memory &Ageing Study, the Older Australian Twins Study and the Sydney
Centenarian Study, and a Stem Cell Laboratory. We have identified risk factors such as high homocysteine,
poor smell sense and the presence of motor abnormalities, and protective factors such as complex cognitive
activity and physical exercise. There are also sex differences in risk factors. We have identified new plasma
biomarkers of early cognitive impairment which will lead to genetic and epigenetic studies. We have
investigated new imaging techniques such as DTI and fMRI (using a stress test) as biomarkers of cognitive
impairment, and examined brains for microbleeds. We have shown that brain connectivity changes with age
and this relates to a slowing of processing speed, which may underlie age-related cognitive decline. We have
shown that the examination of specific fibre tracts may add to the discrimination produced by volumes of brain
structures. We have examined why neurogenesis slows down with age, and launched a trial to examine the
effects of physical and cognitive training in preventing dementia in high risk individuals. We have shown that
cognitive functions in old age are still highly heritable and that inflammatory markers are higher in those with
cognitive impairment. These findings have great significance in understanding the multiple causes of cognitive
decline with age and the development of dementia, and will lead to strategies to prevent dementia.
Expected future outcomes:
The longitudinal studies established in the Program have been enriched by further work in genomics,
proteomics, metabolomics, neuroimaging, falls research, and neuropsychological assessments. As more
individuals develop dementia in these cohorts, they will become more valuable. Genetic data will be ready for
the next wave of analysis in early 2011.
Name of contact:
Prof Perminder Sachdev
Email/Phone no. of contact:
p.sachdev@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 401162
CIA Name: Prof Perminder Sachdev
Admin Inst: University of New South Wales
Main RFCD: Geriatrics and Gerontology
Total funding: $2,162,805
Start Year: 2006
End Year: 2013
Grant Type: NHMRC Strategic Awards
Title of research award:
Gene-environment interaction in healthy brain ageing and age related neurodegenerationGene-environment
interaction in healthy brain ageing and age related neurodegeneration
Lay Description (from application):
Healthy ageing is characterised by low level of disability, high cognitive and functional capacity, and an active
engagement in life. The most important ingredient of healthy ageing is a healthy brain, bereft of age-related
diseases and dysfunction. Brain ageing and brain diseases are determined by multiple genetic factors that
interact with environmental influences. The genes are multiple, the majority of which have a small influence.
This study is an attempt to identify some of these genes and investigate their interactions with environmental
factors. It will use a unique resource, the NHMRC Australian Twin Registry (ATR) to identify elderly twins,
and will also include the siblings of these twins so as to increase the ability to identify the important factors.
The participants, who are listed on the ATR and recruited from NSW, Queensland and Victoria, will receive
detailed neurological, psychiatric and cognitive assessments, and will undergo brain MRI scans. Their blood
samples will be used to measure key chemicals that may affect brain ageing and to extract DNA for genetic
tests. They will be followed-up every two years thereafter, and changes in their brain structure and cognitive
functioning will be examined. Available statistical models will be used to examine gene-environment
interactions and specific genes will be explored for their contribution to the additive genetic effects. This study
will yield an important resource for national and international collaborations and has the potential to discover
new genes.
Research achievements (from final report):
1. This grant enabled the establishment of the Older Australian Twins Study, a cohort of elderly (>65 years)
MZ and DZ twins (N=623) with comprehensive neuropsychiatric assessments over two waves. OATS has
already made significant contributions in relation to the genetic factors underlying many aspects of cognition
and brain imaging parameters. The heritability of processing speed, in particular the high genetic contribution
to performance on Digit Symbol (62%), is high. The heritability of simple and complex reaction time, being
48% and 35% respectively, are however inconsistent with the notion that heritability is dependent on the
difficulty of tasks, with more complex tasks being more heritable. The heritability estimates suggest that
executive function is a mulit-faceted task. The study also showed that the genetic influence on brain volumes,
including both grey and white matter, is high, as is that on subcortical structures, including the hippocampus.
White matter hyperintensities on the other hand, showed high heritability, only some of which was shared with
lacunar infarction., 5. Our data provide stronger support for the speed mediation hypothesis of ageing, although
there is a suggestion that both processes may be operative to some extent, with change in executive function
making a lesser contribution to change in memory with age., 6. Examination of some putative phenotypes of
Alzheimer's disease in brain imaging and plasma proteins .
Expected future outcomes:
1. Continuing follow-up of this cohort for the relative genetic and environmental contributions to mild
cognitive impairment and dementia., 2. Further elaboration of endophenotypes of dementia, including amyloid
load., 3. Exploration of the geentic basis of congitive decline and brain changes in old age, as part of
internatinal consortia .
Name of contact:
Perminder Sachdev, Prof Perminder Sachdev
Email/Phone no. of contact:
p.sachdev@unsw.edua.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455368
CIA Name: Prof Stephen Lord
Admin Inst: University of New South Wales
Main RFCD: Geriatrics and Gerontology
Total funding: $530,741
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Strategic Awards
Title of research award:
Identification and quantification of risk of falls in cognitively impaired older adultsIdentification and
quantification of risk of falls in cognitively impaired older adults
Lay Description (from application):
This study represents the first systematic approach to understanding the complex interaction of factors that
contribute to risk of falling in cognitively impaired older people. The results will provide much needed
information on how to intervene to prevent falls and fractures in this high risk population. In the last decade, 25
randomised controlled trials have been published which show it is possible to prevent falls in older people.
However, a major disappointing outcome of research in this field is that trials that have included or specifically
focused on older people with cognitive impairment have been unsuccessful in preventing falls. Cognitive
impairment has long been known to be a major risk factor for falls and fractures but little research has been
undertaken to understand the underlying mechanisms as to why this is the case. It is likely that previous falls
prevention trials involving people with cognitive impairment were unsuccessful because they did not directly
assess mechanisms for falls in this group and simply translated intervention strategies from studies undertaken
in cognitively intact older people. This study aims to develop our understanding of the important factors that
contribute to risk of falling in older people with cognitive impairment and dementia. Participants will be
recruited from a number of sources including hospitals, out-patient clinics, retirement villages, hostels etc.
Whilst some participants will be able to consent to take part, all participants must have a nominated "person
responsible". Consenting participants will undergo a series of assessments, the majority of which can be
undertaken in their own home. These will include medical and medication history, measures of gait and
balance and tests assessing performance of different regions of the brain. An MRI scan will allow us to
determine whether risk of falling relates to any specific pathology in different parts of the brain. We anticipate
that we will be able to identify which risk factors and underlying mechanisms are most strongly associated with
falling in cognitively impaired older people. We then hope to use the information to design targeted and
tailored intervention strategies to reduce falls and fractures in this high risk population.
Research achievements (from final report):
This project has systematically assessed falls risk in older people with cognitive impairment. It has provided
clear evidence of marked physiological deficits in this population that are potentially amenable to intervention strength, balance and reaction time. It appears that the physical deficits play a greater role in risk of falls than
any of the neurocognitive measures. However, neurocognitive performance is relevant in terms of potential
interventions for the future.
Expected future outcomes:
The study finished in March 2011 and a pilot study for intervention has also been undertaken and has provided
additional information on how to shape an intervention for the future. The next step is to undertake an
intervention study and funding is currently being sought.
Name of contact:
Jacqueline Close
Email/Phone no. of contact:
j.close@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455377
Start Year: 2007
CIA Name: Dr Lee-Fay Low
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: Early Career Fellowships (Australia)
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $299,189
Title of research award:
An exploration of issues relating to dementia risk reduction and care in Australia using epidemiological
research methods.An exploration of issues relating to dementia risk reduction and care in Australia using
epidemiological research methods.
Lay Description (from application):
Not Available
Research achievements (from final report):
Dr Low has attracted over 2.5 Million dollars of funding and has a h-index of 13, and despite two career breaks
to have children, has had 27 publications in the five years since her PhD. Her success in conducting and
translating research into practice is most notably demonstrated by the SMILE clustered randomised trial. As a
result of SMILE, humour therapy is becoming an accepted and desired part of residential aged care provision in
Australia. A documentary about this landmark study was recently screened on the ABC's Compass program in
a prime timeslot.
Expected future outcomes:
Future publications include papers, and a contracted book on activities for persons with dementia. Humour
therapy programs are being rolled out across Australia and it is anticipated that humour will become accepted
as a diversional activity in residential aged care.
Name of contact:
Lee-Fay Low
Email/Phone no. of contact:
lf.low@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 455450
CIA Name: Prof George Paxinos
Admin Inst: University of New South Wales
Main RFCD: Central Nervous System
Total funding: $264,307
Start Year: 2008
End Year: 2009
Grant Type: NHMRC Project Grants
Title of research award:
A New Map of the Human Cerebral Cortex to assist the Interpretation of fMRI and PET StudiesA New Map of
the Human Cerebral Cortex to assist the Interpretation of fMRI and PET Studies
Lay Description (from application):
The cortex is the brain structure most intimately involved in cognition, motivation and emotion. It is thought to
be the principal area affected in diseases such as schizophrenia, and Alzheimer's disease. An enormous and
costly effort is expended in functional neuroimaging with PET and fMRI to establish the relation between
cortical regions and neurologic and psychiatric dysfunction. Unfortunately due to the unavailability of an
accurate map of the human cortex, the researcher is left only with crude estimates of the location of normal and
abnormal cortical activity. Further, there is limited ability to relate the human data to the wealth of knowledge
available on non-human primate brains. Conversely, researchers using animal models of human cortical
pathology cannot readily relate their data to humans because the similarities between the brains of experimental
animals and humans have not yet been comprehensively established. The present project will establish the
similarities between the cortex of humans and rhesus monkeys. By revealing comprehensively the location of
cortical areas this project will provide the context within which hypotheses of cortical function and dysfunction
can be tested. The applicants were the first to use the distribution of chemical substances in the brain to
construct a comprehensive map of the rat brain. This work is the only Australian publication ranked amongst
the 50 most cited items in the history of science. They wish to apply similar techniques to study the least
understood part of the human brain, the cortex. The research proposed herein will not examine human tissue
from individuals who suffered from depression, anxiety, schizophrenia, Alzheimer's disease, or Parkinson's
disease. However, the outcomes of the proposed research will be of assistance to virtually everyone who
studies the relation between these diseases and the brain.
Research achievements (from final report):
The present project has been designed to address a major problem facing investigators studying the cortical
bases of emotion and cognition, including cortical dysfunction in neurologic and psychiatric disease: the lack
of an accurate map of the human cortex., , We have made progress in imaging, sectioning and staining human
brains, which were obtained at the Montreal Neurological Institute (MNI). Our Canadian collaborator Michael
Petrides, has imaged 3 brains with excellent results. One of those brains is being sectioned by a professional
histology laboratory (Neuroscience Associates). , , In collaboration with Japan and Canada, we have nearly
completed an atlas of the marmoset brain. The marmoset cortex is virtually smooth allowing us to study its
anatomy better, and we are now extrapolating to human. The marmoset is being used as a model of ageing,
including diseases such as Alzheimer's Disease. , , We published the Second and Third Editions of The Rhesus
Monkey Brain in Stereotaxic Coordinates including a 3D reconstruction of the whole brain in BrainNavigator.
In these works we identified virtually all areas that exist in the human cortex and many more regions that we
have not yet identified in the human cortex. The rhesus monkey is also used as a model of brain illnesses
including Parkinson's Disease. We have also done the first primate brain ontology - logical relation of
structures., , We also published a third edition of Atlas of the Human Brain in where the lobar anatomy of the
cortex is displayed in all three cardinal planes.
Expected future outcomes:
The maps we have made, or are completing, of the cortex of the rhesus monkey, marmoset and human will be
of value to those who study the brain in relation to neurologic and psychiatric disorders including
schizophrenia and Alzeimer's disease.
Name of contact:
George Paxinos
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
g.paxinos@powmri.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510106
Start Year: 2008
CIA Name: A/Pr Olivier Piguet
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $507,636
Title of research award:
Clinical and biological markers of disease presentation and progression in early frontotemporal
dementiaClinical and biological markers of disease presentation and progression in early frontotemporal
dementia
Lay Description (from application):
Frontotemporal dementia accounts for 12-20% of all dementia cases and is as common as Alzheimer's disease
in the < 65 year olds. Our understanding of this disease remains limited. This project aims to better characterise
the range and progression of deficits in early frontotemporal dementia using tests of brain function and
magnetic resonance imaging. This will assist in better diagnosis of these patients and, ultimately, may be used
to monitor the outcomes of therapeutic interventions.
Research achievements (from final report):
This project investigated early clinical changes in two dementia syndromes (frontotemporal dementia and
Alzheimer's disease). It focused on autobiographical memory, a type of memory that is central to our sense of
self, understanding of emotion and on carer burden. Investigations established the presence of different patterns
of deficits in these domains across dementia syndromes. , First, findings showed that different aspects of
autobiographical memory are affected in frontotemporal dementia and in Alzheimer's disease and the severity
of the deficit also varies depending on the age of the memories. , With regard to emotion processing, this study
showed that all subtypes of frontotemporal dementia experience changes in the ability to understand and
process emotional information. However, the type of deficits varies across subtypes. We also showed that in
two subtypes, these deficits could be compensated by making the emotions more salient. , With regard to carer
burden, this project demonstrated that burden of care tends to be highest in carers looking after frontotemporal
dementia patients who show behavioural changes compared to patients diagnosed with other subtypes of
frontotemporal dementia or with Alzheimer's disease. , Another aspect of this project was to establish the
regional brain atrophy underlying these clinical features. , These findings are contributing to the understanding
of early clinical changes in frontotemporal dementia and will help inform our knowledge about disease
presentations and progression of these dementia syndromes.
Expected future outcomes:
Findings arising from this project will contribute to the improved clinical diagnosis of frontotemporal
dementia, which is commonly misdiagnosed currently. These findings will also result in clinicians being able
to provide patients and their families more accurate information about what the disease means and its possible
progression over time.
Name of contact:
Olivier Piguet
Email/Phone no. of contact:
o.piguet@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510124
Start Year: 2008
CIA Name: A/Pr Julian Trollor
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: NHMRC Strategic Awards
Main RFCD: Neurosciences not elsewhere classified
Total funding: $945,987
Title of research award:
The role of metabolic and inflammatory factors in cognitive decline and cerebrovascular pathology in the
elderlyThe role of metabolic and inflammatory factors in cognitive decline and cerebrovascular pathology in
the elderly
Lay Description (from application):
Metabolic factors and measures of inflammation in the body have recently been shown to influence mental
function and increase the risk of developing age-related disorders such as Alzheimer’s disease. The influence
metabolic factors and inflammation have on function of the ageing brain is likely to be determined by complex
interplay between many factors, such as physical health, lifestyle, nutrition and our genes. By studying these
factors and how they relate to one another in large groups of elderly individuals, we will be able to determine
the role these factors play in brain ageing. In addition we will be able to determine an ‘at risk’ profile for
elderly individuals for accelerated ageing effects. Identification of this profile is important as it will allow the
development of interventions which may prevent or delay the onset of cognitive decline in late life. We plan to
study the impact of metabolic and inflammatory factors on brain ageing and in two groups of elderly
individuals both of which are currently being studied in detail by our research team. By using these existing
groups we will minimize the costs associated with our research, but maximize the research benefit and the
benefit to society. Our groups include a large community sample of elderly individuals aged 70-90 years and a
large group of elderly twins aged over 65 years. Our use of twins for the study is particularly important as it
will help us separate genetic and environmental influences on the measures. We will measure multiple
metabolic and inflammatory factors in the body and determine their relationship to detailed tests of cognitive
function and to cerebrovascular pathology on brain magnetic resonance imaging. We will look at how these
factors relate to one another and which factors are most strongly associated with accelerated ageing. We will be
able to follow subjects in each group over a 2 year interval to see which factors most strongly predict change in
cognitive function and cerebrovascular pathology over time. Our research is unique in its inclusion of multiple
factors which may affect brain ageing, its ability to look in detail at the contribution of genetic influences on
metabolic and inflammatory factors, and in our planned follow-up of these individuals.
Research achievements (from final report):
Using a representative sample of elderly individuals, we have looked at risk factors for poorer thinking skills
and decline of thinking skills over time. We examined used this information to build a better understanding of
why some people are more likely to develop problems with their thinking skills as they age. We looked in
detail at the role of cardiovascular, inflammatory and metabolic factor risk factors in brain ageing, mild
cognitive impairment and dementia. We also looked at a new link- the relationship between a blood marker
(previuosly linked to increased risk of death) called MIC1. We showed it had a relationship with thiking skills
and the development of mild cognitive impairment in late life. Information from our study will help in
designing lifestyle interventions to reduce risk of decline in thinking skills with age.
Expected future outcomes:
We are able to examine the long term impact of the risk factors by carrying out follow up assessments in our
two cohorts, the Sydney and Memory and Aging Study and the Older Australian Twin Study.
Name of contact:
Associate Professor Julian Trollor
Email/Phone no. of contact:
j.trollor@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510148
CIA Name: Prof Brett Garner
Admin Inst: University of New South Wales
Main RFCD: Cellular Nervous System
Total funding: $557,583
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Role of ABCA-G transporters in neuronal cholesterol regulation and Alzheimers diseaseRole of ABCA-G
transporters in neuronal cholesterol regulation and Alzheimers disease
Lay Description (from application):
Alzheimer's disease (AD) prevalence is rising and the contributing factors are poorly understood. Recent
research shows that cholesterol regulates the production of neurotoxic amyloid-beta peptide (Abeta). We will
study a class of proteins, ABC transporters, that we believe regulate neuronal cholesterol and Abeta
metabolism. We will use isolated brain cells, human brain tissue and genetically engineered mice in order to
define how cholesterol influences AD and identify new treatment options.
Research achievements (from final report):
We proposed that members of a family of proteins (ABC transporters) may control the movement of lipids like
cholesterol out of neurons and that this may regulate the production of a toxic peptide (amyloid-β peptide or
simply "Aβ") that is known to contribute to Alzheimer's disease (AD) progression. We discovered that one
such protein, ABCA7, stimulates neuronal cholesterol efflux, inhibits Aβ production and modulates
intracellular APP trafficking (APP gives rise to Aβ). We described the impact that wild type and loss of
function mutant ABC transporters have on membrane lipid composition and APP processing. We discovered
that genetic deletion of Abca7 in mice results in significant problems in cognitive testing. Another major
finding was an increased level of ABCA1 in AD and (APP mouse) brain tissue. Our detailed analysis of human
AD tissue also revealed two unexpected findings: cholesterol transport protein NPC1 induction in AD and
dimerisation of cholesterol transporter apoE in the human brain. We discovered that a mondified form of
cholesterol found in the brain (27OHC) induces ABCA1 and ABCG1 expression and that this potently reduces
the production of Aβ. Recent major genetics screening (GWAS) studies have confirmed that ABCA7 mutations
are associated with AD risk. Thus our research has important implications for understanding the role of ABC
transporters in AD.
Expected future outcomes:
Another two papers dealing with the Abca7KO mouse behavioural phenotype are in preparation.
Name of contact:
Prof Brett Garner
Email/Phone no. of contact:
brettg@uow.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510175
CIA Name: A/Pr Wei Wen
Admin Inst: University of New South Wales
Main RFCD: Psychiatry
Total funding: $583,601
Start Year: 2008
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Early detection of MCI and dementia using multidimensional analysis of structural MRI by computational
methodsEarly detection of MCI and dementia using multidimensional analysis of structural MRI by
computational methods
Lay Description (from application):
Dementia in elderly is a major public health problem, and mild cognitive impairment (MCI), is even more
common. We propose to use recent computational anatomy algorithms from our group to develop novel
multidimensional imaging biomarkers for early detection of brain anatomical changes due to MCI-dementia.
We aim at identifying early signatures of MCI-dementia, thus making early treatment possible. The completion
of our research will provide clinicians with new methods for the early diagnosis.
Research achievements (from final report):
There were 6 specific aims proposed in our original application and we have achieved all of them. We
proposed to examine white matter hyperintensities (WMHs), cortical mantle thickness, hippocampal and
thalamic volume and shape, and longitudinal changes of these measures in relation to cognition, clinical risk
factors and normal ageing. We have made over 55 journal publications so far (peer-reviewed, over 85% of
them appeared in the journals with ranking of A or A+, such as Journal of Neuroscience, Neurology,
NeuroImage etc. ). We have also presented our findings in both oral and/or poster at some international
meetings such as Human Brain Mapping etc. (over 30 conference presentations and/or posters). Using this
money, we supported 2 PhD candidates for their full candidatures (3 years each) who were consequently
employed for 18 months as post-doc fellows after their graduation (Oct. 2011 respectively). Our study has
attracted collaboration both domestically and internationally. We jointly supervised 2 PhD candidates, one
from Newcastle University and the other UTS. Both of them were based at our lab (NeuroImaging Lab - NiL,
Centre for Healthy Brain Ageing, UNSW Medicine) for their full candidature of 3 years and the PhD student
from UTS stayed on for a full year as a post-doc fellow, who has just completed his 12 months fellowship and
returned to China to take an academic position in a top university in Beijing.
Expected future outcomes:
Brain grey matter was our focus for the 1st 3 years (our project was extended to finish end of March, 2013) of
our project and we turned our attention to white matter using DTI and we have published 5 journal papers.
there are another 3-5 papers in the pipeline.
Name of contact:
Wei Wen
Email/Phone no. of contact:
w.wen@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510184
Start Year: 2008
CIA Name: A/Pr Olivier Piguet
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: Career Development Fellowships
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology)
Total funding: $380,559
Title of research award:
Early identification of degenerative dementia syndromesEarly identification of degenerative dementia
syndromes
Lay Description (from application):
With the continuing ageing of the population, an increasing number of adults will experience signs of
dementia. Knowledge of the clinical presentation, disease mechanisms and evolution of frontotemporal
dementia, a syndrome as common as Alzheimer’s disease in the < 65 year-old group, remains suboptimal. This
research project will combine clinical investigations and brain imaging to improve diagnostic accuracy of this
disease. This will lead to better treatment and management interventions.
Research achievements (from final report):
This fellowship supported my research programme into clinical markers of early frontotemporal dementia and
other young-onset dementia syndromes. It has led to significant research findings on frontotemporal dementia
and related conditions in four distincts research areas: (i) autobiographical memory, (ii) emotion processing,
(iii) structural and functional brain integrity (iv) neuropathological correlations. This research programme has
resulted in a number of peer-reviewed publications in high impact journals and contributions to international
and national scientific meetings. A number of publications arising from this research have received wide media
coverage in Australia and overseas. , More broadly, this fellowship has helped develop my independence as a
researcher and has allowed me to establish my research lab, which now consists of 2 RAs, 3 PhD students and
1 postdoctoral fellow. Over the life of my fellowship, I have received over $3 million dollars in research
funding. I have developed national and international collaborations, including a chief investigator on the ARC
Centre of Excellence in Cognition and its Disorders, which was awarded $21 million dollars (2011-2017). I
have attracted undergraduate, postgraduate and postdoctoral students, further demonstrating my leadership
skills in research. , This fellowship has resulted in the successful award of a CDF level 2 in 2012.
Expected future outcomes:
This research programme will contribute to our understanding of frontotemporal dementia and related
conditions. It will result in improved diagnosis and prediction of disease progression. It will also contribute to
models of cognition (e.g., memory) and emotion processing and will help inform clinicians, patients and their
families about these conditions.
Name of contact:
Olivier Piguet
Email/Phone no. of contact:
o.piguet@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510217
CIA Name: Dr John Kwok
Admin Inst: University of New South Wales
Main RFCD: Neurogenetics
Total funding: $480,212
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Biological Characterisation of the Opiod Receptor Sigma 1 Gene in the Frontotemporal Dementia and Motor
Neuron DiseaseBiological Characterisation of the Opiod Receptor Sigma 1 Gene in the Frontotemporal
Dementia and Motor Neuron Disease
Lay Description (from application):
Frontotemporal dementia (FTD) and motor neuron disease (MND) are the two common causes of dementia and
neurodegeneration. We have identified a new genes that causes familial FTD and MND in pedigrees affected
with dementia and/or MND.This project will study the expression and function of this new FTD/MND gene to
determine its role in the aetiology and pathology of this complex of neurodegenerative disorders.
Research achievements (from final report):
1)
Publication of our major finding in a
high ranking journal for the identifcation of SIGMAR1 as a causative gene for frontotemporal dementia-motor
neuron disease in a large Australian family., 2)
Identification of novel SIGMAR1
mutations in other neurodegenerative diseases such as corticobasal degeneration., 3)
The
identification of a potent and clinically relevant candidate Sigma-1 inhibitor with potential as a low toxicity
therapeutic agent for frontotemporal dementia-motor neuron disease.
Expected future outcomes:
The preliminary and published data from this project have allowed us to successfully apply for two further
NHMRC Grants (630428 and APP1005769) to investigate the role of the SIGMAR1 gene in human
populations and in animal models.
Name of contact:
John Bj Kwok
Email/Phone no. of contact:
j.kwok@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510218
CIA Name: Dr John Kwok
Admin Inst: University of New South Wales
Main RFCD: Neurogenetics
Total funding: $583,810
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
The Leucine Rich Repeat Kinase 1 and 2 Genes are Modulators of Alternative Splicing - Implication for
NeurodegenerationThe Leucine Rich Repeat Kinase 1 and 2 Genes are Modulators of Alternative Splicing Implication for Neurodegeneration
Lay Description (from application):
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two common causes of dementia and
neurodegeneration. Through positional cloning, we have identified the leucine rich repeat kinase (LRRK1) 1
gene as a modulator of alternative splicing. We have subsequently shown that its homologue, LRRK2 has a
similar biological activity. We propose to study the the genetic and biochemical role of LRRK1 and LRRK2 in
neurodegeneration in terms of its effect in splicing.
Research achievements (from final report):
Mutations in the LRRK2 gene are the most common cause of familial forms of Parkinson's disease (PD),
although the pathogenic mechanisms remain to be elucidated. We have identified a potential novel mechanism
for LRRK2 in affecting alternative splicing of key neurodegenerative genes.
Expected future outcomes:
N/A
Name of contact:
John Kwok
Email/Phone no. of contact:
j.kwok@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510307
Start Year: 2008
CIA Name: Dr Victor Vickland
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $400,108
Title of research award:
A computer model of service delivery for behavioural and psychological symptoms of dementia: a tool for
policy makers anA computer model of service delivery for behavioural and psychological symptoms of
dementia: a tool for policy makers an
Lay Description (from application):
Behavioural and psychological symptoms of dementia (BPSD) affect approximate 90% of persons with
dementia. BPSD include depression, aggression and psychosis and have negative effects on persons with
dementia and carers. Management of BPSD is costly. This project will update and enhance our theoretical
model of service delivery for BPSD by turning it into a computer-based model to assist health managers and
policy makers. This model will incorporate the projected increase in prevalence of dementia and project
associated costs of care into the future. It will also incorporate information about interventions for BPSD, and
how they may affect prevalence and cost in the future.
Research achievements (from final report):
This project was conducted in three stages (1) Review the scope and level of detail of the model to match its
proposed use, and select published data to calibrate the model (2) Build the computer model of dementia
management which is based on seven-tiered model of service delivery and calibrate the model using new data
on the prevalence and projections of dementia in Australia, associated care costs, and the effectiveness of
interventions, and (3) Test the model with groups of clinicians and health managers and evaluate the ability of
a model to help policy makers better understand the complexities involved in the field of dementia, and in
particular when BPSD are to be managed in a cost effective way.
Expected future outcomes:
The expected benefits are primarily focused on improvements in decisions made by policy makers and
clinicians.
Name of contact:
Dr Victor Vickland
Email/Phone no. of contact:
victor.vickland@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510308
Start Year: 2008
CIA Name: Dr Lee-Fay Low
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $228,473
Title of research award:
Dementia literacy in Greek, Italian and Chinese AustraliansDementia literacy in Greek, Italian and Chinese
Australians
Lay Description (from application):
The dementia knowledge and beliefs of persons from Italian, Greek and Chinese backgrounds will be
compared to third generation Australians. Five hundred persons from each group will be randomly selected
from around Australia to be surveyed by telephone. Questions will assess whether dementia symptoms are
recognised, what these persons think causes dementia, where they would go for help, how likely they are to use
aged care services and stigma towards persons with dementia. Focus groups will be conducted to identify
barriers to service use and identify methods to improve dementia knowledge in Italian, Greek and Chinese
groups. This information will be used to improve community education and service delivery for persons with
dementia from culturally and linguistically diverse backgrounds. The Primary Dementia Collaborative
Research Centre at the University of NSW, NSW Multicultural Health Communication Service and
Alzheimer’s Australia are partners in this research.
Research achievements (from final report):
This study highlighted the similarities and differences on dementia literacy (ie dementia knowledge and
beliefs) between Italian, Greek and Chinese Australians and Australians not from a culturally and linguisticaly
diverse (CALD) background. This information is being used by Alzheimer's Australia's Dementia Crosscultural network to lobby for more education and outreach to persons from CALD backgrounds. The findings
have also been used to develop a social marketing and peer education campaign to increase dementia literacy in
persons from CALD backgrounds, and an application for funding for this campaign has been made. , More
generally the study has added to the growing recognition of the need to cater for persons with dementia from
CALD backgrounds.
Expected future outcomes:
Improved dementia knowledge and beliefs in persons from CALD backgrounds.
Name of contact:
Lee-Fay Low
Email/Phone no. of contact:
lf.low@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510316
Start Year: 2008
CIA Name: Prof Gavin Andrews
End Year: 2010
Admin Inst: University of New South Wales
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $138,085
Title of research award:
Confirming the burden of disease associated with dementia using new empirically driven Australian based
disability ratiConfirming the burden of disease associated with dementia using new empirically driven
Australian based disability rati
Lay Description (from application):
The amount of burden the population experiences as a result of individual diseases influences health policy.
The Australian Burden of Disease project quantifies the relative burden associated with each disease. New
estimates are to be released this year will outline the magnitude of burden associated with dementia now and
estimate that for the year 2023. Although the projections use the best data available, three improvements to the
methodology would improve the accuracy of the dementia burden estimates. First, the dementia calculations
currently use a “disability weight” metric derived from a Dutch study. This is problematic in that the weights
do not reflect an Australian experience of dementia, nor do they reflect the preferences of people closely
affected by the disease (e.g. carers). Second, the dementia estimates do not include cases of mild cognitive
impairment (considered a precursor state of dementia). Hence the dementia estimates may not estimate the full
impact of dementia in Australia. Finally, there is no evidence that the method used by the Burden of Disease
study to account for the impact of disease comorbidity adequately deals with the comorbidity associated with
dementia. Consequently, there is need to develop a new and comprehensive set of disability weights for
dementia that are Australian-based, include all stages of dementia severity and account for comorbidity. The
proposed project aims to develop a new set of empirically derived Australian-based disability weights for
dementia. The project will entail three studies. The first study will generate empirically based case vignettes
that describe a range of dementia case scenarios. These descriptions will then be used in rating exercises (Study
2) to develop new disability weights. The second study involves Australian health practitioners, carers and lay
persons reading case vignettes and completing health valuation rating exercises to generate new disability
weights for dementia. The third study uses the new disability weights to re-calculate the burden of disease
estimates for dementia. The new estimates will be compared to those reported by the 2007 Australian Burden
of Disease project. In knowing the accuracy of the estimates, policy makers can use the burden data for
dementia with confidence when engaging in service planning for the future.
Research achievements (from final report):
This study conducted a re-analysis of the published 2003 Australian Burden of Disease estimates for dementia.
The existing data relied on Dutch disability ratings made by doctors to inform the calculations. The current
study aimed to assess the impact of possible cultural and educational differences in disability ratings by
generating disability data (used in the burden calculations) from Australian participants about the Australian
experience of dementia using the opinions of carers and lay-persons as well as health professionals. "Mild
Cognitive Impairment" will be included as a "prodromal phase or minor form" of dementia in upcoming
revisions to DSM so our study also sought to explore the impact of including it in the dementia burden of
disease estimates. , Our results showed that there was large agreement in ratings between the carers, lay
persons and health professionals and the Australian and Dutch disability ratings were relatively similar. Our
recalculation of the burden of dementia using the new Australian-based ratings therefore did not differ greatly
from the original published national estimates but adding MCI increased the national dementia burden by a
further 45,159 Disability Adjusted Life Years (DALYs). The results of the study suggest that policy-makers
can use existing published estimates knowing that the Dutch disability data used in the calculations is not
largely discordant with Australian views, at least for dementia, but because MCI is soon to be included in the
"dementia-spectrum" the overall DALYs will need to be corrected for policy-makers planning streamlined
neuropsychiatric services.
Expected future outcomes:
NHMRC Research Achievements - SUMMARY
In the future we plan to drill down further into the data to make more refined calculations and estimates,
probably looking dementia and MCI sub-types and focusing on age and gender. As DSM-V re-categorizes and
creates new diseases our methodology could be applied to new areas.
Name of contact:
Gavin Andrews
Email/Phone no. of contact:
gavina@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510347
CIA Name: Prof Robert Cumming
Admin Inst: University of New South Wales
Main RFCD: Indigenous Health
Total funding: $1,571,528
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
What is the burden of dementia in urban dwelling Indigenous Australians?What is the burden of dementia in
urban dwelling Indigenous Australians?
Lay Description (from application):
The main aim of this research project is to determine what proportion of Aboriginal people aged 45 years and
older who live in urban areas of NSW, have dementia. We hope to establish what types of dementia occur
amongst Aboriginal people, what the causes are, and how we can best measure dementia. We will also focus on
what types of problems dementia causes for both people with the condition and their carers. What is the
meaning of dementia for Aboriginal people themselves?
Research achievements (from final report):
The number of older Aboriginal Australians is increasing rapidly, yet little is known about their health and
dementia rates. Our preliminary results from data collected on 336 participants indicate that dementia
prevalence is substantially higher in majority urban Aboriginal Australians compared to the general Australian
population. Dementia prevalence was 13.4%, when age-adjusted the rate is 21% or three times the general
Australian rate of 6.8%, with Alzheimer's disease most common (56% cases), then vascular dementia (23%)
and dementia due to head trauma (12%). Alcohol related dementia was uncommon. The prevalence of mild
cognitive impairment was also high. These preliminary results confirm the results of the KICA study in remote
Aboriginal communities. Importantly, the vast majority of older Aboriginal Australians do not have dementia.
Aboriginal people in urban areas have a disproportionately high burden of many of the risk factors across the
lifespan and systemic diseases that have been linked to dementia in other studies. Key potential associations of
dementia are being explored; including early life factors such as family separation, education, parenting,
childhood trauma and mid-life factors like job opportunities, discrimination, resilience, stroke, diabetes, head
injury, alcohol, and smoking. Improved understanding of these issues has important implications for ensuring
access to appropriate services for Aboriginal people with dementia and their families and for future service
development. We are addressing the immediate need for provision of dementia education and services through
the Koori Dementia Care Project and by assisting with the coordination of visiting aged health care services, to
be delivered by geriatricians from Prince of Wales Hospital (funded through NSW Health Connecting Care).
Our KGOWS MRI pilot study is ongoing & focuses on the effects of early life experiences on the brain in older
Aboriginal people.
Expected future outcomes:
Future plans are to submit a NHMRC Project Grant application in 2014 for a KGOWS follow up study. We are
planning a 'Healthy Aboriginal Brain Ageing Project' for successful ageing in older Aboriginal people and hope
to use KGOWS data to engage with younger Aboriginal people & the non-Indigenous community in
developing educational & employment opportunities.
Name of contact:
Prof Tony Broe
Email/Phone no. of contact:
t.broe@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568746
Start Year: 2009
CIA Name: Dr Lucette Cysique
End Year: 2011
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Biological Psychology (Neuropsychology, Psychopharmacology, Physiological **Psychology)
Total funding: $364,993
Title of research award:
Understanding cognitive decline in aging individuals with chronic HIV infection: A longitudinal
crossdisciplinary studyUnderstanding cognitive decline in aging individuals with chronic HIV infection: A
longitudinal crossdisciplinary study
Lay Description (from application):
People with HIV infection treated with combined antiretroviral drugs are living longer. Some persons are
reaching an age where Alzheimer's Disease (AD) starts to become significant. In addition, emerging results
show an increasing link between brain pathology in HIV and in AD. Using a cross-disciplinary approach, our
study is designed to understand if HIV infection predisposes to AD.
Research achievements (from final report):
Achievements: 1). A study that uniquely documents the prevalence of HIV-associated neurocognitive disorders
(HAND) in Australian aging HIV+ individuals (Lane, Batchelor, Brew, Cysique Neuropsychology, in press;
23% have HAND despite optimal medical management). 2). 1st study to demonstrate independent effects of
cardio-vascular diseases (CVD) related brain injury and premature brain aging in virally-suppressed HIV+
individuals ( Conference for Retroviruses and Opportunistic Infections ,2012 as panel speaker, manuscript
submitted to Plos One). 3) Data enrichment across basic and clinical sciences (Maher, Cysique et al., J
Proteome Res 2011). 4). Pilot amyloid PET study showed that 1/10 participants had high amyloid brain burden.
This indicates that abnormal brain amyloid emergence, as a characteristic of neurodegeneration, is likely to
require longer follow-up and has to be linked to CVD injury. 5). HIV+ genetic data show that APOE allele 2
carriers have better cognitive status (manuscript in preparation). This effect also exists in non-HIV population.
This signifies that our cohort is composed of long-term HIV+ survivors, and yet that we can detect premature
brain aging. 6) Preliminary analyses of CSF data shows abnormal neurodegenerative markers in chronic HIV+
individuals (manuscript in preparation). Significance: Our work shows that HAND neuropathological profile is
evolving, that older HIV+ persons are at greater risk of brain damage and that we can define early cognitive
and brain signatures of these risks based on a multi-disciplinary approach. Our study has relevance for millions
who are aging with HIV infection, in particular, Australian HIV population that is rapidly aging.
Expected future outcomes:
We intend to conduct further investigations on the causes of premature brain aging in chronic HIV+ individuals
in particular the role of early cardio-vascular diseases related brain injury. This can have relevance beyond the
field of NeuroHIV research. We expect that with the completion of the crossssectional longitudinal analyses,
we will publish another 5 papers.
Name of contact:
Lucette Cysique
Email/Phone no. of contact:
lcysique@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568787
CIA Name: Prof Henry Brodaty
Admin Inst: University of New South Wales
Main RFCD: Residential Client Care
Total funding: $852,238
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE): An RCT of humour therapy in
residential careSydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE): An RCT of
humour therapy in residential care
Lay Description (from application):
Sydney Multisite Intervention of LaughterBosses and ElderClowns (SMILE) is a trial of humour therapy.
About 400 residents from 36 hostels and nursing homes will be randomly assigned to receive the SMILE
treatment or usual care. ElderClowns will visit weekly, and staff volunteers will be trained to be
LaughterBosses and bring humour to daily care routines. SMILE will evaluate whether humour therapy
improves resident quality-of-life and mood, and reduces staff burnout and turnover.
Research achievements (from final report):
The SMILE study administered humour therapy to 17 nursing homes (189 residents) and followed 18 usual
care homes (209 residents). Groups did not differ significantly over time on the primary outcome of depression,
or on behavioural disturbances other than agitation, social engagement and quality of life. The secondary
outcome of agitation was significantly reduced in the intervention group compared with controls over 26
weeks. The SMILE study was featured in a documentary showed on ABC Compass in 2012, and the
intervention is being implemented as Play Up, a program run by the not-for-profit organisation the Arts Health
Instiute. At time of writing over 65 nursing homes from around Australia including in rural and remote
Australia are receiving the Play Up program.
Expected future outcomes:
The number of nursing homes receiving humour therapy in Australia is expected to increase.
Name of contact:
Dr Lee-Fay Low
Email/Phone no. of contact:
lf.low@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630428
CIA Name: Dr Carol Dobson-Stone
Admin Inst: University of New South Wales
Main RFCD: Neurogenetics
Total funding: $535,471
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Investigation of dysfunction of OPRS1, a novel gene implicated in neurodegenerationInvestigation of
dysfunction of OPRS1, a novel gene implicated in neurodegeneration
Lay Description (from application):
A new gene has recently been discovered to play an important role in various brain and nerve degeneration
disorders, including frontotemporal dementia and motor neuron disease. The aim of this project is to discover
what biological processes are involved when this gene malfunctions, as this will provide knowledge important
for development of new treatments for the many people worldwide affected with these disorders.
Research achievements (from final report):
This project has identified rare and common DNA variants in the SIGMAR1 gene that may influence whether
someone develops diseases such as frontotemporal dementia, Alzheimer's disease and motor neuron disease.
SIGMAR1 is therefore a good target for designing future therapies to protect against the death of brain and
nerve cells in these diseases. We have also determined which symptoms help to distinguish dementia patients
with a mutation in another gene, C9ORF72, from patients that do not have C9ORF72 mutations and identified
what types of C9ORF72 mutations will lead to disease. Lastly, we have identified a region on chromosome 16
that is responsible for disease in a large family with frontotemporal dementia and motor neuron disease.
Expected future outcomes:
Our currently funded NHMRC Project Grant 1062539 aims to identify which gene is located in the
chromosome 16 region and whether other similar genes are also involved in the development of dementia.
Name of contact:
Carol Dobson-Stone
Email/Phone no. of contact:
c.dobson-stone@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630489
Start Year: 2010
CIA Name: Prof John Hodges
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $528,245
Title of research award:
Progressive aphasia and amyloid deposition: a multidisciplinary approach to improving dementia
diagnosisProgressive aphasia and amyloid deposition: a multidisciplinary approach to improving dementia
diagnosis
Lay Description (from application):
We aim to understand the role of amyloid deposition in the genesis of symptoms in Alzheimer's disease.
Patients presenting with progressive deterioration of language (aphasia) some of whom are known to have
Alzheimer's disease will be studied using brain imaging techniques, including a PET method (PiB) that labels
amyloid in vivo, and to compare imaging changes with a range of language assessments. This will improve the
early diagnosis and management of patients with progressive aphasia.
Research achievements (from final report):
The aim of the project was to identify patients with Alzheimer;s presenting atypically with progressive aphasia
and to shed light on the neural mechanisms of brain injury in such patients We developed a standardised
battery for the evaluation of patients with progressive aphasia (PALS), and published a major paper that
validated the recently proposed International Consensus Criteria for Progressive aphasia substantiating the
syndrome of progressive logopenic aphasia. We showed that the two key defecits in such cases, impaired
naming and span, result from damage to separate brain regions and clarified predictors of Alzheimer pathology
in those with language presentations and/or apraxia.
Expected future outcomes:
Ongoing analysis are directed at undetsanding the relationship of neural loss and reduced function of brain
regions in Alzheimer's disease.
Name of contact:
John Hodges
Email/Phone no. of contact:
j.hodges@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630587
Start Year: 2010
CIA Name: Prof Leonard Kritharides
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Cardiology (incl. Cardiovascular Diseases)
Total funding: $485,000
Title of research award:
Biochemistry and functional significance of glycosylation of apolipoprotein EBiochemistry and functional
significance of glycosylation of apolipoprotein E
Lay Description (from application):
Apolipoprotein E (apoE) is an important molecule which affects our risk of atherosclerosis- coronary disease
and of Alzheimer's disease. We know that apoE's functions are very much affected by its structure. One aspect
of tis structure which has been neglected is the attachment of sugar molecules . These are very likely to
regulate how apoE interacts with other molecules, with cells, and is metabolised in the body and will be
investigated in this project.
Research achievements (from final report):
As a result of this project we identified two novel O-linked glycosylation sites on the C-terminus of apoE. We
further identified that the relative abundance of C-terminal and Threonine 194 glycosylation varies between
cell types- in certain cell lines the C-terminal glycosylation is more abundant. This has important implications
for the relevance of glycosylation to apoE stability in different systems.We established two novel methods for
the isolation of unglycosylated apoE based on site-directed mutagenesis and on the use of unique cell lines
which secrete glycosylated or unglycosylated apoE based on nutrient supplementation of culture medium.
These studies have identifed novel regulation of apoE binding attributable to apoE glycosylation. We have
further identifed that glycosylation of apoE serves as a sensitive readout of perturbations of cellular trafficking
systems. We were able as a result of these studies establish that protein kinase C inhibits apo E secretion after
golgi exit because apoE is normally glycosylated, and that cholesterol accumulation redirects apoE transport
inhibiting its secretion and altering its glycoform profile by reducing its glycosylation, thereby implying bypass
of normal golgi transport.
Expected future outcomes:
We will characterise in more detail biological implications of apoE glycosylation and its variants as a result of
these studies.
Name of contact:
Leonard Kritharides
Email/Phone no. of contact:
leonard.kritharides@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1003139
CIA Name: A/Pr Olivier Piguet
Admin Inst: University of New South Wales
Main RFCD: Geriatrics and Gerontology
Total funding: $428,319
Start Year: 2011
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Feeding disturbance and hypothalamus integrity in early frontotemporal dementiaFeeding disturbance and
hypothalamus integrity in early frontotemporal dementia
Lay Description (from application):
Frontotemporal dementia accounts for 12-20% of all dementia cases. It is as common as Alzheimer’s disease in
the < 65 year olds but understanding of this disease remains limited. Marked eating disturbance (overeating,
snatching food) is a common clinical manifestation. This project will characterise this deficit and define its
biological causes using blood tests and magnetic resonance imaging. Results will help in designing therapeutic
interventions targeting this disabling feature.
Research achievements (from final report):
Overall, this research has contributed to the understanding of the pathological mechanisms in frontotemporal
dementia: its clinical manifestations, progression over time and underlying pathological processes. ,
Frontotemporal dementia is clinically diverse with three phenotypes generally recognised. Brain pathology is
also variable involving focal brain atrophy and the abnormal deposition of one (or more) of at least three
different proteins (tau, TDP-43, FUS). Briefly, we have demonstrated that presence of eating disturbance in
dementia patients is a marker of dementia associated with frontotemporal lobar degeneration and appears to be
specific to a certain type of abnormal protein deposition in the brain (TDP-43). Severity of this disturbance has
also been found to be associated with atrophy in posterior hypothalamus nuclei, brain regions central to
metabolic regulations. Changes in food preference appear to be specifit to each phenotype of frontotemporal
dementia, ranging between sweet foods (more common in semantic dementia) and carbohydrate preferences
(more common in the behavioural variant). These changes were also associated with increased overall caloric
consumption and increased body mass index. , In addition, this research has also uncovered metabolic
abnormalities in frontotemporal dementia patients including elevated total cholesterol, triglyceride and fasting
insulin levels, which may affect prognosis. Indeed, insulin resistance has been found to promote
neurodegeneration, although these variables may offer some protective effects in a subgroup of patients,
exhibiting moto neuron disease (a disorder associated with frontotemporal dementia).
Expected future outcomes:
Continuing research in the area is demonstrating the importance of managing eating disturbance in patients
diagnosed with dementia; with evidence that monitoring food intake can have an impact on disease progression
and the development of comorbidities.
Name of contact:
Olivier Piguet
Email/Phone no. of contact:
o.piguet@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005769
Start Year: 2011
CIA Name: A/Pr John Kwok
End Year: 2013
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $492,119
Title of research award:
Investigation of dysfunction of SIGMAR1 in transgenic mouse models, a novel gene implicated in
neurodegenerationInvestigation of dysfunction of SIGMAR1 in transgenic mouse models, a novel gene
implicated in neurodegeneration
Lay Description (from application):
At present, there are no effective therapies for frontotemporal dementia or motor neuron disease. We have
identified the SIGMAR1 gene as having a crucial role for these diseases. More importantly, there are
therapeutically relevant small molecule drugs that are known to modulate the activity of this gene. We aim to
determine the efficacy of pharmacological modulation of Sigma-1 receptor activity in mouse models of
dementia.
Research achievements (from final report):
From our cell culture experiments, we have identified at least two compounds (progesterone and fluvoxamine)
which impact on the SIGMAR1 mediated effects on the disease-associated molecules involved in
frontotemporal dementias and Alzheimer's disease. These compounds are notable in that they are already in
current therapeutic use, which will allow immediate translation into clinical practice., The first compound,
progesterone, have already been examined in a genetic model of frontotemporal dementia, and we
demonstarted that it was effective at slowing down the progression of the disease., We were also able to
demonstrate in human frontotemporal dementia patients that their porgestreone levels were significantly lower
than unaffected individuals.
Expected future outcomes:
Our data provide strong preliminary evidence that progesterone may be efficacious in slowing down the
progression of frontotemporal dementia patients. Future outcomes may include a pilot clinical trial to
demonstrate the effect of progesterone on disease progression., The examination of our other compound,
fluvoxamine, is nearing completion and we expect to have a definitive answer on its efficacy.
Name of contact:
John B Kwok
Email/Phone no. of contact:
j.kwok@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1008307
Start Year: 2011
CIA Name: Prof Glenda Halliday
End Year: 2013
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $524,820
Title of research award:
Cellular effects of glucocerebrosidase (GBA) mutations in Lewy body diseasesCellular effects of
glucocerebrosidase (GBA) mutations in Lewy body diseases
Lay Description (from application):
Approximately 1 in 100 people are carriers of mutations in the glucocerebrosidase (GBA) gene and are at
considerably greater risk of diseases characterised clinically by parkinsonism and by the presence of Lewy
body-related pathology. This study will provide tissue-based evidence of the cellular lipid and protein changes
relating to Lewy body formation in patients with GBA mutations, providing the information necessary to
identify the pathways and mechanisms involved.
Research achievements (from final report):
Lewy body diseases are as common as Alzheimer's disease. We have confirmed that GBA1 mutations are the
most prevalent risk gene associated with Parkinson's disease (a Lewy body disease), and also found that such
genetic mutations play a larger role in dementia with Lewy bodies. Genetic variation in apolipoprotein E and
other genes involved in cellular lysosome function are associated with dementia with Lewy bodies. In assessing
changes in the brain using new methods, we have found that GBA1 protein and enzyme activity is reduced in
association with increases in the core protein for Lewy body formation, alpha-synuclein. These changes occur
in concert with decreases in the lipid ceramide and a reduction in chaperone-mediated cellular autophagy. In
patients with GBA1 gene mutations, a reduction in macroautophagy also occurs. This project has identified the
main genetic risk factors associated with Lewy body formation and particularly with dementia with Lewy
bodies, as well as determined critical cellular pathways involved in the formation of the pathological inclusions
in the brain. This knowledge is essential for the future development of mechanistic treatments for Lewy body
diseases.
Expected future outcomes:
Additional cellular pathways (lysosome regulation, RNA degradation, mitochondria) and mechanisms of cell
damage (oxidative stress) are currently being evaluated in the same tissues to establish if and how they may
play a role.
Name of contact:
Glenda Halliday
Email/Phone no. of contact:
g.halliday@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1029538
Start Year: 2012
CIA Name: Prof Glenda Halliday
End Year: 2012
Admin Inst: University of New South Wales
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $184,306
Title of research award:
Blood protein biomarkers for frontotemporal lobar degenerationBlood protein biomarkers for frontotemporal
lobar degeneration
Lay Description (from application):
This project will assess blood proteins as biomarkers for different pathogenic forms of frontotemporal dementia
(FTD), one of the major neurodegenerative dementias with a very rapid disease progression (mean survival 3
years). At present, it is not possible to predict which pathological variant is present in any given patient. We
plan to develop blood protein biomarker assays capable of diagnosing the pathology in vivo.
Research achievements (from final report):
This was the first year of a longitudinal project to assess blood proteins as biomarkers for different pathogenic
forms of frontotemporal dementia (FTD), one of the major neurodegenerative dementias with a very rapid
disease progression (mean survival 3 years).We successfully recruited around 250 FTD patients, 85 patients
with Alzheimer's disease and 35 controls. Around 120 patients have follow-up blood samples and 21 patients
have died of their disease and donated their brain tissue. We have performed a small study assessing
progestertone levels which showed a significant reduction in certain case types.
Expected future outcomes:
The NHMRC has now funded this research through a program grant which will start to assess the blood
proteins for the capacity to predict the underlying neuropathology in 2013.
Name of contact:
Glenda Halliday
Email/Phone no. of contact:
g.halliday@neura.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 252746
CIA Name: Prof David Pow
Admin Inst: University of Newcastle
Main RFCD: Cell Neurochemistry
Total funding: $416,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
The cystine glutamate antiporter and classical glutamate transporters in normal and pathological brains and
retinaeThe cystine glutamate antiporter and classical glutamate transporters in normal and pathological brains
and retinae
Lay Description (from application):
This project will examine the role of a system that transports a toxic neurotransmitter, glutamate out of cells
where it is relatively harmless, into the space surrounding nerve cells where it can be highly toxic. Previous
models for the aberrant release of glutamate under pathological conditions such as strokes, have relied on the
notion that other specialised glutamate transporters which normally work to remove glutamate from the space
surrounding nerve cells, actually reverse their direction of action and release glutamate. The current study
investigates a transport system (called the cystine-glutamate antiporter) where the normal direction of action is
to release glutamate. This system has been overlooked despite evidence that it could be involved in releasing
glutamate and thus contribute to the death of nerve cells in a variety of human pathologies including glaucoma
of the eye, epilepsy, and brain damage that occurs when the blood supply to the brain is interrupted, such as
after a heart attack. This study examines both human tissues and animal models of disease states to determine
if similar transport systems are present and if the cystine-glutamate antiporter might contribute to human
nervous diseases. The function and distribution of the cystine-glutamate antiporter will be compared with
classical transporters, under normal and pathological conditions, including situations where we have shown
that it is possible to experimentally perturb normal glutamate transporter expression.
Research achievements (from final report):
The key aim of this project was to evaluate the distribution of special proteins in the brain called glutamate
transporters, and their roles inregulating or releasing glutamate in response to lack of oxygen in the brain. Our
physiological yielded data showing that glutamate transporters are key determinants as to whether the brain
experiences damage in response to hypoxic insults. Our studies on the hypoxic neonatal pig have shown that
there is an extraordinarilly precise spatial correlation between the loss of expression of glutamate transporters
in the pig brain an the paterns of damage. The first paper in a series from these studies has been published (Pow
et al., 2004) and others are currently submitted. As part of this process of understanding the role of transporters
in glutamate homeostasis we made the significant discovery that a molecule called D-serine which is vitalfor
the toxicactionsof glutamate was localised to synaptic-like vesicles in astrocytes and this has greatly enhanced
our understanding of the glutamate system in hypoxia. Our first paper on this is in press (Williams et al., 2006).
We noted during our studies that nerve cells can also switch on glutamate transporters that they would
otherwise never normally express and we believe this to be a protective mechanism . Our recent work now
shows this to be a common theme in diseases states as diverse as glaucoma in the eye, and brain hypoxia.
Expected future outcomes:
The work has continued to generate new insights into the role of glutamate transporters in brain and retinal
disease and we continue to gain further results in this area.
Name of contact:
David Pow
Email/Phone no. of contact:
david.pow@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 351220
CIA Name: Prof Constance Pond
Admin Inst: University of Newcastle
Main RFCD: Primary Health Care
Total funding: $499,977
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Strategic Awards
Title of research award:
THE DETECTION AND MANAGEMENT OF DEMENTIA IN GENERAL PRACTICE.THE DETECTION
AND MANAGEMENT OF DEMENTIA IN GENERAL PRACTICE.
Lay Description (from application):
This research aims to examine a new method and practice guidelines for detection of early dementia. General
practitioners will be screened on their ability to diagnose and manage dementia and to distinguish it from other
diseases. Patient outcomes - including quality of life, depression, and satisfaction with care and referral
indicators - will be examined.
Research achievements (from final report):
oTarget recruitment was achieved with over 2,000 participants were recruited of whom 1896 completed
baseline measures., *Baseline prevalence of dementia was less than expected at 8.5% (162/1896), resulting in
fewer patients with dementia recruited than intended. We require 123 to remain in the study at 12 months for
sufficient power., The benefit of this result is a revised prevalence of dementia in community dwelling elderly
recruited through general practice, which may benefit future studies., All instruments including GP clinical
judgement had low sensitivity to CAMCOG dementia:, *45.6% identified by GP clinical judgement , o56.0%
identified by GPCOG administered by GP , o48.6% identified by MMSE (23/24 cut point, embedded in
CAMCOG) , o63% of cases were identified by GPCOG administered by study nurse, The benefit of this
finding is to emphasise the importance of well trained nurse administration of screening instruments, and the
limitations of screening for dementia in GP. , Few GPs referred to Alzheimer Australia (6.4%) or ACAT
(7.0%), emphasising the need for service provision in this group., There was considerable comorbidity with
depression as participants with CAMCOG dementia scored significantly higher on the Geriatric Depression
Scale (GDS) compared to other participants (p<0.001, t-test). This emphasises the need for GPs to consider
depression in this group. , GPs are reluctant to diagnose dementia because of negative effects of patients but
participants' quality of life ( WHOQOL-BREF) was not affected by the accuracy of GP clinical judgement
about dementia status and their satisfaction with care provided by their GP was significantly higher for those
that had their dementia status correctly identified (see below results). This emphasises the importance of GPs'
making the diagnosis.,
Compared with the population norm,
carers had significantly lower quality of life (see below results), a finding which reinforces the need for
particular attention by GPs.
Expected future outcomes:
*Data on the effectiveness of the intervention when 12 month data is analysed , *A better method of
identifying dementia than either clinical judgmeent or the brief screening instruments used once only using
modelling , * Evidence for education of GPs about 1. the need to refer for services and to Alzheimers
Australia; 2. The need to break the news of dementia 3. The need to support carers
Name of contact:
Prof Dimity Pond
Email/Phone no. of contact:
dimity.pond@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 510745
Start Year: 2008
CIA Name: Prof Constance Pond
End Year: 2011
Admin Inst: University of Newcastle
Grant Type: NHMRC Strategic Awards
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $826,745
Title of research award:
Outcomes of best practice diagnosis and management of dementia in general practiceOutcomes of best practice
diagnosis and management of dementia in general practice
Lay Description (from application):
The outcome of this study will be new Australian data on what happens to people with dementia under the care
of their GP, followed up for two years. In addition we will test the results for patients and carers of GP
adherence to best practice for diagnosis and management of dementia. This is a 3-state randomised intervention
trial in general practice which aims to add an extra year to an already funded study examining the outcomes for
carers and patients of training GPs with extra skills in dementia screening and management guidelines.
Outcomes for those GPs who adhere to the guidelines will be compared to outcomes for those GPs who do not.
Patient and carer outcomes – include quality of life, depression, satisfaction with care and referral indicators,
and patient pathways of care over the 24 month period will be recorded. In addition the study will examine
barriers and enablers to GP best practice in dementia care.
Research achievements (from final report):
This project achieved targets in involving over 170 GPs and over 2000 of their patients aged 75 years and over.
Intervention GPs underwent a comprehensive education program with two peer visits (the first funded under
NHMRC351220) and provision of the GP Dementia Guidelines. Control GPs were provided with Guidelines
only. Preliminary results show marked improvement in dementia diagnosis and management by intervention vs
control GPs and final statistical analysis is underway. If this finding proves robust statistically, it points the
way to future educational approaches to GPs.Barriers to dementia disclosure have been analysed and a paper
on this accepted. This will also help guide future educational and system change efforts. Performance of the
GPCOG is being analysed at the UNSW site and will guide future use of this instrument. Predictors of correct
diagnosis by GPs are being analysed and will assist with developing decision algorithms for GPs in this area
(for example memory complaints by a patient increase the chance of dementia by 2.5 times). We have yet to
examine the flow on effects of the intervention on patient and carer outcomes and the effects of case finding vs
screening and will do that this year.
Expected future outcomes:
Papers on the effect of the intervention on both GPs diagnosis and management and patient's and carers'
outcomes; on case finding vs screening in dementia in primary care, on the performance of the GPCOG; on the
predictors of diagnosis. We will seek funding to modify the GP Dementia Guidelines. We also have funding
for a nurse practitioner in dementia to build on this work.
Name of contact:
Prof Dimity Pond
Email/Phone no. of contact:
Dimity.Pond @newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 210250
CIA Name: Dr Guy Elston
Admin Inst: University of Queensland
Main RFCD: Central Nervous System
Total funding: $362,820
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Anatomical substrates for primate executive cortical functionAnatomical substrates for primate executive
cortical function
Lay Description (from application):
When studying the brain, many have been tempted to look for similarities in organization of cells and circuitry
in different regions involved in various processes. While, at a first approximation, this may be a reasonable
approach to understand how the brain works, it also ignores what makes the brain so complex: the diversity in
its structure. In the late 19th, and early 20th, centuries, pioneering anatomists seized on the diversity in
structure of the human brain. The study of cortical circuitry that underlies the diversity in cortical processing
reached a zenith and there was a renaissance in understanding of brain function. These researchers were,
however, limited by techniques available to them at the time. With the advent of new methodologies which
allowed scientists to explore individual connections between cells (synapses), to probe structure and
transmission across synapses, and to record from live neurones, new and exciting discoveries were made.
However, these methodologies are highly time consuming and studies became necessarily more focussed. As a
result, there was a tendency in the later half of the 20th century to extrapolate findings from one cortical area to
cortex in general. Even more precarious, anatomical and functional findings in highly specialized sensory
cortex of one species were projected to other distantly related species. Such thinking lead to a "dark age" in
neuroscience. It became widely accepted that there exists a "canonical" circuit. Consequently, differences in
function between different cortical areas were attributed solely to the source of their projections. The central
thesis of this project is to study aspects of cell structure and cortical circuitry in the prefrontal lobe. We hope
that the project will provide another step in the pathway that leads to understanding the mind.
Research achievements (from final report):
The PI has made a significant contribution to the understanding of the microstructure of the cerebral cortex, be
it visual, somatosensory, motor, cingulate or prefrontal. He has published a book, six book chapters and 22 peer
reviewed journal articles related to the objectives outlined in his original proposal over the space of three years.
In addition to contributing to the understanding of cortical organization, he has spearheaded new research into
cortical abnormalities in Down syndrome and is studying the effects on cortical structure of commonly
prescribed antipsychotics used in the treatment of schizophrenia. He has set up labs in 4 countries to be able to
do this, has attracted significant international funding, has been inveited to chair special sessions at
international conferences and has been awarded several international prizes.
Expected future outcomes:
A better understanding of regional specialization in cortical circuitry, both structural and functional, which will
be important when developing stem cell therapies and the treatment of mental illness
Name of contact:
Dr Guy Elston
Email/Phone no. of contact:
G.Elston@vthrc.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301119
CIA Name: Dr Elizabeth Coulson
Admin Inst: University of Queensland
Main RFCD: Cellular Nervous System
Total funding: $238,500
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Proteolytic cleavage of the p75 neurotrophin receptor mediates cell deathProteolytic cleavage of the p75
neurotrophin receptor mediates cell death
Lay Description (from application):
The p75 neutrotophin receptor (p75NTR) is a major inducer of nerve cell death, and is active in a wide range of
neurodegenerative conditions, including Alzheimer's disease, motor neuron disease, multiple sclerosis, stroke
and nerve trauma. This study aims to understand and to characterise the events that regulate this receptor. In
particular, we will investigate the role that cleavage or controlled breakdown of the receptor plays in mediating
its cell death activity. A fundamental aspect of this proposal is determining whether cleavage is due to
presenilin-dependent activity, given that presenilin mutations have been demonstrated in most familial
Alzheimer s disease cases. While this will increase our understanding of one of factors contributing to
Alzheimer's disease, it also has much broader implications. A wide range of pharmaceuticals which regulate
presenilin cleavage are already being developed and clinically tested for their efficacy in the treatment of
Alzheimer s disease. Should our research demonstrate that p75NTR cleavage is the key process that regulates
neuronal degeneration it will have major ramifications for approaches to the treatment of other p75NTRassociated neurodegenerative conditions.
Research achievements (from final report):
There is overwhelming evidence that the p75 neurotrophin receptor (p75) is a major regulator of cell death in
development and adult disease. The role that proteolytic cleavage of p75 plays in inducing and regulating cell
death signalling was investigated. We found that extracellular cleavage was required for initiation of death
signalling but that cellular localisation and subsequent cleavage events were also important for modulating the
signal pathway. We also demonstrated that p75 was required for cell death initiated by the amyloid peptide,
widely acknowledged as being causative of neuronal loss in Alzheimer's disease, and that the death signal was
regulated by the characterised cleavage mechanisms.
Expected future outcomes:
Building on these results we expect to identify the second messenger components of the death signalling
pathway activated specifically by the cleaved form of p75. We then aim to identify targets within the death
pathway as candidates for neuroprotective pharmaceutical intervention and to test their roles in
neurodegenerative models.
Name of contact:
Dr Elizabeth Coulson
Email/Phone no. of contact:
e.coulson@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 410002
CIA Name: Prof Stephen Duckett
Admin Inst: University of Queensland
Main RFCD: Health Economics
Total funding: $656,029
Start Year: 2006
End Year: 2009
Grant Type: NHMRC Strategic Awards
Title of research award:
Assessment to Service Outcomes - Care pathways for older Australians with Dementia, CVD and
ArthritisAssessment to Service Outcomes - Care pathways for older Australians with Dementia, CVD and
Arthritis
Lay Description (from application):
The project aims to use existing data source to answer questions similar to ‘What happens to people after they
have been assessed and recommended for aged care?’ in respect of service delivery for people with one of the
three chronic conditions dementia, arthritis or cardiovascular disease. The project is to provide information
about issues such as ‘bed blockers’ and determine if the outcomes are different for people who have been
assessed for aged care while they are in hospital. It is to chart changes in service use over time and examine
factors that affect the type of care used by older people.
Research achievements (from final report):
As in other ageing populations, dementia, musculoskeletal conditions and cardiovascular disease affect a high
proportion of Australians aged over 65 years, and the prevalence of these conditions increases significantly
with age. People with these conditions may need to access a range of care services over time to enable them to
remain living in their homes. Many eventually need to move into a nursing home. , In contrast to the
considerable recent literature on the funding of long-term care systems for population ageing, studies on the
care pathways followed by individuals are much less common. This project identified the effect of disease on
use of community care services and nursing homes over time, focusing on people with dementia,
cardiovascular disease and musculoskeletal conditions. , The different symptoms and courses of diseases meant
that the patterns of aged care service use, both in terms of care services accessed and the timing of this access,
varied considerably for people with different health conditions. These differences persisted across a range of
client characteristics. In particular, people with dementia or cerebrovascular disease as their main health
condition were more likely to enter nursing home care than those with heart disease or musculoskeletal
conditions. , The variation in use of aged care services according to disease group need to be taken into account
in any projections of demand for aged care. Such projections must allow for predictions of disease prevalence,
or else they will yield inaccurate predictions of demand for both community and residential care.
Expected future outcomes:
This project was the first to link aged care data succesfully. This is now done routinely by the Australian
Institute of Health and Welfare
Name of contact:
Stephen Duckett
Email/Phone no. of contact:
stephen.duckett@grattan.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456135
CIA Name: Prof Leonard Gray
Admin Inst: University of Queensland
Main RFCD: Geriatrics and Gerontology
Total funding: $257,261
Start Year: 2007
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Validation of Cognitive Assessments using TelecommunicationValidation of Cognitive Assessments using
Telecommunication
Lay Description (from application):
This project will assess the use of video conferencing to enable geriatricians to assess and diagnose memory
problems including dementia. Establishing the reliability of diagnosis and other related assessments, and
identifying which functions can confidently be carried out via video conferencing, is one step towards
extending the availability of this service to rural and remote communities. Access to accurate diagnosis and
assessment of cognitive impairment is an important step in the management of dementia, Alzheimer's disease
and other associated disorders. High level expertise, such as that offered by a specialist Memory Disorder
Clinic, is particularly important if there is uncertainty about the diagnosis, or if the prescription of
cholinesterase inhibitors and associated medications are being considered. It was estimated that in 2005 there
were 52,000 people diagnosed with dementia in Australia and by 2050 there will be an additional 175,000
cases each year. For the vast number of people who will be affected by dementia, early detection and
intervention will play an important role in their healthy ageing experience. Access to accurate diagnosis and
advice as a function of detection and intervention is often not as freely available to people in rural areas. The
experience of travelling long distances for assessment can be detrimental to the emotional well being of people
who may have dementia. Access to geriatrician services in a local rural area is an important element to
maintaining their sense of well being. Geriatricians are not commonly available in rural areas which means
current access to specialist diagnosis and assessment is either a missed opportunity or involves extensive travel.
Internationally, there are many individuals living in remote regions with no access to geriatrician services, or
reliable cognitive assessment. This study will inform similar experiments in other cultural settings.
Research achievements (from final report):
NHMRC funding was provided to the Centre for Research in Geriatric Medicine (The University of
Queensland) to support research into the reliability of diagnosing dementia via video conferencing. This
research has important implications for patients with cognitive decline who live outside the main city centres,
both in Australia and internationally. Most specialist memory assessment clinics are based in large teaching
hospitals. Travelling long distances, in unfamiliar surroundings, can be difficult, both physically and mentally
for older people, along with the significant burden this places on a carer who must attend with them. , To date,
this study is the largest international, multi-site study to address this issue. Two-hundred patients underwent
dual specialist assessments to identify the presence of dementia. Agreement between specialists was excellent.
A portion of the assessments were carried out via video conferencing, the remainder occurred face-to-face. ,
This study examined a range of outcomes in the context of the most challenging diagnostic patient group in
dementia-related clinical practice, those attending a Memory Disorder Clinic, and concluded that video
conferencing was a reliable tool for the purpose of cognitive assessment. , This work supports the future
development of telehealth networks for use in health service provision to older persons, particularly those
where there is concern about their cognitive function. Clinicians can be confident that an assessment of
cognition, carried out via video conference, is a reliable mode for making a diagnosis of dementia.
Expected future outcomes:
Increase in the use of video conferencing equipment for the purpose of cognitive assessment, particualy for
patients in rural or remote locations. Usually, specialists are located in main city centres. Now, specialists and
patients can be connected seamlessly for assessment interviews, without the economic and social costs
assocatied with extensive travel.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr. Melinda Martin-Khan
Email/Phone no. of contact:
m.martinkhan@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456182
Start Year: 2007
CIA Name: Prof Gerard Byrne
End Year: 2011
Admin Inst: University of Queensland
Grant Type: NHMRC Strategic Awards
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $555,697
Title of research award:
Prospective study of the emergence of syndromal and sub syndromal anxiety and depression during cognitive
decline.Prospective study of the emergence of syndromal and sub syndromal anxiety and depression during
cognitive decline.
Lay Description (from application):
In older people it is well known that memory impairment and cognitive decline are associated with depression
and anxiety. However, it is remains quite uncertain which comes first. For a long time it had been thought that
deteriorating brain function associated with ageing and the development of dementia is also the cause of new
symptoms of depression and anxiety found in older people. Recently, some evidence has emerged to challenge
this hypothesis. So we plan to study this question in detail with data from an existing longitudinal study of
ageing women.
Research achievements (from final report):
Our NHMRC funding enabled us to investigate the relationship between changes in memory and the
development of depressive and anxiety symptoms in a cohort of middle aged and older female volunteers. We
found that those women whose memory function stayed the same or improved between 2001 and 2008 were
less likely to report depressive symptoms in 2008. In other words, we found that depression was more likely in
those who showed signs of deteriorating memory function over time, even in the absence of dementia. This
finding suggests that maintenance of good cognitive function is likely to be important for the prevention of
depression in middle aged and older women.
Expected future outcomes:
We are still analysing the results of specialised genetic tests looking at genes that might increase the risk of
depression in the context of deteriorating memory function. In a subgroup of our volunteers we are also
investigating whether MRI brain scans might help identify those at risk of depression during cognitive decline.
Name of contact:
A/Prof Gerard Byrne
Email/Phone no. of contact:
gerard.byrne@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 456232
CIA Name: Ms Deborah Parker
Admin Inst: University of Queensland
Main RFCD: Nursing not elsewhere classified
Total funding: $137,000
Start Year: 2008
End Year: 2009
Grant Type: SRDC - People
Title of research award:
Development of a palliative care in residential care outcome scale (PARCOS)Development of a palliative care
in residential care outcome scale (PARCOS)
Lay Description (from application):
The project seeks to develop and undertake psychometric testing of a scale suitable to measure outcomes for
residents in residential aged care facilities for whom a palliative approach is appropriate. The project will
include a Joanna Briggs Institute systematic review of existing outcome measures in palliative care with
emphasis on their use in residential aged care facilities.
Research achievements (from final report):
This fellowship provided the opportunity to identify the most appropriate palliative care outcomes measures for
use in residential aged care. A Joanna Briggs systematic literature review was conducted which identified two
outcome measures - The Family Perceptions of Care Scale and the Quality of Dying in Long Term Care scale
most suitable for use in this setting. However, neither of these scales has been tested in the Australian context.
The second phase of this fellowship was to conduct a validity study of both these scales for a sample of
bereaved carers from a large not-for-profit organisation. The Family Perceptions of Care Scale was identifed as
the most valid scale for use and is recommended for use in Australian residential aged care settings.
Expected future outcomes:
The validation study of the two scales has identified that the Family Perceptions of Care scale is valid for use in
the Australian setting. Currently I am working collaboratively with the original scale developer (Canada) as
well as researchers in England and the Netherlands on a cross country comparison of this scale.
Name of contact:
A/Prof Deborah Parker
Email/Phone no. of contact:
deborah.parker@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511119
Start Year: 2008
CIA Name: Prof Nancy Pachana
End Year: 2012
Admin Inst: University of Queensland
Grant Type: NHMRC Strategic Awards
Main RFCD: Clinical Sciences not elsewhere classified
Total funding: $580,452
Title of research award:
Validation of a competency assessment method for persons with dementiaValidation of a competency
assessment method for persons with dementia
Lay Description (from application):
Deciding what if any aspects of their financial affairs a person with dementia or suspected dementia can
responsibly manage is a difficult process for health and legal professionals as well as for guardianship boards
and tribunals. This process is often stressful for the older person, and families can find deciding when to “take
over” stressful. Also, having family members manage the older person’s assets may result in family conflict.
There is a small amount of overseas research examining this issue. However, no comprehensive and validated
method exists internationally or in Australia to determine competency in this context. We will test a
methodology for assessing the capacity of individuals to manage their own financial affairs where dementia is
an issue. This method involves the use of a number of reliable and well-validated instruments measuring the
older person’s mental state, anxiety levels, depression, and social vulnerability combined with an interview
exploring the personal circumstances of the older adult in relation to their financial affairs. We will work with
the Office of the Adult Guardian in Queensland to recruit participants and to verify both the utility and
usability of our methodology with stakeholders (e.g. solicitors, the Office of the Adult Guardian). A
comparison will be made between the results obtained in approximately 200 financial competency cases with
the competency opinions independently arrived at by the Office of the Adult Guardian in Queensland. As a
result of this research, we will be able to ascertain the viability and utility of this assessment method, improve
the method as per the data gathered, and ultimately seek future funding to trial the methods across multiple
jurisdictions (e.g. other states) and contexts (e.g. various cultural contexts).
Research achievements (from final report):
This grant tackles perhaps one of the most delicate issues in aged care clinical practice, namely capacity
assessment for those identified as potentially lacking capacity but for whom a formal judgment of genuine lack
of capacity has not been ascertained. Determining the point at which a cognitively impaired person is no longer
capable of managing their finances poses a difficult task. The literature on financial capacity and its assessment
in older adults has been difficult to translate into sound clinical practice. Capacity assessments often rely on
imprecise standards of clinical judgement, which is not evidence-based and may be vulnerable to bias.
Comparability and consistency between approaches, even in a single case, may be lacking, and approaches
used to determine capacity have rarely been empirically validated with respect to "real world" reliability and
utility. Important contextual issues regarding the person being assessed, including the specific capacity
behaviours and decisions in question, clinical and health status, and the circumstances of daily living are often
ignored. Thus, contextual information forms a vital backdrop to the interpretation of objective data. This grant
brought together clinically sound, empirically valid brief measures of capacity and a specifically adapted
clinical contextual capacity interview, and compared results of a clinical and healthy community control group
on the assessment measures. The measures proved robust in separating those with impaired financial capacity
from those for whom such capacity was still intact.
Expected future outcomes:
It is thought that findings from this work will enhance our understanding of important predictors and
considerations associated with financial capacity assessments, and the role that mood, anxiety and social
vulnerability may play in this. The results will assist clinicians in the field to identify relevant domains to
assess for in financial capacity cases in the field.
Name of contact:
Professor Nancy Pachana Professor Nancy Pachan
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
n.pachana@psy.uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511125
CIA Name: Prof Len Gray
Admin Inst: University of Queensland
Main RFCD: Geriatrics and Gerontology
Total funding: $541,746
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Strategic Awards
Title of research award:
Clinical outcomes, staff and carer perceptions of acute hospitalisation of patients with dementiaClinical
outcomes, staff and carer perceptions of acute hospitalisation of patients with dementia
Lay Description (from application):
This work will provide a clear picture of the problem of dementia in hospital, including how often people with
dementia are admitted, what happens to them, how hospitals respond to their needs, and how well carers
perceive their needs are met. Our key objective is to provide sufficient information to inform better design of
hospital procedures for people with dementia. The study will examine the illnesses and cognitive function of
500 people aged over 70 years, who are admitted to 14 wards in 4 hospitals in an around Brisbane. At
admission, the study will identify people with cognitive impairment and follow them through the episode to
identify what happens to them. The care protocols in relation to cognition and behaviour (if any) of the 14
wards under study will be examined, and the records of at least 100 patients will be reviewed to determine how
well the cognitive problems are recognized and managed by staff. A substudy of 30 carers of people with preexisting dementia will involve interviews at the time of admission to ascertain expectations, and at the
conclusion of the hospital stay to understand carers’ perceptions of how well they considered the care was
delivered. In each aspect of the study, a comparison with a similar group of older people without dementia will
be made, both objectively and subjectively. Hospital admissions appear to be full of risks for older people with
dementia – they appear to be at risk of health incidents (delirium, falls, over-medication, etc), may decline in
function and behaviour, and ultimately may be discharged prematurely to institutional care. Our research aims
to provide a basis for planning a logical, careful response to the problem of dementia in hospital.
Research achievements (from final report):
The results of this research, undertaken using valid and reliable assessment tools, showed that approximately
30% of older patients (patients aged 70 years and older) admitted to Australian acute care hospitals had
cognitive impairment - either dementia or delirium. These findings are consistent with findings from studies
undertaken overseas and confirm the high prevalence of cognitive impairment among older patients admitted to
acute care hospitals. Cognitive impairment is frequently undetected in patients admitted to hospital although
patients with cognitive impairment are at increased risk of adverse outcomes. Our findings serve to confirm the
magnitude of the problem and indicate that clinicians should maintain a high index of suspicion for cognitive
impairment in older patients, particularly in the oldest old, as some preventive strategies can be effective in
minimising these risks and potentially improve patient outcomes.
Expected future outcomes:
It is expected that another 5 journal articles will arise from this project for publication in peer-reviewed
journals.
Name of contact:
Professor Len Gray
Email/Phone no. of contact:
len.gray@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511180
Start Year: 2008
CIA Name: Prof Jonathan Adams
End Year: 2011
Admin Inst: University of Queensland
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $456,279
Title of research award:
Family care-giving for CALD people living with dementia: the perspectives of family carers and health service
providersFamily care-giving for CALD people living with dementia: the perspectives of family carers and
health service providers
Lay Description (from application):
Not Available
Research achievements (from final report):
Our project was the first qualitative in-depth investigation of this topic ever to be conducted in Australia with
CALD communities. These communities are under-researched and their service use and provision is a
challenge for the Australian health care system. Our research papers (4 to date with 2 more submitted) have
been published in leading international journals for the dementia field and our international conference
presentations have also helped to introduce vital insights for practice and service provision relating to CALD
and dementia caring. We have already received extremely positive feedback and interest from service
providers, carers and consumer support organisations and our findings have been implemented in local Sydney
ethnic health worker support for CALD commuties swith dementia. Our project design included active
participation of such practitioners and support providers (via fieldwork, CIs and fieldwork support workers)
and these elements of design have proven effective in research capacity building amongst health care workers
on this topic. Our project Research Fellow has since taken up a position with a local Area Health Service
providing services and research development for CALD specific services.
Expected future outcomes:
The findings from our project have already received excellent feedback from service providers (ethnic health
workers) and patient/carer support organisations. Dementia carer and consumer organisations for CALD
communities in Sydney and other capital cities have already shown interest in integrating our findings into
service and information provision.
Name of contact:
Professor Jon Adams
Email/Phone no. of contact:
jon.adams@uts.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511208
CIA Name: Prof Helen Chenery
Admin Inst: University of Queensland
Main RFCD: Residential Client Care
Total funding: $681,083
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Strategic Awards
Title of research award:
An efficacy study of a cognitive-communicative intervention to improve transition to residential care in
dementiaAn efficacy study of a cognitive-communicative intervention to improve transition to residential care
in dementia
Lay Description (from application):
The transition from home to a residential aged care facility (RACF) is a potentially traumatic process that has a
negative impact on the health and well-being of both people with dementia and their caregivers. This project
will develop an intervention program for people with dementia that maximizes their ability to learn and retain
functional skills and that enhances the communicative competence of both people with dementia and their
carergivers. This will serve to minimize the stress and disorientation, as well as accompanying increased risk of
illness, of entering residential care. We will investigate whether this intervention program has good outcomes
both for the people with dementia as well as their caregivers. The research will develop guidelines for the
development of best-practice policies for service providers and the government, which will assist both health
workers and homebased caregivers to better manage the transition of people with dementia from home to the
RACF environment.
Research achievements (from final report):
This grant enabled a multidisciplinary team of researchers from The University of Queensland to develop a set
of research-based memory and communication strategies for caregivers of people with dementia. The team
involved clinicians, researchers and educators in neuropsychology, psychogeriatrics, nursing, speech
pathology, and communication, who engaged with end-users of the research including experienced professional
and informal caregivers. Using an evidence-based approach, two sets of practical strategies were developed:
MESSAGE: Communication Strategies in Dementia and RECAPS: Memory Strategies in Dementia. The
strategies were developed into educational DVDs for family caregivers and care staff. The videos contain
information about the importance of communication and memory, difficulties commonly experienced by
people with dementia, acted vignettes demonstrating application of the strategies, and teaching examples.
These are available for use and distribution under a creative commons licence. Research on the development of
the strategies, and the usefulness of the training programs has been published in research journals. The
development of these strategies for consistent use by both community carers (including paid and family carers)
and residential aged care workers has enhanced the transition into residential care for people with dementia and
their carers.
Expected future outcomes:
The dementia training material has been adopted in residential care facilities across Australia and has been
widely disseminated through our partner organisations including BlueCare, RSL Care and Alzheimer's
Australia. Various education and training organisation are also using this dementia training material to educate
the next generation of dementia care workers. ?
Name of contact:
Professor Helen Chenery
Email/Phone no. of contact:
h.chenery@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569507
CIA Name: A/Pr Elizabeth Coulson
Admin Inst: University of Queensland
Main RFCD: Cellular Nervous System
Total funding: $546,383
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
A -induced cell death signalling by the p75 neurotrophin receptor.A -induced cell death signalling by the p75
neurotrophin receptor.
Lay Description (from application):
The amyloid peptide A is central to the cause of Alzheimer's disease. We have recently found that A can
activate the cell death receptor p75NTR which is found in the nerve cells that die in Alzheimer's disease. This
project will study whether this death pathway underpins the neuronal death associated with Alzheimer's
disease. It will also determine the mechanism by which A activates p75NTR death signalling, and identify
biochemical ways to prevent this from occurring.
Research achievements (from final report):
Our work from this grant has contributed to our fundamental understanding of how the structure-function
relationship of a neuronal protein p75 neurotrophin receptor (p75NTR) is involved in regulating cell death and
survival in the developing and adult nervous sytstems. In addition, we uncovered mechanisms by which
neuronal death signalling mediated by p75NTR is enhanced in Alzheimer's disease, thereby explaining why
expression of p75NTR is a contributor to neurodegeneration in this condition.
Expected future outcomes:
The research identified a number of possible ways by which cell death signalling might be inhibited through
manipulating its structure. Whether such manipulations do affect signalling remains to be determined. Any that
do inhibit death signalling would be candidate drug tragets for neurodegnerative diseases.
Name of contact:
Elizabeth Coulson
Email/Phone no. of contact:
e.coulson@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569564
CIA Name: Dr John Power
Admin Inst: University of Queensland
Main RFCD: Cellular Nervous System
Total funding: $266,748
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Modulation of Calcium Signalling by Acetylcholine in the Basolateral AmygdalaModulation of Calcium
Signalling by Acetylcholine in the Basolateral Amygdala
Lay Description (from application):
The amygdala is an area of the brain involved in assigning emotional significance to sensory stimuli. This
grant examines the cellular processes involved in making these associations. Specifically, it studies the
relationship between two signalling molecules implicated in association learning, acetylcholine and calcium.
This research will test hypotheses of memory formation and provide insight into disorders linked to detrimental
emotional associations, such as anxiety and addiction.
Research achievements (from final report):
Our stored memories and the emotions they evoke in large part determine our sense of self. Emotional
associations are made and stored in a brain region called the amygdala. However, the cellular changes that
mediate the formation of these associations are not fully understood. This grant examined the relationship
between two signalling molecules implicated in associative memory formation, calcium and the acetylcholine.
Using fluorescent probes, high-speed laser scanning microscopy and electrical recordings of individual neurons
we were able show that acetylcholine induced wave-like rises in the concentration of calcium within neurons.
Memory involves a rewiring of the brain; making new or stronger connections between some neurons and
weakening or breaking connections between others. The calcium waves invaded the specialised processes
where neurons connect, and weakened a subset of inactive connections. This weakening signal complements
strengthening signals from other signalling molecules and is vital to maintaining the level of connections
between neuron. Acetylcholine was also shown to alter the electrical properties of neurons in manner that
facilitated the integration of information, thus favouring the formation of new memories. Aberrant memory
formation in the amygdala underlies a variety of anxiety-related disorders, such as generalised anxiety,
phobias, and post-traumatic stress disorder. Furthermore, a loss of cholinergic function has been implicated in
the memory impairments associated with Alzheimer's disease and the amygdala is one of the first brain regions
impacted by this disorder. Thus, our results provide insight into these disorders and may have future
implications in their treatment.
Expected future outcomes:
Our experiments have revealed some novel actions of acetylcholine, a molecule known to facilitate memory
formation. The data have been presented at national and international conferences and published in leading
scientific journals. Thus, our results are likely to influence future treatments for these disorders.
Name of contact:
John Power
Email/Phone no. of contact:
john.power@unsw.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569596
CIA Name: Prof Frederic Meunier
Admin Inst: University of Queensland
Main RFCD: Cell Neurochemistry
Total funding: $580,752
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Research Fellowships
Title of research award:
Uncoupled Research FellowshipUncoupled Research Fellowship
Lay Description (from application):
I am a neuroscientist-cell biologist determining the dynamics of molecular events underlying vesicular
exocytosis during synaptic transmission.
Research achievements (from final report):
My lab focusses on the mechanism underpinning the trafficking of secretory vesicles SVs in the nervous
system. Since commencing my SRF in 2009 my lab has made notable progress in our understanding of steps
conveying SVs to the plasma membrane of neurosecretory cells to undergo Ca2+-dependent fusion. We have
discovered the existence of a cellular conveyor belt allowing SV to reach the plasma membrane in an activitydependent manner Maucort PLoS One 2014. We demonstrated that an anchor molecule called Myosin-VI
mediates the attachment of SVs to the cortical actin network in a Ca2+-dependent Tomatis J. Cell Biol. 2012.
We revealed that the cortical actin network itself undergo plasticity changes leading to filopodial formation and
the creation of novel release sites Papadopulos J. Neurosci. 2013; Front in Neuroendocrinol. 2013. Once SV
are on the plasma membrane Munc18-1 is required for priming a mechanism by which they aquire the ability to
fuse. My team has been the first to dismiss an emerging new theory Malintan JBC 2009; Han et al. MBoC 2009
in the field and has led the way in the discovery of a novel priming model controlled by a loop in Munc18-1
domain 3a Martin JCS 2014. We have uncovered novel regulations of SV exocytosis by phosphoinositide
lipids. After our initial discovery that type 2 PI3-kinase C2a and PIKvye positively and negatively regulate
neuroexocytosis Wen MBoC 2008; Prog Lipid Res. 2011; Osborne JBC 2008 we demonstrated that PI3Kdelta
and lipid PI45P2 controls SV docking Wen Nat Commun. 2011. Our work on phosphoinositides also helped to
unravel two novel cell death pathways controled by PI35P2 in neurons Martin PLoS One 2013 and PI45P2
Coulson J Neurosc. 2008. We have also established a translatable neuroprotective role for PI3Kdelta inhibition
in stroke-induced neuroinflammation Low JCB 2010; Nat Commun. 2014.
Expected future outcomes:
Thanks to my SRFA I am in a position to concentrate on key aspects of presynaptic and neurosecretory
vesicular trafficking using new technologies such as super-resolution microscopy. Projects including
presynaptic trafficking of survival factors protective role of PI3Kdelta in Alzheimer's disease control of
exocytosis by Munc18 key residues and deciphering functionally distinct pools of SVs.
Name of contact:
Frederic Meunier
Email/Phone no. of contact:
f.meunier@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 569688
CIA Name: Prof Len Gray
Admin Inst: University of Queensland
Main RFCD: Geriatrics and Gerontology
Total funding: $343,823
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
Reliability of an Online Geriatric Assessment ProcedureReliability of an Online Geriatric Assessment
Procedure
Lay Description (from application):
This study will examine the reliability, safety and cost of a novel new method of providing geriatrician
assessment to older people in hospital. Nurses consult with the patient and enter their findings on a web-based
software system that enables the geriatrician to review, report and make recommendations over the internet.
Research achievements (from final report):
The current project was designed to test the reliability and safety of CGA performed "online" in making
geriatric triage decisions. It also explored the accuracy of the procedure in identifying common geriatric
syndromes, and its cost relative to conventional "live" consultations. The online approach was found to be as
reliable as live assessment. Geraitric specialists, the staff usually involved in making this decisions at large city
based hospitals, are present at rural and remote hospitals to help with this decision making process. This study
has provided evidence based research to support the invovlement of geriatric specialists in the medical care of
older people in rural and remote hospital using an online system which enables assess to information from a
distance.
Expected future outcomes:
This research will enable a protocol to be developed that avoids unsafe clinical decisions at a distance. It
provides evidence based research to support the involvement of geriatric specialists in the care of older people
using telehealth assessment protocols. There is an enormous opportunity to improve the efficacy of aged care
specialists.
Name of contact:
Professor Len Gray
Email/Phone no. of contact:
len.gray@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 631418
CIA Name: Dr Shona Osborne
Admin Inst: University of Queensland
Main RFCD: Cellular Nervous System
Total funding: $372,966
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
The neuronal PIKfyve complex regulates neurotransmission and neurodegenerationThe neuronal PIKfyve
complex regulates neurotransmission and neurodegeneration
Lay Description (from application):
Neuronal communication is essential for the functioning of our bodies and mind. We have identified a novel
pathway for the regulation of this process involving a little studied lipid, PI3,5P2. This lipid also appears to be
important for neuronal survival. We will investigate the regulation and function of this lipid in neurons. The
outcomes of this proposal will be an important step closer to understanding the processes underlying neuronal
communication and neurodegeneration.
Research achievements (from final report):
Phosphoinositides (PIs) are a class of signalling lipid that regulate a wide variety of cellular processes. The PI,
PI3,5P2 has been implicated in neurodegenerative diseases such as Charcot Marie Tooth type 4J (CMT4J) and
Amyotropic Lateral Sclerosis (ALS). Here we have demonstrated a link between the enzyme that produces
PI3,5P2, PIKfyve, the cellular trafficking process of autophagy and neuronal cell death (Martin et al, PLoS
ONE, 2013). Future studies based on this may contribute to determining how the balance of lipid metabolism
can be restored to overcome pathology in patients with ALS and CMT4J. Other research outcomes related to
work addressing the role of lipids in neuronal communication, for example, we determined the mechanism
through which the PI, PI4,5P2, coordinates secretory vesicle recruitment to the plasma membrane (Wen et al,
Nature Communications, 2011). This work extends our current understanding of the role of PI in fundamental
cellular mechanisms, and in particular the contribution of PI3,5P2 to neuronal cell death. In the future, this
work may lead to novel treatment avenues for neurodegenerative diseases.
Expected future outcomes:
Expected future outcomes include full characterisation of the molecular mechanisms of PI3,5P2 in autophagy
in neurons and work to determine whether manipulating PI3,5P2 levels in animal models of CMT4J and ALS
can alter the disease process.
Name of contact:
Shona Osborne
Email/Phone no. of contact:
s.osborne@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 511343
CIA Name: Dr Barbara Anderson
Admin Inst: University of South Australia
Main RFCD: Mental Health
Total funding: $50,000
Start Year: 2009
End Year: 2009
Grant Type: SRDC - Research
Title of research award:
Identification of the palliative care needs of home-based people with end-stage dementiaIdentification of the
palliative care needs of home-based people with end-stage dementia
Lay Description (from application):
This project seeks to identify the palliative care needs of home-based people with end-stage dementia.
Although the need for home-based palliative care may apply to people with dementia as well as to those with
cancer and other terminal illnesses, few people with end-stage dementia receive such care. For this reason,
people with dementia may experience suffering and unmet needs towards the end of life. The proposed
research is important because as the population ages and the prevalence of dementia increases, home-based
care will be the preferred option for many people. Palliative care practice however is not necessarily
transferable between cancer care and dementia care. The needs of people with end-stage dementia may be
different to those of people with cancers because of the different trajectories and symptoms experienced. There
is evidence to suggest that a palliative care approach in dementia is favoured by formal and informal carers,
however the preferences of people with dementia are not known. Understanding the palliative care needs of
home-based people with end-stage dementia, carers and care providers is required, hence the motivation for
this inquiry.
Research achievements (from final report):
Dementia ia a terminal condition. A range of palliative care needs have been identificed which, if met, can
assist carers to fultill the desire of people with late-stage dementia who want to die at home. Although a
complex process, it is important that a diagnosis of dementia be made. Receiving the diagnosis helps carers to
understand the changes occuring in the person for whom they are caring and in theory, allows them to start to
make plans for the future care of this person. A diagnosis also provides carers with access to a range of services
needed to support them in their demanding caring role. However, this project found that the majority of carers
interviewed, had difficulty obtaining a diagnosis of dementia and due to reasons, such as denial on the part of
the person with dementia, advance care plans were seldom prepared. A range of organizations provided valued
assistance in the form of in-home, short-term and long-term respite, assistance with activities of daily living,
such as showering and feeding, and equipment including beds, hoists and shower chairs. The complexity of the
health care system is evidenced by the number of organisations from which carers had accessed services, if
they did not have a care package. Representatives of service organsiations also expressed their frustration with
the complexity and the fragmentatin of the system, highlighting the need for consumer directed care, so that
services could be responsive and tailored to the needs of their clients and carers.
Expected future outcomes:
Future outcomes will include preparation of several book chapters and conference presentations.
Name of contact:
Dr Barbara Anderson
Email/Phone no. of contact:
barbara.anderson@rdns.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568890
CIA Name: Dr Hannah Keage
Admin Inst: University of South Australia
Main RFCD: Diagnostic Applications
Total funding: $264,705
Start Year: 2009
End Year: 2013
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Investigating biomarkers of dementia and improving clinical criteria using population- and clinic-based
approachesInvestigating biomarkers of dementia and improving clinical criteria using population- and clinicbased approaches
Lay Description (from application):
It is difficult to accurately diagnose an individual with dementia especially at early stages of the disease. This
project aims to see what markers in the brain differentiate those with and without subtypes of dementia and to
see what clinical criteria best relate to these markers. It is hoped that results will improve clinical criteria for
dementia and its subtypes, thus improving the diagnostic accuracy of dementia.
Research achievements (from final report):
Work completed under this fellowship helped broadened the accepted understanding of the underlying biology
and correlates of late life dementia. For example, Keage et al. (2012, Journal of Alzheimer's Disease) reported
that pathologies in the brain which are not traditionally considered to be associated with a dementia diagnosis,
do in fact significantly contribute. Further, Davis et al. (2012, Brain) showed that delirium in late life is
associated with an increased risk of dementia diagnosis, but the pathological basis of this dementia is different
from those without a history of delirium. In another paper, Dr Keage (2012, Sleep Medicine) reported that
sleep characteristics (e.g. napping, sleepiness and sleep duration) are related to cognitive decline over a 10 year
period. These and other papers are feeding into an increasing acceptance that the pathological basis of late life
dementia is very different from early onset dementia, one which is very heterogeneous and impacted heavily
upon by lifestyle factors in early- and mid-life. This understanding is hugely significant in terms of developing
appropriate diagnostic and neuropathological classification systems.?????????
Expected future outcomes:
We are currently looking at the significance of a new neuropathological marker of late life dementia, funded
under a NHMRC Project grant. Further, we are assessing how some people are able to cognitively cope with
neuropathologies associated with dementia and ageing better than other people.
Name of contact:
Dr Hannah Keage
Email/Phone no. of contact:
Hannah.Keage@unisa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153789
CIA Name: Prof Tailoi Chan-Ling
Admin Inst: University of Sydney
Main RFCD: Sensory Systems
Total funding: $679,617
Start Year: 2001
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Astrocytes and mural cells in the retina: Normal development and pathophysiologyAstrocytes and mural cells
in the retina: Normal development and pathophysiology
Lay Description (from application):
The blood vessels that supply the nerve cells of the brain and retina are associated with support cells known as
mural cells and astrocytes. Whereas astrocytes both ensure that the vessels do not leak and produce factors that
induce vessel growth, mural cells control blood flow and are thought to promote vessel stability. We aim to
characterise the development of astrocytes and mural cells as well as the interactions of these cells with blood
vessels that influence vessel shape, growth, and loss. Aging is associated with changes in the vasculature of the
central nervous system that confer a predisposition to certain conditions, such as dementia, caused by abnormal
blood supply and consequent nerve cell death. We plan to investigate the contribution of astrocytes and mural
cells to the vascular changes that accompany aging. These studies may lead to the development of interventions
to prevent such changes and their associated pathologies. Finally, astrocyte degeneration is implicated in
various neuropathological conditions, including dementia, Alzheimer's disease, and trauma. We aim to purify
and characterise a population of astrocyte precursor cells whose transplantation might result in the repopulation
of damaged regions of the central nervous system.
Research achievements (from final report):
AIMS AND HYPOTHESES Part I 1. To characterise type-1 astrocyte precursor cells (APCs) of the rat retina
in vivo and in vitro., 2. To characterise the differentiation of cells of the astrocytic lineage in the human retina
in vivo., 3. To isolate & purify type 1 APCs from embryonic rat retinae & to determine culture conditions that
support their expansion & controlled differentiation in vitro., Part II. 1.To characterise the differentiation of
mural cells by immunohistochemical analysis with antibodies to intermediate filaments, growth factor
receptors and contractile proteins., 2. To determine whether smooth muscle cell or pericyte differentiation is
required for vessel stabilisation as evidenced by resistance to experimental hyperoxia., Part III: 1. To
characterise the glial, microvascular, & inflammatory responses of the CNS to aging., 2. To determine the role
of breakdown of blood-brain barrier (BBB), the astrocytes, mural cells & inflammatory cell infiltration in the
initiation of the microvascular changes associated with aging.
Expected future outcomes:
- A provisional patent lodged was lodged by Michael Weible II and myself 920077.403P1 - Y/R: DCC Ref:
12722530 - termed "Generation of lineage specific cells" in the USA on 1st February, 2006., - Three
manuscripts are currently in preparation, - Stem Cells and Chemicon have signed confidential agreements with
our laboratory and are considering future licensing of our intellectual property
Name of contact:
Tailoi Chan-Ling
Email/Phone no. of contact:
tailoi@anatomy.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 153888
CIA Name: Prof Basil Roufogalis
Admin Inst: University of Sydney
Main RFCD: Cellular Nervous System
Total funding: $317,546
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Ral-mediated signalling pathways in neuronsRal-mediated signalling pathways in neurons
Lay Description (from application):
Within the nervous system, neurons communicate through the release of neurotransmitter chemicals across
connections between individual neurons (synapses). Before their release, neurotransmitters are stored inside
nerve endings, within small membranous spheres called synaptic vesicles. Neuronal cell shape and the neuron's
ability to migrate to different regions of the brain during development affect the way that the adult brain
functions. Alterations in any of these brain functions may lead to diseases affecting normal mental function.
Ral is a small GTPase enzyme found in brain, and particularly in neurons. Small GTPases are responsible for
regulating cell functions by acting as switches, turning biochemical processes on and off inside the cell. Within
neurons, Ral is found on the surface of synaptic vesicles, implicating it in the regulation of neurotransmitter
release. Other Ral functions have been demonstrated in non-neuronal cells that may be of particular
significance in neuronal cells. However, no studies have previously investigated Ral function in the nervous
system. The research proposed aims to establish what role RalA performs within neuronal cells, and by what
biochemical mechanism it performs this role. Techniques of molecular biology, biochemistry and microscopy
will be used to establish these functions. This research will lead to increased knowledge of the significance of
this protein to cellular, and particularly neuronal cell function. This forms the basis for the understanding
normal neuronal function, and for the identification of factors causing diseases of the nervous system. In time,
such research aids in the development of specific therapies for sufferers of such diseases of the nervous system.
Research achievements (from final report):
AIM: The project is to investigate Ral-mediated signalling pathways in neuronal cells and seeks to establish a
role for Ral proteins in neuronal cell function. Ral is a member of a family of small GTPases, which function
by binding specific signalling molecules in either their active (GTP-bound) or inactive (GDP-bound) states.
The work is based on the premise that identification of Ral binding proteins in neurons will illuminate new
functions for Ral. We focussed on the neuronal gene product RalA. Substantial progress was achieved. We
have made innovative use of GST-fusion proteins of RalA in pull-down assays (a method resulting in its own
publication (BDR32) from brain lysates), combined with MALDI mass spectrometry and bioinformatics to
identify a number of proteins which bound RalA in a nucleotide-dependent manner (BDR34)., , FINDINGS: ,
The first exciting finding was that activated RalA (in its GTP-bound state) bound to the exocyst complex, a
complex of eight subunit proteins involved in directing sites of exocytosis in polarised cells and localised to
growth cone filopodia. , o
Since RalA was the first small
GTPase to be identified to bind the exocyst, we proposed that it regulates targeted exocytosis, neurite
outgrowth and growth cone filopodia formation. , o
The results were published in J Biol
Chem (BDR33). Within months of this landmark publication, our findings were rapidly confirmed with a flurry
of follow-up publications by other labs., The second pivotal discovery was that inactive RalA (in its GDPbound state) bound to ERp57. , o
ERp57 is a redox sensitive protein
belonging to the protein disulfide isomerase family, which controls disulfide bond formation in proteins. , o We
reconstituted the Ral/ERp57 association in vitro with recombinant proteins and we have shown that their
interaction is direct, and dependent on the redox state of the medium. ,
Expected future outcomes:
Our work on RalA has led to numerous new findings regarding its cellular role. This has already generated
considerable scientific interest, and led to the elucidation of critical new functions for RalA. Our new findings
also reveal a new mechanism for the control of RalA and will lead to a description of its cellular role.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Phillip Robinson
Email/Phone no. of contact:
Phrobins@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 300457
CIA Name: Prof Des Richardson
Admin Inst: University of Sydney
Main RFCD: Cell Metabolism
Total funding: $513,438
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
The Physiological and Pathophysiological Roles of MelanotransferrinThe Physiological and
Pathophysiological Roles of Melanotransferrin
Lay Description (from application):
Melanotransferrin (MTf) is a membrane-bound molecule that was originally identified at very high levels in
malignant melanoma cells and other tumours. To our surprise, our recent studies showed that MTf was also
widely expressed in normal tissues (DR EJB 2000). MTf has many similarities to the iron (Fe)-binding
protein, transferrin (Tf), and initially, MTf was thought to play a critical role in Fe uptake that is crucial for
DNA synthesis. However, we demonstrated that MTf did not play a major role in Fe uptake by melanoma cells
(DR 1990, 1991a,b, 2000). We also showed that the tissue distribution of MTf was very different to Tf and the
Tf-receptor 1 (TfR1) that are well known to be involved in Fe transport. For instance, TfR1 is highly expressed
in tissues with large Fe needs (e.g., placenta), while MTf is not expressed at high levels in these tissues and is
found in unexpected locations (i.e., salivary gland). In contrast to expectations, MTf was also found at higher
levels in normal than foetal tissue. Also interesting was the finding that MTf is found in the serum and brain of
Alzheimer's disease patients. Over the last 2 years under our current NHMRC grant on MTf we have
significantly extended our knowledge on this molecule. As proposed in this grant, we generated a MTf
knockout mouse. This is a very exciting model that is the best way of determining the function of MTf.
Furthermore, we used recombinant MTf to show that soluble MTf that is found in the plasma is not an effective
Fe donor to cells (DR EJB 2002). Our results over the last 12 years indicate that MTf may play unexpected
biological roles (see DR FEBS Lett 2000). For the first time, generation of our MTf knockout mouse will
provide the exciting opportunity of characterising its role(s). This will be important in understanding the
function of MTf in cancer cells, Alzheimer's disease and in other tissues (eg., salivary gland and kidney) where
it is expressed at high levels.
Research achievements (from final report):
Melanotransferrin (MTf) is a homologue of the serum iron (Fe) transport protein, transferrin. Traditionally,
MTf is associated with malignant melanoma and other tumours. Due to the high Fe requirement of cancer cells
and the fact that MTf: (i) is highly expressed in melanoma; (ii) has high homology with transferrin (Tf); and
(iii) has the ability to bind Fe, it potentially could play a role in Fe uptake by melanoma cells. Despite very
high MTf expression on melanoma cells, in this study, we demonstrated that it does not play a marked role in
Fe uptake in this cell type. However, excitingly, our study also demonstrated that MTf plays roles in cellular
proliferation, migration and tumourigenesis. , In this study, we also developed five, in vivo and in vitro, models
of MTf down- and up-regulation. Assessing these five models, we identified three genes modulated by MTf.
These included ATP-binding cassette subfamily B member 5, thiamine triphosphatase and transcription factor
4. Hence, this study identifies novel molecular targets directly or indirectly regulated by MTf and the potential
pathways involved in its function, including modulation of proliferation
Expected future outcomes:
Possible understanding of the rapid growth and metastasis of melanoma and other cancer
Name of contact:
Des Richardson
Email/Phone no. of contact:
d.richardson@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301916
CIA Name: Prof Robert Cumming
Admin Inst: University of Sydney
Main RFCD: Epidemiology
Total funding: $1,780,888
Start Year: 2004
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Concord Hormones and Ageing in Men Project (CHAMP)Concord Hormones and Ageing in Men Project
(CHAMP)
Lay Description (from application):
Throughout life men have poorer health than women, a health difference that extends into old age. In Australia
in 2001, life expectancy for a 65 year old man was 20% less than for a 65 year old woman (81.6 years for men
and 85.2 years for women). The study proposed here will fill major gaps in knowledge about key health
problems in older men. The study will be called CHAMP: Concord Hormones and Ageing in Men Project. As
people grow older, health problems that cause loss of independence and reduced quality of life become
increasingly important. The term 'geriatric giants' is sometimes used to describe these disabling syndromes:
falls and fractures, cognitive impairment and dementia, urinary incontinence, and poor mobility and functional
dependence. CHAMP has been designed to investigate the causes of, and inter-relationships between, these
geriatric syndromes in men. Reproductive hormones are responsible for the fundamental biological differences
between men and women. Underpinning CHAMP is the idea that age-related changes in reproductive
hormones play an important role in the development of the geriatric syndromes in older men. There have been
numerous studies of oestrogen and health in older women but only limited research on testosterone and other
reproductive hormones in older men. CHAMP will be the largest study of the geriatric syndromes in older men
ever conducted. The study will inlvolve 2800 men aged 65 years and over recruited from the community
around Concord Hospital in Sydney. These men will each spend 3 hours at the study centre, where they will
have a comprehensive physical examination and tests for osteoporosis, muscle weakness, dementia and urinary
problems, as well as blood tests. This will all be repeated 2 years later.
Research achievements (from final report):
We successfully recruited 1705 men aged 70 years and over from the local community in the area around
Concord Hospital in Sydney. The participation rate was about 50%. All subjects had detailed clinical
examinations and completed a detailed questionnaire. Over 1300 subjects were re-examined after 2 years. We
are currently extracting DNA from blood samples and testing blood for levels of reproductive hormones and
vitamin D. This is one of the most comprehensive studies of the health of older men evr conducted anywhere in
the world., , The study has provided important information on the prevalence in older men of chronic pain,
dementia, disability, falls, fraility, osteoporosis and urinary incontinence. Data on risk factors for these
conditions are currently being analysed. A key analysis in the next few months will be to study the reaktiosnhip
between changes in testosterin and oestradiol levels and mortality. Over 300 of the men in CHAMP were born
in Italy, providing a wonderful opportunity to study the heralth of this migrant group.
Expected future outcomes:
Epidemiological cohort studies only achieve their full potential after long-term follow-up of subjects. To date,
follow-up has only been for two years. Numerous publications are expected in the next few years as we
continue follow-up of the cohort.
Name of contact:
Robert Cumming
Email/Phone no. of contact:
bobc@health.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 301964
Start Year: 2004
CIA Name: Prof Jillian Kril
End Year: 2006
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $417,750
Title of research award:
Understanding the variation in frontotemporal dementiaUnderstanding the variation in frontotemporal dementia
Lay Description (from application):
Frontotemporal dementia (FTD) is one of the non-Alzheimer dementias which accounts for between 12 and
20% of all dementia and as much as 50% of early onset dementia. It is characterised by marked behavioural
change and thus patients with this disease present a major management challenge. The cause of FTD is
unknown and at present there is no effective treatment for the disease. There are a number of different clinical
subtypes of FTD, namely behavioural variant, language variant, and FTD with motor neuron disease
(FTD+MND). Similarly there are pathological subtypes of FTD (Pick's disease, frontotemporal lobar
degeneration and FTD with ubiquitin-positive MND inclusions). However, there appears to be little
correspondence between these two subdivisions. The purpose of this study is to investigate the pathological
differences and similarities between the different clinical subtypes of FTD. Furthermore, we will investigate
the changes in brain atrophy which occur over the course of the disease to allow us to understand better the
initial focus of the disease. We will also evaluate the role of cellular protein changes (ubiquitin and tau) in the
pathogenesis of neuronal death. This research will allow us (i) to better diagnose and characterise FTD and (ii)
establish any common mechanisms of neurodegeneration in the subtypes of FTD.
Research achievements (from final report):
Frontotemporal dementia (FTD) is a major cause of dementia yet little is known about its natural history or
pathological causes. We have identified that there is a similar progression of brain tissue loss for most subtypes
of FTD and used this information to develop a novel and simple clinical tool to assist in predicting disease
severity and survival time. By carefully analysing the clinical onset of features in patients with autopsyconfirmed disease, we have been able to establish that ~10% of patients with FTD pathology are clinically
misdiagnosed with Alzheimer's disease because of their early severe and similar type of memory impairment.
This has significant implications for clinical diagnosis. In terms of pathology, it was previously thought that
FTD largely occurred due to abnormalities in the cellular processing of the tau protein. We have shown that
increased tau protein expression does not contribute to the pathology in the majority of cases, and have been
involved in identifying an alternate genetic mutation that contributes to the disease spectrum.
Expected future outcomes:
The use of the evidence gathered will assist in refining diagnostic criteria. The clinical tool we have developed
can be used to assess disease progression and develop patient management strategies. The underlying
pathology for certain clinical subtypes can now be predicted and disease modifying treatments trialled.
Name of contact:
Error! Contact not defined.
Email/Phone no. of contact:
jilliank@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 352473
CIA Name: Prof Graham Johnston
Admin Inst: University of Sydney
Main RFCD: Basic Pharmacology
Total funding: $519,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Cage compounds as blockers of GABA and glycine receptor-channelsCage compounds as blockers of GABA
and glycine receptor-channels
Lay Description (from application):
GABA and glycine are the major inhibitory neurotransmitters in the brain and, together with their associated
receptors (GABARs and GlyRs), they are responsible for rapid inhibitory neurotransmission. The importance
of these receptors in brain function and dysfunction is emphasized by their implication in a number of
hereditary and more complex disorders, such as anxiety, epilepsy, dementias, alcoholism and lack of motor
control. Many compounds act on these receptor-channels and modulate their function and some of these are
used clinically (e.g., anti-anxiolytics, some anaesthetics). Recently, some compounds which inhibit these
receptor-channels (typically convulsant drugs) have, in low doses, been shown to enhance learning and
memory and to provide some improvement in different senile dementias. Ginkgo biloba extract is used
worldwide and has been shown to be effective in the symptomatic treatment of cognitive disorders associated
with old age dementia and Alzheimer's disease. Some of the active constituents, the ginkgo compounds, inhibit
the GABA and glycine receptors but, importantly for therapeutic activity, are not convulsants. It is suspected
that these and related compounds bind within the pore of these receptor-channels to mediate their inhibition,
although the data is conflicting and no-one precisely knows how they act. This project aims to directly
investigate how the ginkgo compounds, and the related compound picrotoxinin, act on the GABA and glycine
receptors, and to determine the site on the protein to which they bind. Furthermore, this project will shed some
light on why picrotoxin is a convulsant but the gingko compounds are not. A more thorough understanding of
exactly how these compounds work will give us important information on how these receptor-channels work
and will lead to the development of better therapeutics, particularly those targeted against old-age dementias
and Alzheimers disease.
Research achievements (from final report):
This project studied the mechanism by which a group of compounds with cage-like structures block GABA and
glycine receptor-channels. Representative cage compounds include picrotoxinin, the common chloride channel
blocker, and the ginkgo terpene trilactones and their derivatives. While some progress was made both the
chemistry and the pharmacology proved more difficult than anticipated.
Expected future outcomes:
More work is needed on this project before we can predict future outcomes
Name of contact:
Prof Graham Johnston
Email/Phone no. of contact:
grahamj@mail.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 358779
CIA Name: Dr Renae Ryan
Admin Inst: University of Sydney
Main RFCD: Central Nervous System
Total funding: $310,157
Start Year: 2005
End Year: 2009
Grant Type: Early Career Fellowships (Overseas)
Title of research award:
Investigations into the crystal structure and function of a bacterial glutamate transporter.Investigations into the
crystal structure and function of a bacterial glutamate transporter.
Lay Description (from application):
Not Available
Research achievements (from final report):
This project investigated the function of a bacterial cousin of a protein in the brain known as a glutamate
transporter. This human protein is important for the normal functioning of the brain and its dysfunction has
been implicated in diseases such as Alzheimer's disease and motor neuron disease. The reason I study a
bacterial cousin of this protein is that we have an atomic level picture of this bacterial protein that is a very
good model for the human glutamate transporters. Understanding the specific details of the bacterial protein
gives us a lot of information about how the human transporters work.
Expected future outcomes:
Further elucidation of the mechanism of the bacterial transporter will allow us to better understand the human
glutamate transporters and develop drugs to treat neurodegenerative diseases.
Name of contact:
Renae Ryan
Email/Phone no. of contact:
renaer@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 402596
CIA Name: Prof Jurgen Goetz
Admin Inst: University of Sydney
Main RFCD: Central Nervous System
Total funding: $423,018
Start Year: 2006
End Year: 2008
Grant Type: NHMRC Project Grants
Title of research award:
Alzheimer's disease and related disorders: Mechanism of tau pathology in established and novel transgenic
animal modelsAlzheimer's disease and related disorders: Mechanism of tau pathology in established and novel
transgenic animal models
Lay Description (from application):
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects
more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians
will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major
brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau
which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal
model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that
injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By
"Functional Genomics" we identied genes and proteins, which are induced by tau expression. The specific aim
of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and
whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this
question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased,
secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second
aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are
disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV
regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the
pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range
of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease.
Ultimately, these efforts will assist in the development of a safe treatment of AD.
Research achievements (from final report):
Tau and Aβ42 are the principal components of the lesions characterising brains of Alzheimer's disease (AD)
patients, while tau lesions in the absence of Aβ42 are found in frontotemporal dementia (FTD). FTD is
characterized by cognitive and behavioural changes and, in a significant subset of patients, Parkinsonism. We
established a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I.
K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I
mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy, in the absence of overt
neurodegeneration. We found that the early-onset symptoms in the K3 mice are mechanistically related to
selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic
SN neurons that occurs in aged mice. Together, our K3 mouse is a unique model of FTD-associated
Parkinsonism, with pathomechanistic implications for the human pathology. We further found that both
oligomeric and fibrillar, but not monomeric, forms of Aβ42 cause a decreased mitochondrial membrane
potential in cortical brain cells obtained from P301L tau mice. Finally, we determined how a truncated form of
tau rescues lethality associated with Aβ42. Our data have important implications for the development of a
therapy for AD and FTD, two debilitating diseases for which at present no cure is available.
Expected future outcomes:
We expect that our findings will lead to a treatment startegy for AD and FTD. Besides that it has instigated
intensive research both by our group and by our peers.
Name of contact:
Jürgen Götz
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
jgoetz@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 512484
CIA Name: Prof Jurgen Gotz
Admin Inst: University of Sydney
Main RFCD: Central Nervous System
Total funding: $468,119
Start Year: 2008
End Year: 2010
Grant Type: NHMRC Project Grants
Title of research award:
Comparative analysis of novel transgenic mouse models for brain and islet amyloidosesComparative analysis
of novel transgenic mouse models for brain and islet amyloidoses
Lay Description (from application):
We aim to understand what two highly prevalent diseases, the brain disorder Alzheimer's disease (AD) and the
metabolic disorder Type 2 Diabetes mellitus (DM), have in common. Through understanding pathogenesis and
the development of novel transgenic models our long-term research goal is to identify new drug targets, to
develop screening assays and to patent new findings. Collectively, this hopefully leads to AD and DM drugs
and reduces the socio-economic burden of both debilitating diseases.
Research achievements (from final report):
Not Available
Expected future outcomes:
N/A
Name of contact:
Jürgen Götz
Email/Phone no. of contact:
juergen.goetz@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570850
Start Year: 2009
CIA Name: Prof Jillian Kril
End Year: 2011
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $511,295
Title of research award:
Pathogenic mechanisms common to all subtypes of frontotemporal dementiaPathogenic mechanisms common
to all subtypes of frontotemporal dementia
Lay Description (from application):
Frontotemporal dementia (FTD) is a neurodegerative disease of unknown cause and without effective
treatment. While there are a number of clinical and pathological subtypes of FTD all have abnormal protein
deposition. In this project we will investigate using brain tissue from patients with FTD, transgenic mice and
culture models the cellular mechanisms which underly the protein depsotion. In addition, we will look at the
brain's response to injury and investigate modulation of this response.
Research achievements (from final report):
Frontotemporal dementia (FTD) is characterised by marked clinical and pathological heterogeneity. In this
study we used postmortem brain tissue from patients with FTD and cell and animal models of FTD to
investigate abnormal protein deposition in FTD. Importantly we have helped to clarify the type of deposits seen
in FTD and the classification system used in the pathological diagnosis of FTD subtypes. We have also found
differences in the type of depsoits between FTD and Alzheimer's disease. Furthermore, we have developed
novel cell and animal models of TDP-43 deposition, one of the subtypes of FTD and explored ways to disrupt
protein deposition and subsequent neurodegeneration.
Expected future outcomes:
The findings from this study will be used to further investigate the mechanisms through which tau causes
neurodegneration. Furthermore, the models of TDP accumulation will advance knowledge of the rle of TDP in
FTD. The results of the immunisations studies will be used to explore ways of preventing tau deposition.
Name of contact:
Professor Jillian Kril
Email/Phone no. of contact:
jillian.kril@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570920
CIA Name: Prof Jurgen Gotz
Admin Inst: University of Sydney
Main RFCD: Cell Neurochemistry
Total funding: $295,984
Start Year: 2009
End Year: 2011
Grant Type: NHMRC Project Grants
Title of research award:
PATHOGENESIS OF ALZHEIMERS DISEASE AND RELATED DISORDERS: MECHANISM OF TAU
PATHOLOGYPATHOGENESIS OF ALZHEIMERS DISEASE AND RELATED DISORDERS:
MECHANISM OF TAU PATHOLOGY
Lay Description (from application):
A protein called tau has an essential role in the pathogenesis of Alzheimer's disease (AD), frontotemporal
dementia (FTD) and related dementias. We have developed novel transgenic models, which allow us to treat
the mice and to abrogate the clinical symptoms. As we have dissected the underlying molecular mechanisms,
our ultimate goal is to develop a treatment approach based on these mechanisms and thereby reduce the socioeconomic burden of these debilitating diseases.
Research achievements (from final report):
Our general aim is to understand how elevated tau interferes with cellular functions and to use this information
for novel therapeutic approaches and as the application has not been fully funded we concentrated on what we
considered as the most important aspects of the application. Regarding the K369I tau mutant K3 model we
provide more information on the interaction between tau and JIP1 (Ittner et al., JBC 2009). Regarding the role
of Δtau in mediating Aβ toxicity we achieved a milestone publication in Cell (Ittner et al., 2010). Regarding a
treatment, we used the Δtau mice, among others, to show efficacy of a peptide in preventing from excitotoxic
seizures and premature lethality (Ittner et al., Cell 2010) and the K3 and P301L tau transgenic pR5 mice to
determine efficacy of a PP2A (protein phosphatase 2A) activator (van Eersel et al, PNAS 2010).
Expected future outcomes:
The findings of this study will be further used to investigate pathological protein/protein interactions and how
this can be utilised for therapeutic interventions in Alzheimer's disease and related disorders.
Name of contact:
Prof Jürgen Götz
Email/Phone no. of contact:
j.goetz@uq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 570982
CIA Name: Dr R. M. Damian Holsinger
Admin Inst: University of Sydney
Main RFCD: Central Nervous System
Total funding: $287,659
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
In vivo regulation of the Alzheimers disease beta-secretase, BACE1In vivo regulation of the Alzheimers
disease beta-secretase, BACE1
Lay Description (from application):
Dementia claims 1000 Australians weekly. Alzheimer's disease (AD) is the leading cause of dementia. A
hallmark of AD is the presence of beta-amyloid (Ab) plaques in brain. Accumulation of Ab leads to toxicity
and cell death. We will use cutting-edge technologies to reduce the level of an enzyme (BACE1) that generates
Ab. This study will provide seminal information relating to in vivo regulation of Ab and establish a foundation
for our ultimate goal of decreasing BACE1 and Ab in human brain.
Research achievements (from final report):
We have designed a small hairpin RNA molecule that is capable of decreasing levels of a pivotal Alzheimer's
disease-related enzyme, BACE1. We have tested this molecule in cell culture and have established its efficacy
showing that it can decrease levels of amyloid-beta peptide, the key constituent of plaques that destroy the
brain of patients with the disease.
Expected future outcomes:
We are continuing this research through a collaboration in nanomedicine with A/Prof Zdenka Kuncic (Physics,
USyd). We are developing nanoparticles that can simultaneously act as a molecular probe, a drug delivery
agent and enhance image contrast.
Name of contact:
R. M. Damian Holsinger
Email/Phone no. of contact:
damian.holsinger@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 571378
CIA Name: A/Pr Roger Fulton
Admin Inst: University of Sydney
Main RFCD: Instruments and Techniques
Total funding: $190,450
Start Year: 2009
End Year: 2009
Grant Type: NHMRC Development Grants
Title of research award:
A Motion Correction Technique for Accurate PET/CT Brain Imaging in Paediatric and Dementia PatientsA
Motion Correction Technique for Accurate PET/CT Brain Imaging in Paediatric and Dementia Patients
Lay Description (from application):
PET/CT imaging is a vital tool in the diagnosis and management of patients with brain disorders including
dementia, epilepsy and cancer. However images are often distorted by patient motion, particularly in demented
and paediatric patients. The CI has recently developed a motion tracking and correction method to derive
images nearly free of motion effects. This aim of this project is to evaluate its impact on image quality in a
variety of patients referred for PET/ CT brain investigations
Research achievements (from final report):
Dual-modality positron emission computed tomography (PET) and computed tomography (CT) scanners are
extremely powerful, and technologically advanced, diagnostic imaging devices. The PET and CT scans,
performed during the same inaging sequence, provide fused images of unparalleled clarity, depicting both
function and anatomy. A major problem, however, is the propensity for patients to move during the scans,
which blurs the images or causes image artifacts that make interpretation by the physician difficult. In this
project we set out to develop and evaluate motion tracking and motion correction methods that could deliver
clear images, even in the presence of patient motion. The methods are specifically intended for application in
those patient groups least able to remain stationary during the scans - patients with dementia and young
children. Both typicall exhibit rapid, uncontrolled motion during PET/CT examinations. With the support of
this grant our team was able to develop and implement these methods on the Siemens Biograph 16 PET/CT
scanner at Westmead Hospital, and demonstrate their effectiveness in test scans with motion artificially applied
to a 3D brain phantom. Some unexpected problems due to new innovations in the PET scanner design delayed
the work, and we were grateful for the assistance of engineers from the Siemens factory in Knoxville USA
which allowed us to overcome them. Thus, although our techniques are now in place and ready for clinical
evaluation, we were unable to conduct patient trials during the lifetime of the grant. The grant has placed in a
good position to undertake the clincial evaluation and establish the utility of motion correction in the clinical
setting.
Expected future outcomes:
We have been successful in attracting an NHMRC Project Grant (ID 632677) to support this work in paediatric
PET/CT brain imaging for 3 years, commencing in 2010. With this additional support we are confident of
achieving our original objective of conclusively determining the impact of motion correction in clinical
PET/CT.
Name of contact:
Roger Fulton
Email/Phone no. of contact:
r.fulton@physics.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 630551
CIA Name: A/Pr Michael Valenzuela
Admin Inst: University of Sydney
Main RFCD: Epidemiology
Total funding: $183,218
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Which Mental Activities and When for Dementia Prevention? The Four Nations Longitudinal
CollaborationWhich Mental Activities and When for Dementia Prevention? The Four Nations Longitudinal
Collaboration
Lay Description (from application):
We will examine the link between lifetime participation in complex mental activities and long term dementia
risk in a level of detail not previously possible. Four major studies of brain health from around the world will
join forces for the first time to determine which mental activities are most closely linked to protection from
dementia, and when during the lifespan these are most important. Mental activity will be assessed using our
recently published Lifetime of Experiences Questionnaire.
Research achievements (from final report):
In this study, we for the first time are identifying what are the typical cognitive lifestyle patterns of your
average older Australian, older British person, older French person and older American. This has been
achieved using our Lifetime of Experiences Questionnaire (LEQ), developed and valdiated in Austalia and
culturally-appropriately translated into French and American Spanish. These country-specific versions of the
LEQ were administered to large community-based research populations in Sydney, Montpellier (France),
Cambridge (UK) and New York (USA). We have already produced a detailed picture of the complexity and
nature of lifecourse changes in cognitive lifestyle for older Australians, and now have the data to compare and
contrast these patterns with those of older individuals from our other collaborating centres around the world.
Expected future outcomes:
Understand similarities and differences in cognitive lifestyle between older persons in four different countries
as well as identify which specific activities may be particularly protective against development of dementia.
Name of contact:
Michael Valenzuela
Email/Phone no. of contact:
michael.valenzuela@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632689
Start Year: 2010
CIA Name: A/Pr Simon Lewis
End Year: 2013
Admin Inst: University of Sydney
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $496,341
Title of research award:
The impact of circadian disturbances on sleep quality, cognition and psychiatric symptoms in
neurodegenerative diseaseThe impact of circadian disturbances on sleep quality, cognition and psychiatric
symptoms in neurodegenerative disease
Lay Description (from application):
There is an increasing awareness that neurodegenerative diseases are associated with disturbances in sleep. Our
group have recognised that patterns of sleep disturbance in these patients are also related to problems with
memory and mood. The proposed study will be the first of its kind to explore whether disruptions in the
circadian system represent a common mechanism underlying these comorbid disease features. Understanding
this pathology will hopefully lead to the development of new therapies.
Research achievements (from final report):
This Project grant provided the first studies to demonstrate the circadian disturbances that might predict
dementia, the impact of Parkinson's medications on circadian processes and changes in the brain revealed by
functional neuroimaging that are associatred with sleep and cognition. The work conducted in this Project
allowed successful participation of two of the CIs in the award of the Centre for Translational Sleep and
Circadian Neurobiology, an NHMRC Centre for Research Excellence awarded in 2014.
Expected future outcomes:
Likely clinical translation with novel therapies. Already we have an ongoing RCT exploring the use of
melatonin for sleep disturbance in PD.
Name of contact:
Simon Lewis
Email/Phone no. of contact:
simonl@med.usyd.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 632876
CIA Name: Prof Lars Ittner
Admin Inst: University of Sydney
Main RFCD: Cell Neurochemistry
Total funding: $629,260
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The translocator protein (TSPO) as a novel target for the treatment of Alzheimers diseaseThe translocator
protein (TSPO) as a novel target for the treatment of Alzheimers disease
Lay Description (from application):
Alzheimer's disease (AD) is the most prevalent dementia, characterized by progressive loss of memory. An
estimated 230,000 Australians currently suffer from AD, causing a huge impact on their families and carers, as
well as on national finances. The present therapies are very limited, and there is no cure. Thus, there is a need
for novel treatment strategies. We have developed novel drugs that represent an innovative approach to the
treatment of AD.
Research achievements (from final report):
The project investigated the role of TSPO in microglial activation during Alzheimer's disease and the use of
novel TSPO molecules for the treatment of Alzheimer's disease and other neurodegenerative disorders. We
used chemical synthesis for the development of several series of novel molecules, which interact with the
TSPO and evaluated their ability to modulate the activity of microglia by using in vitro binding and functional
assays before use of these molecules in Alzheimer disease mouse models. In particular, we have been able to
synthesis a series of pyrazolopyrimidines to extend the profile and understanding of structural motifs within
this series that are important for TSPO binding and for enhanced steroidogenesis. This data has been published
in Current Molecular Medicine. Furthermore we have extended the chemotypes to included benzoxazepines
and extended our testing to human TSPO. We furthermore, established for the first time that the TSPO forms
dimers independent of its activity, data which is currently prepared for publication. We could also show
localization of TSPO within mitochondria. Together, we extended our understanding of the physiological
function of TSPO significantly. We also tested our new compounds in a mouse model of Alzheimer's disease,
and injected oozytes to generate transgenic mice for TSPO.
Expected future outcomes:
We expect to be able to isolate candidate compounds for TSPO that show efficacy in the tretament of
Alzheimer's disease, with hopefully one or more compounds progressing eventually into clinical trials.
Furthermore, we have generated in vivo tools to understand the TSPO and its role in disease in vivo in the
furture.
Name of contact:
Lars Ittner
Email/Phone no. of contact:
lars.ittner@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1025065
CIA Name: Prof Jillian Kril
Admin Inst: University of Sydney
Main RFCD: Central Nervous System
Total funding: $136,593
Start Year: 2012
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Finding clinical predictors for the underlying pathology in different frontotemporal dementia (FTD)
syndromesFinding clinical predictors for the underlying pathology in different frontotemporal dementia (FTD)
syndromes
Lay Description (from application):
Due to the ageing population in Australia it is predicted that the prevalence of dementia will increase four-fold
by 2050. Developing disease-modifying therapies for dementia is therefore a priority, however we also need to
be able to accurately identify patients for whom these therapies will be beneficial. Here we will develop
strategies for identifying patients with particular protein abnormalities in their brain, the substrate of most
therapeutic interventions.
Research achievements (from final report):
Frontotemporal dementia (FTD is a unique neurodegenerative disorder which is characterised by a variety of
clinical syndromes with a variety of underllying pathologies. In order to better diagnose and manage patients
with FTD we need to better understand the relationship between the clinical syndromes and their underlying
pathology. This project will investigate these relationships.
Expected future outcomes:
This project formed part of a successful program grant application. The next 5 years will bring a significant
body of research aimed at clarifying the clinical and neuropathological aspects of FTD and related MND,
explore animal models of these disorders and develop stategies for the treatment and management.
Name of contact:
Jillian Kril
Email/Phone no. of contact:
jillian.kril@sydney.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 106915
Start Year: 2000
CIA Name: Prof James Vickers
End Year: 2004
Admin Inst: University of Tasmania
Grant Type: NHMRC Project Grants
Main RFCD: Neurosciences not elsewhere classified
Total funding: $390,326
Title of research award:
The neural reaction to injury: Clues to the cause and prevention of acquired brain damage and Alzheimer's
disease.The neural reaction to injury: Clues to the cause and prevention of acquired brain damage and
Alzheimer's disease.
Lay Description (from application):
The cellular mechanism underlying neuronal degeneration following head trauma and Alzheimer?s disease is
not known and represents the major impediment to developing therapeutic strategies to protect nerve cells. This
grant application will utilise a variety of modern research methods to determine the key changes in the brain
that are associated with the response of nerve cells to physical trauma. These include not only the structural
alterations that immediately follow such injury, but the complex cellular and gene expression changes that
determine the ultimate fate of the cell. Both acquired brain injury and degenerative conditions such as
Alzheimer?s disease represent an enormous health, social and economic burden. Furthermore, with predictions
that Alzheimer?s disease will increase by 3-4 times by the middle of the next century due to the Oaging? of the
population, it is becoming even more crucial to establish effective therapeutic interventions. The animal models
investigated in this project can be used to unravel the crucial neuronal alterations associated with head trauma
and the early stages of Alzheimer?s disease and, more importantly, may be the key to discovering novel
strategies to prevent neuronal degeneration in these conditions.
Research achievements (from final report):
This project focussed on understanding how nerve cells and the mature brain respond to injury. We determined
that mature nerve cells undergo a series of cellular changes in response to damage, from initial reactive
alterations through to an attempt at regeneration. This demonstrated that nerve cells do not respond passively to
injury, but actively adapt to damage and seek to re-establish contact with other nerve cells. This indicates that
there is a window of opportunity to seek new approaches to protect nerve cells from injury and promote
appropriate regeneration. In this regard, we developed new culture models to test the effectiveness of drugs to
manipulate the nerve cell response to injury to promote the regeneration of damaged neurons. We determined
that filamentous proteins within nerve cells were crucial to this adaptive property of nerve cells and that agents
that promote or inhibit the stability of these proteins can affect the regenerative response following injury.
Furthermore, we determined that a class of metal-binding proteins has dramatic effects on nerve cell
regeneration and the University of Tasmania is currently seeking international patent protection for this
discovery. Finally, this project also examined how nerve cells and non-neuronal cells interact in the brain
healing response to damage. We recently determined that neural stem and progenitor cells are stimulated by
cortical injury but that these subsequently contribute to the glial response to injury and do not result in the
generation of new nerve cells.
Expected future outcomes:
These studies have indicated the cellular processes underlying appropriate and inappropriate forms of nerve
cell regeneration following injury. We have identified new potential therapeutic agents for the brain and the
platform technologies developed will be useful for further drug development.
Name of contact:
James Vickers
Email/Phone no. of contact:
James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 219297
Start Year: 2003
CIA Name: Prof James Vickers
End Year: 2006
Admin Inst: University of Tasmania
Grant Type: SRDC - Research
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $300,000
Title of research award:
Healthy & Pathological ageing of the human brain: Cellular, gene expression & diagnostic studiesHealthy &
Pathological ageing of the human brain: Cellular, gene expression & diagnostic studies
Lay Description (from application):
Not Available
Research achievements (from final report):
This study investigated the stageing of brain pathology associated with Alzheimer's disease, the main cause of
age-related dementia. Our studies focussed on the earliest cellular changes of Alzheimer's disease, as this may
be the best point to both diagnose and treat this degenerative condition. In addition, our studies focussed on the
cellular mechanism underlying nerve cell degeneration which leads to the gradual erosion of higher brain
functions that characterises Alzheimer's-type dementia. Our studies have demonstrated, for the first time, the
earliest alterations in nerve cells that heralds the onset of Alzheimer's pathology in the brain. We have shown
that these early brain changes involve cellular alterations in nerve cell processes associated plaque formation in
the neocortex. Critically, our studies indicate that nerve cell processes are compressed by plaque formation and
respond in a reactive fashion, attempting to regenerate and grow new processes. However, this regeneration is
abnormal and is likely to lead to a cascade of degenerative changes in nerve cells, leading to synaptic
disconnection and eventual nerve cell death. Other gene expression and cellular studies have determined that
nerve cells may have a unique pattern of cellular degeneration and are unlikely to die through the process of
apoptosis, a form of programmed cell death that many other Alzheimer's disease investigators are focussed on.
In summary, our investigations demonstrated that nerve cell degeneration in Alzheimer's disease is due to a
prolonged abnormal regenerative response of nerve cells to the presence of plaques. This provides critical new
targets for diagnostic studies and therapeutic intervention.
Expected future outcomes:
Our investigations have determined new leads on the underlying cause of nerve cell degeneration in
Alzheimer's disease and we are currently developing experimental models that replicate this pathology for
testing new therapeutic approaches for the early stages of dementia.
Name of contact:
James Vickers
Email/Phone no. of contact:
James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 605528
CIA Name: Prof Roger Chung
Admin Inst: University of Tasmania
Main RFCD: Central Nervous System
Total funding: $399,244
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Modulating beta-amyloid aggregation and toxicity with natural metal-binding proteinsModulating betaamyloid aggregation and toxicity with natural metal-binding proteins
Lay Description (from application):
Alzheimer's disease (AD) is a devastating disorder that afflicts millions of people worldwide. It is well
established that the small peptide beta-amyloid, has a direct and important role in the development of AD. This
project will investigate the ability of a small naturally occurring metal-binding protein to block the toxic
actions of beta-amyloid.
Research achievements (from final report):
N/A
Expected future outcomes:
N/A
Name of contact:
Roger Chung
Email/Phone no. of contact:
roger.chung@mq.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 605530
CIA Name: Prof David Small
Admin Inst: University of Tasmania
Main RFCD: Cell Neurochemistry
Total funding: $402,404
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
The receptor-associated protein (RAP) as a molecular chaperone for the amyloid protein (Abeta) of Alzheimers
diseaseThe receptor-associated protein (RAP) as a molecular chaperone for the amyloid protein (Abeta) of
Alzheimers disease
Lay Description (from application):
Our research will examine the role of a protein known as the receptor-associated protein (RAP) in Alzheimer's
disease. We will determine whether the protein contributes to the progression of Alzheimer's disease and we
will examine the possiblity that that RAP may be used as a drug to treat the disease. The project could
potentially have direct benefit for patients by leading to an effective treatment for dementia associated with
Alzheimer's disease.
Research achievements (from final report):
The research has provided important insights into the mechanism of A? metabolism and the role of the
receptor-associated protein in the pathogenesis of Alzheimer's disease.
Expected future outcomes:
The research may ultimately lead to the identification of novel targets for drug development in the field of
Alzheimer's disease.
Name of contact:
David Small
Email/Phone no. of contact:
d.h.small@menzies.utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 967749
Start Year: 1996
CIA Name: Prof James Vickers
End Year: 2001
Admin Inst: University of Tasmania
Grant Type: Career Development Fellowships
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $257,811
Title of research award:
Selective neuronal vulnerability and cellular changes associated with alzheimer's diseaseSelective neuronal
vulnerability and cellular changes associated with alzheimer's disease
Lay Description (from application):
Not Available
Research achievements (from final report):
This project focussed on understanding how nerve cells and the mature brain respond to injury. We determined
that mature nerve cells undergo a series of cellular changes in response to damage, from initial reactive
alterations through to an attempt at regeneration. This demonstrated that nerve cells do not respond passively to
injury, but actively adapt to damage and seek to re-establish contact with other nerve cells. This indicates that
there is a window of opportunity to seek new approaches to protect nerve cells from injury and promote
appropriate regeneration. In this regard, we developed new culture models to test the effectiveness of drugs to
manipulate the nerve cell response to injury to promote the regeneration of damaged neurons. We determined
that filamentous proteins within nerve cells were crucial to this adaptive property of nerve cells and that agents
that promote or inhibit the stability of these proteins can affect the regenerative response following injury.
Furthermore, we determined that a class of metal-binding proteins has dramatic effects on nerve cell
regeneration and the University of Tasmania is currently seeking international patent protection for this
discovery. Finally, this project also examined how nerve cells and non-neuronal cells interact in the brain
healing response to damage. We recently determined that neural stem and progenitor cells are stimulated by
cortical injury but that these subsequently contribute to the glial response to injury and do not result in the
generation of new nerve cells.
Expected future outcomes:
These studies have indicated the cellular processes underlying appropriate and inappropriate forms of nerve
cell regeneration following injury. We have identified new potential therapeutic agents for the brain and the
platform technologies developed will be useful for further drug development.
Name of contact:
James Vickers
Email/Phone no. of contact:
James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1011156
Start Year: 2011
CIA Name: Prof James Vickers
End Year: 2013
Admin Inst: University of Tasmania
Grant Type: NHMRC Project Grants
Main RFCD: Neurology and Neuromuscular Diseases
Total funding: $334,054
Title of research award:
Focal demyelination in Alzheimer's diseaseFocal demyelination in Alzheimer's disease
Lay Description (from application):
There are escalating numbers of Alzheimer’s disease sufferers. This Project aims to provide a better
understanding of the fundamental process underlying the damage to brain circuitry in this condition. This
proposal may provide key information regarding the relationship between the major pathological changes of
Alzheimer’s disease, identifying the cellular mechanisms that are crucial to this process, and providing new
avenues for therapeutic agents targeted at the earliest stage of AD.
Research achievements (from final report):
This project investigated the changes in nerve cells processes (axons) associated with one of the major
neuropathological features of Alzheimer's disease, beta-amyloid plaques. The study involved the analysis of
bot experimental animals that have been genetically engineered to develop beta-amyloid plaques with ageing,
as well as human brains, using advanced imaging techniques. The project showed that specific types of axons
and their synaptic connections degenerate, and that this was related to the loss of insulating myelin around
affected axons. The types of neurons that were affected were nerve cells that utilise excitatory neuroransmitters
and have long myelinated processes. In contrast, unmyelinated axons that utilise inhibitory neurotransmitters
were relatively spared by Alzheimer's pathology The project also determined that Alzheimer's pathology did
not involve specific degeneration of non-neuronal cells (oligodendrocytes) that provide myelin to axons,
indicating that these cells may potentially be able to assist the remyelination of axons if rescued from
degeneration.
Expected future outcomes:
The main outcome of this project has been to specificy which neurons and their processes and connections are
vulnerable in Alzheimer's disease, where therapeutic interventions should be targeted with respect to
neurotransmitter deficits, and how the brain retains a capacity to adapt and repair when exposed to Alzheimer's
disease-related pathology.
Name of contact:
James Vickers
Email/Phone no. of contact:
James.Vickers@utas.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513103
CIA Name: Prof Lynnette Chenoweth
Admin Inst: University of Technology Sydney
Main RFCD: Health Economics
Total funding: $1,548,805
Start Year: 2008
End Year: 2013
Grant Type: NHMRC Strategic Awards
Title of research award:
Person-centred environment and care for residents with dementia: a cost-effective way of improving quality of
life and qPerson-centred environment and care for residents with dementia: a cost-effective way of improving
quality of life and q
Lay Description (from application):
Improving the quality of life (QOL) and quality of care for persons with dementia are important areas of
Australian health research. A growing body of evidence shows that QOL in dementia can be improved by
relatively simple and inexpensive modifications to nursing care practices and the physical environment. Most
studies in these areas are observational, few have utilized a randomized control group design, and none has
included economic evaluation. This study will address these deficiencies. This is the first time that a
randomized controlled trial of Person-Centred Care (PCC) and Person-Centred Environment Design (PCD)
will be undertaken. The study will be conducted in 40 residential aged care services in New South Wales, to
determine the efficacy and cost effectiveness of implementing PCC and PCD separately, and in combination, in
improving resident quality of life and quality of care.
Research achievements (from final report):
From 38 aged care homes randomised, 601 people with dementia were recruited. At follow-up the mean
change for resident quality of life and agitation from zero was significantly different for homes with a Person
Centred Environment (PCE) (p=0.02, p=0.05, respectively) and for homes offering Person Centred Care (PCC)
(p=0.0003, p=0.002 respectively), compared with non-intervention homes (p=0.48, p=0.93 respectively).
Quality of life improved non-significantly for homes providing PCC+PCE (p=0.08), but not for agitation
(p=0.37). Improvements in care interaction quality (p=0.006) and in emotional responses to care (p=0.01) in
PCC+PCE homes were not observed in the other homes. Findings are, therefore, inconsistent. By themselves
PCE and PCC improved quality of life and reduced agitation in residents with dementia, compared with nonintervention homes. Contrary to studies showing reductions in agitation being associated with environmental
improvements (Davis et al., 2009; Fleming and Purandare, 2010), the residents in the PCE+PCC homes (27%
exposed to intervention) had no significant improvements in their mean level of agitation. The negative impact
of the low level of implementation in the PCE and PCC homes may have been amplified by the reduced
opportunities for improvement due to two of these homes being very new. Nevertheless, there were significant
reductions in agitation for residents in PCE only homes where 54% were exposed to intervention. The
hypothesis that PCC+PCE would improve quality of life and agitation even further was not supported, even
though there were improved quality of care interactions and resident emotional responses in care in only the
PCC+PCE homes.The lack of a strong association between PCE, depression and quality of life may have been
due to reported difficulties in measurement by self-report.
Expected future outcomes:
This is the first study to rigorously test the effect of environmental alterations that were adapted to the
requirements of the aged care home and its residents, providing a firm basis for more sophisticated assessment
of depression and quality of life for people with moderate to severe levels of dementia in relation to their living
environment.
Name of contact:
Lynn Chenoweth
Email/Phone no. of contact:
Lynnette.Chenoweth@uts.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1016737
CIA Name: Dr Meng Wang
Admin Inst: University of Technology Sydney
Fellowships
Main RFCD: Biologically Active Molecules
Total funding: $221,137
Start Year: 2011
End Year: 2012
Grant Type: International Exchange Early Career
Title of research award:
Element labeling antibodies for bio-imaging of proteins: a case study of beta-amyloid in Alzheimer's disease
mouse modelsElement labeling antibodies for bio-imaging of proteins: a case study of beta-amyloid in
Alzheimer's disease mouse models
Lay Description (from application):
This project will develop new analytical methods for quantitative in-situ imaging of beta-amyloid in mouse
brains. Beta-amyloid deposition in the brain is associated with Alzheimer’s disease. It is also planned to
simultaneously image metal ions, which are also implicated in the deposition of beta-amyloid. Application of
these novel methods to Alzheimer’s disease mouse models will provide new knowledge and significant insights
into the aetiology of Alzheimer’s disease by determining the relationship between amyloid proteins and metal
ions.
Research achievements (from final report):
In this project, we develop new analytical methods based on synchrotron radiation x-ray fluroscence for bioimaging of proteins.Application of these novel analytical methods to Alzheimer's disease mouse models will
provide new knowledge and significant insights into the aetiology of Alzheimer's disease by determining the
relationship between amyloid proteins and metal ions.
Expected future outcomes:
The developed method makes the technology more accessible as a routine analytical tool for medical
researchers. The technology may also be applied to any diseases in which metals and trace elements are
thought to play a role including Parkinson's disease, Wilson's disease and many types of cancer.
Name of contact:
Meng Wang
Email/Phone no. of contact:
WANGMENG@IHEP.AC.CN
NHMRC Research Achievements - SUMMARY
Grant ID: 139093
CIA Name: Prof Paul Norman
Admin Inst: University of Western Australia
Main RFCD: Epidemiology
Total funding: $891,110
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Perth Elderly Cohort StudyPerth Elderly Cohort Study
Lay Description (from application):
This study will follow up over 12,000 men aged 65-83 years who have previously completed a questionnaire
about their medical, social, family and occupational history and lifestyle and have undergone a simple physical
examination (height, weight, waist, girth at the hips and blood pressure). The first aim is to determine which of
these factors predicts serious ill-health from heart disease, stroke and certain cancers in old age. In addition,
we will test the hypothesis that risk factors for heart disease also predict the development of dementia because
it seems that part of dementia in some patients is explained by their having suffered multiple small strokes.
Finally, we will examine the relationship between development of dementia and previous major surgery as
there is growing evidence that major surgical operations in older patients can be followed by confusion and
impairment of thinking that may never recover fully. The overall aim is to discover preventable factors for
several of the leading causes of ill-health in old age.
Research achievements (from final report):
The main achievment over the period 2001-4 has been the assessment of 4,500 men at a research clinic. Each
man completed an extensive questionnaire, under went screening for dementia and had blood tests including
measurement of cholesterol, sugar, kidney function. The health outcomes in all these men will now be
monitored over the next decade. To date, only a small number of the numerous projected analyses have been
completed. These include an assessment of the role of a simple lifestyle score in predicting cardiovascular
disease and the demonstration that the diameter of the abdominal aorta predicts future death from any cause.
Expected future outcomes:
As the cohort of men age, they will inevitably experience a range of fatal and non-fatal illnesses that can be
identified using centralised Health data. The diagnoses include various types of cardiovascular disease and the
common cancers. We plan to study the relationship between a wide range of risk factors present in older age
and subsequent outcome.
Name of contact:
Paul Norman
Email/Phone no. of contact:
pnorman@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 139123
CIA Name: Prof Leon Flicker
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $286,018
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
An Intervention Trial to Prevent Cognitive Impairment and Depression in Older MenAn Intervention Trial to
Prevent Cognitive Impairment and Depression in Older Men
Lay Description (from application):
A gradual decline in the thinking processes, dementia and depression are major health issues for older people.
There is already some evidence that deficiency in certain vitamins may be contributing to these problems. This
project seeks to evaluate an inexpensive and simple vitamin supplement which may provide a highly costeffective method of preventing cognitive decline, dementia and depression in older people. This research will
also allow the evaluation of the role of certain biological and genetic risk factors which may also impact on
these problems. This project seeks to do a trial of these vitamins in older men who are at particular risk for
these problems. The men in this project will be monitored by simple tests of their thinking and evaluating any
symptoms of depression.
Research achievements (from final report):
It is a little early and will depend on the outcome of the analyses once the full analyses have taken place (we
still have not unblinded). Others have demonstrated that there is an association between the toxic protein
homocysteine in the blood and the important problems of depression and memory problems in older people.
We have demonstrated that there are high rates of B12 deficiency and elevated levels of homocysteine in well
older men. We are currently waiting for the results of our study to see if vitamin supplements can correct some
of these problems
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 139139
CIA Name: Prof David Bruce
Admin Inst: University of Western Australia
Main RFCD: Psychiatry
Total funding: $315,509
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Project Grants
Title of research award:
Diabetes and dementia: studies with the Fremantle Diabetes Study cohort.Diabetes and dementia: studies with
the Fremantle Diabetes Study cohort.
Lay Description (from application):
Dementia is an extremely serious condition which affects a large proportion of the older population. Recent
evidence has shown that diabetes, which is another common condition in the elderly, doubles the risk of an
older person developing Alzheimer's disease and other forms of dementia. Why this happens is unknown but
insulin therapy has been highlighted as a possible cause. As many older people are on insulin for their
diabetes, it is extremely important to confirm or refute this finding. It seems possible that insulin may not be
the direct cause but that some other associated factor such as poor diabetes control, recurrent hypoglycaemic
attacks or cerebrovascular disease causes dementia. On theoretical grounds, Alzheimer's disease may have a
vascular basis. If Alzheimer's disease was, in part, caused by vascular disease then there is the potential to
prevent cases of dementia developing by paying attention to the known risk factors for vascular disease such as
hypertension. The Fremantle Diabetes Study is an ideal group of community living diabetic individuals in
which we can study whether some or all of these factors cause Alzheimer's disease or dementia and gain
insights into the potential for prevention.
Research achievements (from final report):
The problem of dementia and cognitive impairment in people with diabetes has become a hot topic as the
combination of disorders implies the presence of some common, preventable factor that could have immense
public health importance. The findings from the present study are therefore eagerly awaited. The study design
included serial assessments and we have just now completed the data collection phase and so the major
achievements from this project are not yet fully realised. We were able to study a large group of older people
who had long-standing diabetes and carry out detailed assessments of their cognitive function and several other
important aspects of their mental health. We are in the process of analysing the data and expect to be able to
determine whether the development of cognitive impairment in these older people was related to either their
blood pressure or their blood glucose control in the decade preceding the cognitive assessments or whether it
was related to diabetes treatments, particularly insulin therapy as we originally hypothesized. We have
established that both cognitive impairment and mood disorders occur more frequently in diabetes than
expected. We also found that many subjects had subtle brain abnormalities known as white-matter lesions and
due to chronic ischaemia, that were shown using MRI scans. Importantly, the presence of these abnormalities
correlated with some of the cognitive measurements and also with measures of depression. As white-matter
lesions are usually the result of long-standing hypertension, these findings suggest that cognitive impairment
and depression could be preventable in such patients by improved control of hypertension. The significance of
this project includes the potential for designing preventive strategies and the need for staff in diabetes services
to be able to diagnose and manage these common but under-recognised problems.
Expected future outcomes:
N/A
Name of contact:
N/A
Email/Phone no. of contact:
N/A
NHMRC Research Achievements - SUMMARY
Grant ID: 211976
CIA Name: Prof Osvaldo Almeida
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $170,990
Start Year: 2002
End Year: 2004
Grant Type: NHMRC Project Grants
Title of research award:
Effects of oestrogen on mood, memory and quality of life of women aged 70 years or overEffects of oestrogen
on mood, memory and quality of life of women aged 70 years or over
Lay Description (from application):
Oestrogen has a number of actions that extend well beyond the regulation of the reproductive cycle and sexual
behaviour. The results of recent studies indicate that oestrogen may influence mood and a number of
intellectual abilities such as memory and language. In addition, oestrogen replacement therapy seems to reduce
the risk of Alzheimer's disease (the most frequent cause of dementia in Western societies) amongst
postmenopausal women. The present study aims to: (1) investigate the association of depression and memory
performance with physiological levels of oestrogen in women aged 70 years or over; and (2) investigate the
evolution of depression and memory scores in old women treated with oestrogen replacement therapy as
compared to placebo. The results of the present study may have important implications in the prevention and
management of two of the most relevant mental health disorders of later life: depression and Alzheimer's
disease.
Research achievements (from final report):
Recruitment for this study has been completed. A total of 278 women were recruited for the cross-sectional
component of the study. This number is larger than predicted in our original proposal (planned n=220), as the
percentage of refusal and ineligibility to enrol into the clinical trial was higher than anticipated. The trial has
been completed as planned, with 58 women having been randomised to treatment with estradiol and 57 to
placebo. The results of this study have been presented at several scientific meetings and 9 papers have been
published so far with the data originating from this project.
Expected future outcomes:
The results of the 1-year follow-up of women recruited into the trial will be analysed and reported towards the
end of 2005.
Name of contact:
Osvaldo P. Almeida
Email/Phone no. of contact:
osvalm@cyllene.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 254594
CIA Name: Dr Elizabeth Milward
Admin Inst: University of Western Australia
Main RFCD: Mental Health
Total funding: $473,000
Start Year: 2003
End Year: 2005
Grant Type: NHMRC Project Grants
Title of research award:
Iron and Cognition in Older AdultsIron and Cognition in Older Adults
Lay Description (from application):
Iron is essential for brain health. Too little iron can cause problems with memory, concentration and attention
and can result in below average intellectual performance or even stroke in children. Too much iron can also be
harmful. In the iron overload disease haemochromatosis, iron deposition throughout the body can lead to organ
damage in the liver and other tissues. Concentrations of iron in the brain can equal those in liver. Yet
surprisingly little is known about the effects of iron on the adult human brain. Although the adult brain has
traditionally been considered to be protected from the effects of high body iron by the blood-brain barrier,
modern techniques show brain iron loading in patients with iron overload disorders or with various brain
diseases such as Alzheimer's disease and Parkinson's disease. Several recent studies, including our own, have
found associations between mutations in genes important in iron metabolism and brain diseases such as
Alzheimer's disease. As many as 30% of Australians have abnormal iron levels (too high or too low) that are
often undiagnosed and untreated. There is growing reason to believe these men and women are more likely to
have memory problems as well as being at increased risk of brain diseases such as Alzheimer's disease. There
is an urgent need for a large-scale study of the short-term and long-term effects of iron levels and related
genetic factors on brain health and function. Residents of the Western Australian town of Busselton have
participated in a set of health surveys since 1966. We have studied the iron status and related genetic factors in
over 3,000 Busselton people. We now propose to perform tests of memory, attention, concentration and related
brain activities on the older members of this community group. This will allow us to discover the effects of
relevant gene factors, and short- and long-term iron status on memory and other brain functions and on
Alzheimer's disease and related disorders.
Research achievements (from final report):
Earlier small studies using various approaches including animal models and human genetic and brain tissue
analyses have led to speculation that too much iron contributes to brain problems in Alzheimer's disease and
related disorders. , To examine this more rigourously our study extended a bank of existing longitudinal
archival data collected in community health surveys dating back to 1966. We estimate the present study
(n=1,008 people 60 years or more) adds over a million pieces of new data, including unique information on
memory and other areas of brain function in addition to new information on iron status and general health. This
provides a unique and valuable resource for research on ageing in Australia. , We found that prevalence of
Alzheimer's disease and other dementias, assessed by specialists in geriatric medicine following cognitive
screening, was substantially lower than expected in this community group. The reasons are unclear but may be
important to pursue in view of community concerns about dementia risks. All participants with dementia and
also essentially all participants with cognitive impairment without dementia (potentially at higher risk of going
on to develop dementia) had iron measures within normal ranges. Although about 10% of the group had one or
more high iron measures this was never accompanied by clinically significant functional impairment
attributable to memory impairment. While high iron might still affect other cognitive domains, these findings
may help alleviate anxiety about developing memory loss and dementia experienced by some people with high
body iron status (haemochromatosis) and their families.
Expected future outcomes:
The information collected in the study provides a unique basis for future research identifying genetic and
environmental factors that contribute to, or protect against, the development of both iron-related health
problems and to memory loss, Alzheimer's disease and other health problems in older Australians.
Name of contact:
NHMRC Research Achievements - SUMMARY
Dr Liz Milward
Email/Phone no. of contact:
Liz.Milward@newcastle.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 303172
CIA Name: Prof Nicola Lautenschlager
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $280,250
Start Year: 2004
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
A randomised clinical trial of Physical activity for the treatment of older adults with mild cognitive
impairmentA randomised clinical trial of Physical activity for the treatment of older adults with mild cognitive
impairment
Lay Description (from application):
Australia's population is aging rapidly and so is the frequency of age-related diseases. Dementia and depression
are the most frequent mental health disorders of older people. They are also the leading causes of years of life
lost due to disability in Australia. The results of recent studies have shown that memory difficulties and
dementia are associated with potentially modifiable risk factors, such as physical activity. The purpose of this
study is to investigate whether a physical activity program for older adults decreases cognitive decline and
conversion to dementia in a population at risk: mild cognitive impairment (MCI). 168 subjects with MCI will
be randomised (by chance, like the flip of a coin) to either the intervention program of physical activity or
usual care - their cognitive (such as memory) performance will be compared at the end of 24 months.
Research achievements (from final report):
Data collection for this trial has been completed in January 2007. Preliminary results of ths study show that
participants, who were randomised to the intervention, could complete the physical activity program
successfully. After completion of the intervention they were significantly more physical active than the control
group and they also performed significantly better on cognitive tests.
Expected future outcomes:
To promote phsycial activity as a lifestyle intervention which can positively affect cognitive function in older
adults with memory complaints.
Name of contact:
Prof Nicola Lautenschlager
Email/Phone no. of contact:
nicola.lautenschlager@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353566
CIA Name: Prof Nicola Lautenschlager
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $399,600
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
Insight and cognitive decline in older adults with Mild Cognitive ImpairmentInsight and cognitive decline in
older adults with Mild Cognitive Impairment
Lay Description (from application):
Australia's population is aging rapidly and so is the frequency of age-related disorders. Dementia is one of the
most frequent mental health disorders and one of the leading causes of years of life lost due to disability in
Australia. Therefore it is important to be able to identify older adults at high risk of developing dementia in
order to be able to introduce preventative strategies. One important risk factor for cognitive decline is the
presence of mild cognitive impairment (MCI) in older adults who complain about memory problems. However
many subjects with MCI do not develop dementia and it remains a challenge to identify those with "predementia" amongst those with MCI. The purpose of this study is to investigate whether reduced awareness of
cognitive impairment is a better predictor of cognitive decline and dementia than having memory complaints .
To investigate the association of reduced awareness and cognitive decline, 80 participants with MCI and 80
healthy controls will be followed over a period of 24 months. Awareness will be measured and compared to
information on cognitive and functional impairment given by the participant and an informant. Additionally,
information from neuroimaging and laboratory studies will be collected to determine it's interaction with
reduced awareness.
Research achievements (from final report):
Data collection for this project was successfully completed in 2007. 183 participants commenced the study of
which 92 had mild cognitive impairment and 91 were cognitively healthy controls. These were followed up
over 18 months with cognitive and health assessments. All participants and a nominated informant were given
questionnaires on the participant's current memory ability. 66 MCI participants and 55 controls consented to
have a cranial MRI scan - the analysis of these scans is pending and expected to occur in 2009. , Cross
sectional analysis of cognitive and memory self and informant reports has taken place. Overall, reduced
awareness was rare in this group even in people with MCI. Self-report of memory problems was correlated
with objective cognitive performance. Neurological soft signs were also associated with cognitive performance
at baseline. These results were reported at an invited symposium presentation at the 13th International
Congress o fInternational Psychogeriatric Association in Osaka, Japan, (published in International
Psychogeriatrics, vol 19, supp 1, p 44-45. and as free papers at two other confernces. 18-month results have
been analysed and submission of a manuscript is currently in preparation. Overall, reduced awareness was not
prevalent in our group and not associated with cognitive performance/decline, but self-reports and informant
reports were. Informants in this group generally rated participants as less impaired as the participants
themselves did. This result is important as current clinical guidelines see the informant report as most
important when assessing memory - self reports may be just as important and should not be ignored by
clinicians even if they contradict informant reports.
Expected future outcomes:
A manuscript is in preparation for the results concerning self-and informant- memory reports and cognitive
performance. MRI data will be analysed in 2009/10. An abstract concerning the follow up results has been
submitted to the Australasian Society for Psychiatric Research's 2009 conference.
Name of contact:
Nicola Lautenschlager
Email/Phone no. of contact:
nicolat@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353590
CIA Name: Prof Sergio Starkstein
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $361,000
Start Year: 2005
End Year: 2007
Grant Type: NHMRC Project Grants
Title of research award:
The Diagnosis of Depression in Alzheimer's DiseaseThe Diagnosis of Depression in Alzheimer's Disease
Lay Description (from application):
During the next 3 decades the number of persons older than 85 years will more than double, and the health care
need of this burgeoning population are assuming greater importance. Among the most significant but often
overlooked conditions in the elderly is depression, which is associated with marked disability, functional
decline, risk of hospitalization, diminished quality of life, caregiver burden, increased service utilization, and
mortality from comorbid medical conditions or suicide. The World Health Organization predicts that by 2020
depression will be second only to heart disease as a cause of disability and premature death in established
market economies. Depression is missed in approximately half of all elderly persons with mood disorder, and
this frequency is certainly higher among individuals with dementia. The strategy to diagnose depression in
dementia needs to be revised. Patients' reports are often unreliable due to memory problems and lack of full
insight into their mood and behavioural changes. Caregivers may overestimate patients' symptoms of
depression, especially when they themselves are depressed and overburdened, and clinicians' diagnoses are
sometimes based on biased information and short observation periods. The situation in nursing homes is even
worse, and there is a shortage of studies on how to diagnose depression in institutionalised patients with
dementia. Using specific instruments to assess mood, behaviour and cognition we will develop valid and
reliable criteria to diagnose depression in the different stages of dementia, and for patients living in different
settings. This will facilitate the early recognition and adequate treatment of depression in individuals with
dementia, it will greatly improve patient's quality of life, and will have a positive impact on caregivers'
psychological well-being.
Research achievements (from final report):
Our study demonstrated that about half of the patients with Alzheimer's disease (AD) will suffer from
depression at some stage of the disease. Major depression was the most common type of affective disorder in
our sample. We also found that depression in AD is not a fleeting phenomenon, but may last for about 12
months. Furthermore, 34% of AD patients without depression at baseline developed depression during a 12month follow-up period. We found that many patients with depression were not treated for their mood disorder,
but we also found a high proportion of AD patients on antidepressants who continued to be depressed,
suggesting that the treatment had poor efficacy. , Another important finding was that loss of interest, loss of
pleasure, feelings of guilt, suicide ideation, psychomotor slowness, agitation, anxiety, loss of energy, nihilistic
ideas, and oversleeping were all significantly associated with sad mood. Therefore, these symptoms should be
used to diagnose depression in AD patients with mild and moderate dementia. Among patients with severe
dementia and difficult communication, poor appetite was the symptom most strongly associated with sad
mood., One limitation to the diagnosis of depression in dementia is that patient may not be fully aware of the
extent of their depressive symptoms. In support, we found that AD patients significantly minimized their
depressive symptoms, as compared with reports provided by their respective caregivers., Finally, we also found
that depression in AD patients partially accounted for the severity of depression among caregivers, suggesting
that the successful treatment of depression in dementia may improve the psychological well-being of
caregivers.
Expected future outcomes:
We empirically valididate specific criteria to diagnose depression in AD. This will help to identify more
homogeneous groups of patients who may benefit from specific therapeutic intervention. We plan to explore
the efficacy of pharmacological and psychological treatments of depression in AD.
Name of contact:
NHMRC Research Achievements - SUMMARY
Sergio E Starkstein
Email/Phone no. of contact:
ses@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 353612
CIA Name: Dr Dina Logiudice
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $242,000
Start Year: 2005
End Year: 2006
Grant Type: NHMRC Project Grants
Title of research award:
Assessing the health needs of older Indigenous Australians living in the KimberleyAssessing the health needs
of older Indigenous Australians living in the Kimberley
Lay Description (from application):
This study was designed to address the need for accurate assessment of the health care needs of older
Indigenous people, particularly in remote regions of Australia. Indigenous people have higher rates of
premature chronic medical illness, and there is substantial evidence that chronic functional disorders start at
younger ages in this population. Common conditions of older age, such as dementia, falls and incontinence, are
associated with substantial morbidity, disability and health care expenditure; yet, little is known about the
extent of these problems amongst Indigenous Australians. This study builds on a successful project conducted
in the Kimberley in 2003 that was designed with the aim of developing and validating a screening instrument
for the assessment of dementia amongst Indigenous people. The present project proposes to expand the scope
of our previous work to include the assessment of other common conditions associated with older age, such as
depression, incontinence and falls and determine use of health services and potential impediments to their
access.
Research achievements (from final report):
The evidence for a high prevalence rate of dementia among rural and remote Indigenous people is provided by
our pioneering work. Over the last 5 years this important research has focussed on developing an assessment
tool (the Kimberley Indigenous Cognitive Assessment tool) in order to identify those Indigenous people who
may have dementia. We then validated the results of this assessment tool against specialist assessment. This is
the first research to be done on the number of Indigenous people with dementia in Australia based on a
validated assessment instrument. A target sample was selected of 400. To make the research possible,
community members 45 years or older. The method of research was first to assess individuals using the KICA
assessment tool. Subsequently, within three months, the same individuals were assessed by two independent
experts blinded to the KICA results. The refusal rate was lass than 10%. The prevalence rate for demntia was
4.8 times that of the non-Indigenous population. Currently the investogators are analysing service gaps for
people with dementia in the Kimberleys.
Expected future outcomes:
Develop awareness of the problem of dementia in Indigenous Communities and assist in culturally appropriate
services
Name of contact:
Dr Dina Logiudice
Email/Phone no. of contact:
dina.logiudice@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 403963
Start Year: 2006
CIA Name: Prof Paul Norman
End Year: 2008
Admin Inst: University of Western Australia
Grant Type: NHMRC Project Grants
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $403,015
Title of research award:
Maintaining and developing the Health In Men StudyMaintaining and developing the Health In Men Study
Lay Description (from application):
The aim of this study is to improve our understanding of healthy aging in older men. The outcomes we are
interested in include common acute medical problems such as heart attacks or stroke, chronic debitilating
problems such as dementia or heart failure and psycho-social challenges of ageing such as depression and
isolation. We have been studying a group (4,250) men for nearly a decade. These men have provided us with a
large amount of information about their background, life style and health and we are now following them to
see what predicts the outcomes of interest. This research is important because the proportion of the population
aged 75 years and over is expanding rapidly. Although we know a lot about predictors of health and illness in
middle age, we know surprisingly little about these things in the elderly. This research aims to answer some of
these questions.
Research achievements (from final report):
This grant made it possible to maximise the potential of an existing collection of research data obtained from a
large group of men aged 65 and over who have participated in a number of health surveys since 1996. The
electronic data was re-organised and made accessible to researchers, some data was checked for accuracy and
additional biochemical results were obtained from stored blood samples. The grant also contributed funding
towards a new questionnaire. As a result of this, a wide range of issues relevant to the health of older men have
been studied. These include: risk factors for depression and dementia; the influence of sex hormone level on
health and illness in older men, genetic and other factors causing various forms of cardiovascular disease
(particularly aortic aneurysms).
Expected future outcomes:
The project has archived blood samples which can be used for future analyses and the outcome of men in the
cohort can be follwed indefinitely, it is possible to continue accrueing new data for many years.
Name of contact:
Paul Norman
Email/Phone no. of contact:
paul.norman@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458791
CIA Name: Prof Nicola Lautenschlager
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $646,602
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Strategic Awards
Title of research award:
Does vitamin D supplementation reduce cognitive decline?Does vitamin D supplementation reduce cognitive
decline?
Lay Description (from application):
Australia's population is ageing rapidly and so is the frequency of age-related disorders. Dementia is one of the
most frequent mental health disorders of older people and one of the leading causes of years of life lost due to
disability in Australia. Mild Cognitive Impairment (MCI) in old age is considered an important clinical state
predictive of future cognitive decline. There is increasing evidence that the onset of dementia can be delayed
with targeting potentially modifiable risk factors. Vitamin D is important for healthy bones and muscle
function, but is now also discussed as being important for healthy brain function. The purpose of this
randomised placebo-controlled clinical trial is to investigate whether supplementation with vitamin D for 18
months in older adults with MCI who have low vitamin D levels, can help to reduce cognitive decline. 110
older adults with MCI will be randomised (by chance, like the flip of a coin) to either active treatment or
placebo. Their cognition (such as memory) performance, quality of life and functional level will be compared
at 6, 12, and 18 months. If our hypothesis is confirmed, vitamin D supplementation might prove to be a simple,
effective and inexpensive way of delaying cognitive decline in people at risk for dementia. This could lead to
the reconsideration of current sun exposure policies in Australia and the more widespread use of food
fortification and supplementation.
Research achievements (from final report):
This randomised trial of vitamin D supplements failed to find benefit in a global cognitive outcome in
participants with mild cognitive impairment. In fact there was reasonable evidence that vitamin D
supplementation may have contributed to harm cognitive function over 18 months. The results in the primary
efficacy variable of the CAMCOG were supported by ratings made on the CDR, implying not only cognitive
changes but also everyday impairment. This is directly opposed to our a priori hypothesis and we can only
speculate about the reasons this may have occurred. The most likely explanation is that this dose of vitamin D
supplements in this group of participants may have produced unexpected negative consequences. Overall, the
results of our trial suggest that older adults with MCI and no overt vitamin D deficiency who receive
supplementation show a small but significant worsening of cognitive function over 18 months compared with
placebo treatment. The results of this study may not apply to those individuals with more pronounced vitamin
D deficiency, but raise concerns about the non-indicated use of vitamin D in later life.
Expected future outcomes:
The findings of this RCT will contribute to the knowledge in this area. A main trail outcome publication is
expected to be submitted soon to a high impact international scientific journal. the results of this study might
affect public health policies in relation to Vitamin D supplementation in older adults.
Name of contact:
Nicola Lautenschlager
Email/Phone no. of contact:
nicolatl@unimelb.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458792
CIA Name: Prof Sergio Starkstein
Admin Inst: University of Western Australia
Main RFCD: Mental Health
Total funding: $459,983
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Strategic Awards
Title of research award:
Deficits of Insight and Judgment in Alzheimers Disease: Diagnostic Strategy and Clinical SignificanceDeficits
of Insight and Judgment in Alzheimers Disease: Diagnostic Strategy and Clinical Significance
Lay Description (from application):
During the next three decades the number of persons older than 85 years will more than double, and the health
care need of this burgeoning population are assuming greater importance. Recent studies suggest that the
prevalence of dementia in Australia will increase from 172 000 cases in 2000 to 588 000 in 2050. This rapid
increase in number of dementia cases will result in an increasing burden for caregivers, and in financial terms,
for the working-age population. One of the main clinical problems suffered by individuals of dementia is
psychological and behavioural changes such as poor insight, irritability and apathy. These problems account for
a large proportion of medical expenses, predict early institutionalization, and are associated with poor quality
of life of caregivers. Unfortunately, little is known about the true frequency of problems of insight in dementia,
about their impact upon caregivers, and about how to best diagnose the problems of loss of insight and
judgment in this condition. Our study will examine the frequency and clinical correlates of poor insight and
judgment in dementia, it will establish whether these problems predict other common behavioural problems of
Alzheimer’s disease such as apathy and dangerous behaviours, and will demonstrate the reliability and validity
of a specific instrument to measure insight and judgment in dementia. This will facilitate the early recognition
and adequate treatment of behavioural problems in patients with dementia; it will improve patients’ quality of
life, and will have a positive impact on both caregivers’ psychological well-being and on clinical practice.
Research achievements (from final report):
We designed the Structured Interview for Insight and Judgment in Dementia (SIJID) for use in patients with
Alzheimer's disease (AD). We demonstrated a high test-retest and inter-rater reliability, a high internal
consistency, and two factors that included items of insight and judgment, respectively. We also demonstrated
the concurrent validity of the scale, as patients divided into groups with mild, moderate or severe risk based on
the SIJID had significantly different anosognosia scores (i.e. patients with severe risk had higher anosognosia
scores than the other 2 groups). We also demonstrated the criterion validity of the SIJID, as patients in the
severe risk group had a significantly higher frequency of anosognosia than patients in the mild risk group.
Finally, we also demonstrated that loss of insight and judgment have a negative impact on patients' behaviour
and caregivers' quality of life There was a significant correlation between SIJID total scores and disinhibition
scores as measured with the Neuropsychiatric Inventory, and caregivers of patients in the severe risk group had
significantly higher scores on the Caregiver Strain Index scale than caregivers of patients in the mild or
moderate risk groups., In conclusion, we demonstrated that the SIJID is a valid instrument to assess insight,
judgment, and competency among patients with AD and we believe this instrument will be used world-wide to
assess these important psychiatric concomitants of patients with dementia. Additionally, we also demonstrated
that loss of insight and judgment are significantly associated with abnormal behaviours in demented patients
and with increased strain in caregivers.
Expected future outcomes:
We expect the SIJID will become the instrument of choice to assess insight, judgment and competency among
patients with dementia. Therefore, the SIJID should be further validated in patients with non-AD dementias
such as vascular, frontotemporal and Lewy body dementias.
Name of contact:
Professor Sergio Starkstein
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
ses@meddent.uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458793
Start Year: 2007
CIA Name: A/Pr Dina LoGiudice
End Year: 2010
Admin Inst: University of Western Australia
Grant Type: NHMRC Strategic Awards
Main RFCD: Public Health and Health Services not elsewhere classified
Total funding: $1,081,061
Title of research award:
Models of care to address unmet of older Indigenous with dementia their families and communites living in
remote WAModels of care to address unmet of older Indigenous with dementia their families and communites
living in remote WA
Lay Description (from application):
The health and unmet needs of older Indigenous people, particularly in remote and rural areas is generally
under researched. It is well known that the life expectancy of indigenous people is approximately 20 years
younger than non-Indigenous counterparts. Many illnesses generally experienced by non Indigenous people in
older ages (e.g. 75 years) are seen at a much younger age in Indigenous populations. These conditions include
dementia, falls, incontinence, premature heart disease and strokes. Over the last 4 years the applicants of this
project have started to address some of the health related problems faced by older Indigenous people,
particularly the challenging area of dementia. The authors have developed a culturally appropriate assessment
tool to help determine if an older Indigenous person has dementia. This has been very successful and is now
frequently used by health professionals in remote and rural areas of Australia. A survey is in the final stages of
completion to determine the estimated number of people in remote areas of the Kimberley who manifest signs
and symptoms of dementia and associated old age diseases. Preliminary data sadly indicate that the frequency
of dementia is higher than expected for people of this age group. The next phase of this project is to determine
the unmet needs of this vulnerable group, by interviewing those with dementia and their families, communities
and service providers in remote areas of Kimberley and Pilbara. This will determine culturally appropriate and
practical ways to provide care to assist those with this condition and their families and communities.
Research achievements (from final report):
The unmet needs of people living with dementia in remote Aboriginal communities in the Kimberley region of
Western Australia and Central Australia were determined. A model of care that addresses the identified needs
of people living with dementia, mental illness, the frail aged and people of all ages with disabilities in remote
Aboriginal communities was developed, trialed and evaluated in the Kimberley region. The final report and
evaluation are available from www.wacha.org.au. The key unmet needs were addressed. Aboriginal staff were
employed and trained to provide care to their community members, including completing Certificate III or IV
in Aged Care. Community consultation improved, with the Aboriginal community council being an integral
component of the management committee and Aboriginal community members being formally engaged at all
levels. Service coordination improved through co-owning a project with the remote community, developing
shared objectives and regular management and local action group meetings facilitated by an independent body.
A greater range of quality, culturally safe services were provided. The community and service providers had
one community access point for a range of community-based and external services. Client advocacy improved
through a community-based coordinator. Recommendations were made in the final report on ways to improve
the model of care so that it can be implemented in other interested remote regions. Dementia guidelines for the
Kimberley region were developed and disseminated. Newsletters outlining the progress of the study were
developed and disseminated widely around Australia. Funding has been gained to trial dementia care and
education pathways for Central Australia.
Expected future outcomes:
Growth funding has been gained for the model to continue. The Kimberley region is adopting some of the key
components of the model and restructuring the government aged care service to meet the recommendations
from the project evaluation. In Central Australia pathways to dementia care and education are being developed.
Name of contact:
Dina Logiudice
NHMRC Research Achievements - SUMMARY
Email/Phone no. of contact:
Dina.Logiudice@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 458797
CIA Name: Prof Christopher Etherton-Beer
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $777,410
Start Year: 2007
End Year: 2010
Grant Type: NHMRC Strategic Awards
Title of research award:
Improving quality of life of people with dementia living in residential care facilities a randomised trail of
educat intImproving quality of life of people with dementia living in residential care facilities a randomised
trail of educat int
Lay Description (from application):
The DIRECT study aims to determine if education of General Practitioners (GPs) and Residential Care Staff
can improve the quality of life (QOL) of people with dementia living in Residential Care Facilities (RCF). Our
hypothesis is that a systematic educational intervention delivered to GPs and RCF staff will improve care
delivery, leading to measurable improvements in the quality of life of residential care recipients. We
hypothesise that education delivered to GPs will have additive effects to education delivered to RCF staff.
Dementia is the leading cause of non-fatal disease burden among older Australians. Of people with dementia,
nearly half live in RCF. There appears to be much scope to improve care, and thus QOL, for people with
dementia living in residential facilities. However, the most effective way to translate knowledge regarding the
components of high quality care into practice is uncertain and there is a paucity of Australian data to guide
practice. Education of RCF staff is likely to be the cornerstone of improved care for recipients of residential
care who have dementia. GPs also play a key-role in the care of older people living in RCF, including
collaboration in the development of management plans, prescription of medications and initiation of health
referrals. A detailed action research process with data collected from surveys, focus groups and pilots will be
used to develop educational programmes for delivery to GPs and RCF staff. The primary outcome of the study
will be quality of life of the people with dementia, assessed by themselves, their family carers and the staff
looking after them. Several tools incorporating different sources of information will be used to assess QOL in a
comprehensive fashion. Secondary outcomes will include knowledge among GPs and RCF staff regarding
dementia, markers of quality care, participants’ sleep quality, and carer satisfaction. It is anticipated that the
results will fill this current gap in evidence and will be of value to policy makers and stakeholders from the
Residential Care Industry and Peak Community and General Practice bodies. The study results will have
tangible implications for proprietors, managers and staff from the residential care sector and policy makers.
The results have potential to directly benefit the quality of life of both patients and carers.
Research achievements (from final report):
The DIRECT study determined the perceived educational needs of general practitioners and staff caring for
people with dementia living in residential facilities. A tailored educational intervention for general practitioners
and staff caring for people with dementia living in residential facilities was developed and evaluated. The
education intervention has been delivered to participants in a randomised controlled trial. Quality of life of care
recipients has been measured as the primary outcome. The outputs of the project have informed understanding
of the experiences of staff working in residential care, the quality of life of people with dementia, and the
utility of educational interventions.
Expected future outcomes:
The final DIRECT outcomes manuscript is currently under review; publication is anticipated during 2011.
Name of contact:
Christopher Beer
Email/Phone no. of contact:
christopher.beer@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513772
CIA Name: Ms Mandy Vidovich
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $490,127
Start Year: 2008
End Year: 2011
Grant Type: NHMRC Strategic Awards
Title of research award:
A Randomised Clinical Trial of Cognitive Activity for Older Adults with Mild Cognitive ImpairmentA
Randomised Clinical Trial of Cognitive Activity for Older Adults with Mild Cognitive Impairment
Lay Description (from application):
Australia’s population is ageing rapidly and so is the frequency of age-related disorders. Dementia is one of
the most frequent mental health disorders of older people and one of the leading causes of years of life lost due
to disability in Australia. Mild Cognitive Impairment (MCI) in old age is considered an important clinical state
potentially predictive of future cognitive decline. There is increasing evidence that the onset of dementia can be
delayed with targeting potentially modifiable risk factors. In older adults, frequent participation in mentally
stimulating leisure activities has been associated with stronger cognitive (abilities such as memory)
performances and reduced risk of dementia. Further, the rate of cognitive and functional decline can be
influenced by cognitive intervention strategies, though few randomised control studies have explored these
findings with individuals who have a diagnosis of MCI. The primary focus of this research is to determine
whether a structured program of cognitive activity (CA) can delay progression of cognitive decline amongst
older adults with MCI. 160 older adults will be randomised (by chance, like the flip of a coin) to either a 10
week CA intervention with a focus on cognitive training and rehabilitation techniques or a 10 week control
educational intervention providing information on aging and retirement. Their cognitive performance, quality
of life and functional level will be monitored during follow-up. The proposed study will improve the
understanding of possible modifying factors of cognition and highlight the potential of intervention in an older
age population. The obtained results will have implications for policy recommendations regarding health care
resources and facilitate changes in the approach and management of individuals with MCI.
Research achievements (from final report):
The role of cognition-focussed interventions in reducing the rate of decline in older adults remains uncertain,
with a paucity of randomised controlled trials investigating this issue. The aim of the Promoting Healthy
Ageing with Cognitive Exercise (PACE) study was to determine whether a cognitive activity intervention
could decrease the rate of cognitive decline amongst older adults with mild cognitive impairment (MCI). We
were successful in developing an intervention of cognitive activity that was very well received by the older
adults enrolled in the trial. Specific outcomes from the trial with respect to the impact of the intervention on
cognitive and psychosocial measures remain pending.
Expected future outcomes:
The main findings of the study are currently under review. Presently, we are completing the analyses and will
be anticipating the completion of an outcomes paper, with a view to publication in the next few weeks.
Name of contact:
Mandy Vidovich
Email/Phone no. of contact:
Mandy.Vidovich@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 513814
CIA Name: Prof Sergio Starkstein
Admin Inst: University of Western Australia
Main RFCD: Mental Health
Total funding: $542,370
Start Year: 2008
End Year: 2012
Grant Type: NHMRC Strategic Awards
Title of research award:
The mechanism, predictive value and impact of apathy in patients with Alzheimers disease and their
caregiversThe mechanism, predictive value and impact of apathy in patients with Alzheimers disease and their
caregivers
Lay Description (from application):
Behavioural and psychological symptoms of dementia have been consistently associated with increased
patients’ distress, and are considered by caregivers as the most difficult symptoms to manage. Apathy is the
state of loss of motivation and emotional withdrawal that occurs in a high proportion of patients with
Alzheimer’s disease. These patients require more management and support, given their reliance on others to
schedule their activities and initiate behaviours even when they are still capable of performing the activities. In
spite of the high frequency of apathy in dementia and the high potential of negative effects on patients and
caregivers, little is known about the cause of this phenomenon, its potential influence upon the long-term
progression of Alzheimer’s disease, and on its impact upon caregivers’ emotional well-being. The main aim of
our proposal is to examine the mechanism, clinical relevance and impact of apathy in Alzheimer’s disease.
More specifically, we will determine whether apathy predicts more severe depression, increasing motor
problems, and a faster progression of cognitive and functional problems. Using state-of-the-art neuroimaging
techniques we will examine the association between apathy and abnormalities in specific brain regions. Finally,
we will examine whether caregivers of patients with apathy have relatively more severe emotional problems, a
higher care giving burden and poor quality of life.
Research achievements (from final report):
We comprehensively studied the concept of apathy in Alzheimer's Disease (AD), in a community based study
over 2 years. We were able to demonstrate that AD patients with apathy experience more severe depression,
faster decline in thinking, faster decline in activities of daily living and more severe motor problems than AD
patients without apathy. We also found that apathy in AD generates more severe depression, increased burden
and worse quality of life among caregivers. This knowledge will inform medical and health professionals that
screening for apathy in all settings where patients with AD attend (ie memory clinics, GP clinics, hostels and
nursing homes) should be included as a routine assessment. Our research will inform other researchers in the
field, provide them with a better understanding of the nature of apathy in AD, thus allowing future research to
focus on the development of specific and efficient treatment options. This will reduce the significant impact
that apathy has on caregivers, and potentially reduce the cost to the health system by allowing patients to be
cared for longer in the community setting.
Expected future outcomes:
We expect medical and health professionals to routinely screen for apathy in all settings where patients with
AD present. We further expect this research to guide future studies to examine and develop effeective and
efficient treatment options for AD patients with apathy
Name of contact:
Professor Sergio Starkstein
Email/Phone no. of contact:
ses@meddent .uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 572604
CIA Name: A/Pr Kun Zhu
Admin Inst: University of Western Australia
Main RFCD: Endocrinology
Total funding: $869,724
Start Year: 2009
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Determinants of musculoskeletal and other diseases, health service utilisation and mortality in a cohort of older
womenDeterminants of musculoskeletal and other diseases, health service utilisation and mortality in a cohort
of older women
Lay Description (from application):
This longitudinal study aims to identify determinants of musculoskeletal and cardiovascular diseases, cognitive
decline, mortality and health service utilisation with ageing in a cohort of well-characterised older women,
whose health has been monitored since 1998. This study is unique in that it will have followed patients from
mean age 75 to 90 years with longitudinal clinical data collected and complete ascertainment of health service
utilisation through the WA Data Linkage System.
Research achievements (from final report):
The aim of this project was to determine the importance of lifestyle, physiological measures, performance
measures, and genetic factors as determinants of the health outcomes in a cohort of 1,500 older Western
Australian women, whose health has been monitored since 1998. This aim has been realised through the
publication of 26 peer-reviewed journal articles since 2009 with majority of them in high impact journals. , In
particular our studies have played a critical role in:, 1. Proving the hypothesis that nutrition, physical
performance and physiological factors predict disease outcomes in old age in the area of musculoskeletal
disease. We had 7 publications in this area and showed the importance of adequate intake of dairy, protein and
potassium intake in maintaining bone health in older women, and the negative influence of homocystine on
bone. We are the first to show that physical performance as measured by the Timed Up and Go test is a
predictor of fracture in older women, and to study the predictors of knee replacement. , 2. Providing important
evidence that oral calcium supplementation do not increase the risk of atherosclerotic vascular disease in older
women. We had 3 publications in this area. , 3. Proving the hypothesis that physiological and nutritional factors
predict disease outcomes in old age in the area of cardiovascular disease. We had 4 publications in this area and
showed that the decline in estimated glomerular filtration rate and elevated osteoprotegerin concentrations are
associated with increased cardiovascular disease risk, whereas chocolate intake and yogurt intake are
associated reduced risk. , 4. Proving the hypothesis that genetic factors predict bone quality and fracture, and
participated in the genome-wide association study on determinants of osteoporotic fracture, bone density and
heel bone properties. We had 5 publications in this area.
Expected future outcomes:
We have recently obtained 15 years hospital morbidity and mortality data in this cohort via the Western
Australia Data Linkage System. Therefore, further publications in the areas for determinants of fracture,
cardiovascular disease, cancer and mortality are expected from this cohort study.
Name of contact:
Kun Zhu
Email/Phone no. of contact:
kun.zhu@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 634486
CIA Name: A/Pr Dina LoGiudice
Admin Inst: University of Western Australia
Main RFCD: Aged Health Care
Total funding: $833,759
Start Year: 2010
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Health Outcomes of Older Indigenous Australians- a 5 year follow up study of a population at riskHealth
Outcomes of Older Indigenous Australians- a 5 year follow up study of a population at risk
Lay Description (from application):
The health of Indigenous people is poor and a number of risk factors contribute to lower life expectancy and
the development of 'aged care syndromes' such as falls, incontinence, and dementia at a younger age. The
research team has described high levels of dementia in a population survey completed in 2005 on 363 older
people from the Kimberley. This population will be re-surveyed to document ageing syndromes and determine
factors that may improve health for this population at risk
Research achievements (from final report):
This study documented comprehensively for the first time, the frequency and burden associated with the most
common age associated syndromes in older people of ATSI background living in remote and rural areas of
Australia. This health survey was completed in 6 Aboriginal communities in the Kimberely, in individuals over
the age of 45 years. In previous work by the researchers, the prevalence of dementia was noted to be 4-5 times
higher in this group, and the current study reviewed the initial cohort to determine rate of dementia and
associated risk factors contributing to this condition. In addition, other common conditions of the aged,
including depression, falls, chronic pain and incontinence have been little addressed. The researchers adapted
and validated appropriate assessment scales for these conditions, and documented their frequency in this cohort
over the age of 45 years, with associated carer burden and functional loss. This information will inform policy
and service development for this population. Guidelines will be developed and dissenimnated through an
education program in the near future.
Expected future outcomes:
The development and utilisation of culturally appropriate assessment scales and guidelines for the most
common conditions of the aged, for use by older people of ATSI background. This information is of clinical
relevance for health professionals and aged care workers. Documentation of these conditions will inform policy
and service development.
Name of contact:
Assoc Prof Dina Logiudice
Email/Phone no. of contact:
dina.logiudice@mh.org.au
NHMRC Research Achievements - SUMMARY
Grant ID: 634492
CIA Name: Prof Leon Flicker
Admin Inst: University of Western Australia
Main RFCD: Geriatrics and Gerontology
Total funding: $528,754
Start Year: 2010
End Year: 2013
Grant Type: NHMRC Project Grants
Title of research award:
Predicting health and disease in Australian men over the age of 80 years - the Health in Men StudyPredicting
health and disease in Australian men over the age of 80 years - the Health in Men Study
Lay Description (from application):
Australia is ageing rapidly but we still do not know whether the risk factors, such as health and lifestyle, that
predict ill health in middle aged people, apply to people as they reach old age. This study of a large group of
older men will examine the type and level of risk factors that apply to men aged beyond 75 years. It will not
only determine rates of disability and mortality but also health service outcomes, including hospitalisation, and
residential and community care usage.
Research achievements (from final report):
The aims of this project were to determine factors associated with increased morbidity, disability and mortality
in ageing men. We also sought to determine how common risk factors associated with increased morbidity,
disability and mortality in later life interact with each other in the modulation of morbidity and mortality risk.
By the end of 2012 we had completed the Wave 4 survey, as planned. Just under 2,000 men, all over the age of
80 years have been reassessed with questionnaires and measures of physical performance. Approximately 1500
men have provided another blood specimen which has been analysed for some biocemical tests and plasma has
been stored for future hormonal measures dependent on further funding. There have been numerous analyses
based on existing clinical, biochemical, genetic and outcome data. Areas of interest have included
cardiovascular diseases, mental health (depression and dementia), cancer, frailty, and hormonal changes with
ageing. 66 peer reviewed publications have arisen from this cohort since 2010. Importantly these publications
have provided clear evidence regarding factors associated with avoidance of disease, disability and frality as
people age.
Expected future outcomes:
Ongoing analyses will continue to explore many factors associated with ill health in men of advanced age.
Name of contact:
Leon Flicker
Email/Phone no. of contact:
Leon.flicker@uwa.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 162722
CIA Name: Prof Anatoly Rozenfeld
Admin Inst: University of Wollongong
Main RFCD: Medical Physics
Total funding: $360,906
Start Year: 2001
End Year: 2003
Grant Type: NHMRC Development Grants
Title of research award:
Development of a PET detection system prototype with depth of interaction capabilityDevelopment of a PET
detection system prototype with depth of interaction capability
Lay Description (from application):
This development project invovles the development of a slim-line Positron Emission Tomogrphy (PET)
detection sub-module, the crucial component of PET scanners, that is small and extremely flexible. It is
planned to utilize this module in the design of customized new commercial PET scanners ideal for diagnosing
human brain and breast disorders. The development will proceed in collaboration with Insight Oceania/ADAC,
Sydney. Insight Oceania/ADAC are very excited by the potential applications and future markets (Australia
and overseas) of the newly developing PET detection sub-modules for dedicated PET scanners. Positron
Emission Tomography (PET) is a functional imaging tool, which is able to quantify physiological and
biochemical processes in vivo, using short-lived cyclotron-produced radiotracers. PET is emerging as an
extremely important diagnostic procedure used in the early detection of cancers, neurological diseases and as
an aid in treatment monitoring and drug development. The unique advantage of PET over anatomical imaging
techniques, such as X-ray CT and MRI, arises from its ability to measure changes in tumour biology, at the
molecular level, prior to anatomical changes in involved tissues, using trace amounts of a radiolabelled
compound (radiotracer). The full potential of PET however, is not being completely utilized due to constraints
within the current designs of PET scanners. When used to its full potential PET, in principle, would be an
excellent diagnostic and treatment monitoring tool for breast cancer, brain tumours and other neurological
conditions such as epilepsy, Alzheimer's, Parkinson's disease, post stress disorder, dementia, and depression.
Lack of flexibility in current PET scanner designs to date has meant that no commercial human brain or breast
imaging scanners exist. Pilot project data proved the feasibility of our new flexible PET detection module
design.
Research achievements (from final report):
During the three years of this project we have achieved essential and significant progress toward the creation of
the first PET animal scanner with depth of interaction capability based on silicon photodiodes. We have further
established solid relations with our industrial collaborator, Insight Oceania, who have strongly supported the
project. The following milestones have been successfully reached over the duration of the project:, , Silicon
pixel detector development for the PET detector module: it was first theoretically simulated which optimized
the design of the silicon pixelated detectors, coupled with a new kind of scintillators for PET application. This
optimization and established collaboration with the overseas microelectronics facility allowed production of
PET pixel detectors for very minimal cost that will make the future production of the PET scanner economical.,
, Pixelated scintillator coupling: a model was developed and realized in practise as the best optical coupling of
pixelated scintillator to develop silicon detectors. Obtained energy resolution was12%, the best ever published.
, , Detector Module production: the prototype version of the PET detector module, utilizing parallel readout of
all 64 channels, was developed and tested with radiation sources demonstrating functionality., , Gantry
Development: a computer control gantry has been designed and developed by us with two detector rings so that
dual PET/SPECT and CT imaging can be performed with our System. , , Developed technology, detectors and
the results obtained are an excellent platform for the final assembling of the PET animal scanner with multiple
modules following commercializing. The developed technology and instruments have many applications
including other imaging and non-imaging radiation probes for cancer detection, and radiation detection
instruments for national security.
Expected future outcomes:
Final assembling of PET animal scanner with multiple detectors, testing on animals and commercialization
with Australian company. Developed gantry can be used as a separate product for animal imaging facilities and
NHMRC Research Achievements - SUMMARY
distributed worldwide. Developed detector technology currently has been utilized in new commercial project:
development of advance radiation probe for guided surgery for PET and SPECT
Name of contact:
Prof Anatoly Rozenfeld
Email/Phone no. of contact:
anatoly@uow.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 568651
CIA Name: Prof Brett Garner
Admin Inst: University of Wollongong
Main RFCD: Cellular Nervous System
Total funding: $549,925
Start Year: 2009
End Year: 2012
Grant Type: NHMRC Project Grants
Title of research award:
Regulation of amyloid-beta production by glycosphingolipid synthesis inhibitionRegulation of amyloid-beta
production by glycosphingolipid synthesis inhibition
Lay Description (from application):
Alzheimer's disease (AD) prevalence is rising and there is currently no curative treatment. Production of
neurotoxic amyloid-beta peptide (Abeta) in the brain is thought to be one causative factor in AD. We have
recently discovered a new drug that alters lipid levels in cell membranes and potently inhibits Abeta production
by neurons. We will define precisely how this drug works and examine its potential to reduce Abeta
accumulation in the brains of mice genetically engineered to mimic AD.
Research achievements (from final report):
We tested a panel of specialised lipid synthesis inhibitor compounds and determined their totoxicty in cells
grown in culture dishes (1). We discovered that two of the compounds prevented the production of a toxic
peptide that is thought to cause Alzheimer's disease (AD) (1). We characterized the protective mechanisms
used by these compounds that may be helpful in the AD setting (2). We used molecular biology approaches to
mimic the mechanisms used by the compounds and found that the drugs targetted different pathways in the cell
(2). An improved model for assessing memory problems in a mouse model of AD was developed (3). A new
method for AD brain lipid research was developed (4)., 1.
H Li, WS Kim, AF Hill, G Evin, B
Garner (2010) Modulation of amyloid precursor protein processing by synthetic ceramide analogues. Biochim
Biophys Acta 1801, 887-895, 2.
Li, H., Evin, G., Hill, A. F., Hung, Y.
H., Bush, A. I., Garner, B. (2012) Dissociation of ERK signalling inhibition from the anti-amyloidogenic
action of synthetic ceramide analogues. Clin Sci. 122, 409-19, 3.
Karl, T., Bhatia, S., Cheng, D., Kim,
W. S., Garner, B. (2012) Cognitive phenotyping of amyloid precursor protein transgenic J20 mice. Behav
Brain Res. 228, 392-7, 4.
Hejazi, L., Wong J.W.H., Cheng, D.,
Ebrahimi, D., Garner, B., Don, A.S. (2011) Mass and Relative Elution Time Profiling: two-dimensional
analysis of sphingolipids in brain extracts. Biochem J, 438, 165-75
Expected future outcomes:
We expect at least one more publication on this aspect of the project. We believe these outcomes make a
significant contribution towards understanding the role that sphingolipids play in AD and the potential avenues
that may be therapeutically targeted.
Name of contact:
Prof Brett Garner
Email/Phone no. of contact:
brettg@uow.edu.au
NHMRC Research Achievements - SUMMARY
Grant ID: 1005896
Start Year: 2011
CIA Name: A/Pr Michael Lawrence
End Year: 2013
Admin Inst: Walter and Eliza Hall Institute
Grant Type: NHMRC Project Grants
Main RFCD: Structural Biology (incl. Macromolecular Modelling)
Total funding: $752,712
Title of research award:
How insulin and the insulin-like growth factors bind to their receptors - the key role of the a-chain C-terminal
helixHow insulin and the insulin-like growth factors bind to their receptors - the key role of the a-chain Cterminal helix
Lay Description (from application):
Cancer, Alzheimer’s disease and diabetes are three of the most important health issues facing Australia.
Aberrant signalling into the cell interior by the related insulin receptor and Type 1 insulin-like growth factor
receptor is implicated in all three of these disease states. Our research is aimed at understanding how these
signalling events occur at the atomic level of detail – such knowledge has the potential to contribute to the
development of novel therapeutics aimed at treating these diseases.
Research achievements (from final report):
During this grant period we discovered the atomic level detail of the way in which insulin interacts with its
partner protein the insulin receptor on the surface of cells. These findings were published in the prestigious
journal Nature and are the culmination of a two-decade long research endeavour on the part of our laboratory.
The findings are not only of immediate impact in the field of diabetes research but also of potential impact in
the fields of cancer research and Alzheimer's disease, with the latter increasingly being seen to be "diabeteslike".
Expected future outcomes:
Additional funding has now been secured to exploit the above findings. Together with our collaborators, we
will seek to design novel insulins and to obtain yet more detailed information about how this system works.
Name of contact:
Penny Fannin
Email/Phone no. of contact:
fannin@wehi.edu.au