WPC 2013 Hot Topics
Day 1- October 2nd
Moderator: Thomas Gasser
Michelle Lin (Canada)
Exome sequencing of Norwegian families with PD reveals novel gene mutations
Exome sequencing of Norwegian families with PD reveals novel gene mutations
Michelle K. Lin1*, Jan Aasly2*, Daniel Evans1, Carles Vilarino-Guell1, Brinda Shah1, Chelsea Szu
Tu1, Heather Han1, Holly Sherman1, Christina Thompson1, Mathias Toft3, Karin Wirdefeldt4,
Andrea C. Belin5, Maria S. Petersen6, Joanne Trinh1, Vanessa Silva1, Frederick Pishotta1 and
Matthew Farrer1 on behalf of the GEO-PD consortium.
1Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada
2Department of Neuroscience, Norwegian University of Science and Technology, Trondheim,
Norway
3Department of Neurology, Oslo University Hospital, Oslo, Norway
4Department of Medical Epidemiology and Biostatistics and Department of Clinical
Neuroscience, Karolinska Instiutet, Stockholm, Sweden
5Department of Neuroscience, Karolinska Instiutet, Stockholm, Sweden
6Department of Occupational Medicine and Public Health, The
Faroese Hospital System, Torshavn, Faroe Islands
*authors contribute equally to this work
Objective: Approximately 14% of patients with Parkinson disease (PD) have a family history of
parkinsonism. In larger, multi-incident families, pathogenic mutations/genes have now been
identified using traditional linkage and contemporary exome sequencing methods. We report a
clinical and comparative genetic study of Norwegian families.
Methods: Four Norwegian families (pedigree structure of 3-5 generations, 93 individuals, of
whom 22 have parkinsonism) were invited; 17 affected (mean age-of-onset 62.8±4.9SD,
range=55-75 years) and 10 unaffected members participated in the study. Late-onset,
asymmetric, levodopa-responsive PD appears to segregate in an autosomal dominant fashion.
Three affected members from each pedigree, screened negative for known genetic mutations
1
using a proprietary diagnostic panela, were exome-sequenced on an Illumina HiSeq platform.
Genome alignment, annotation and pair-wise bioinformatic comparisons of affected family
members were performed. Coding variants observed at <1% frequency were validated by
Sanger sequencing in all family members and matched control subjects. Mutations segregating
with PD but not observed in controls were genotyped in 3112 subjects (1613 patients) of
Scandinavian origin. Subsequently, mutations were genotyped in multi-ethnic GEO-PDb samples
using Sequenom and TaqMan technologies. Additional exonic sequencing was performed in
candidate genes.
Results: One mutation in each family was ultimately found to segregate with PD in four genes
(NOVA2, PABPC1L, RPE65 and OR56B4). Each mutation was highly conserved through evolution,
and those substitutions were predicted to have deleterious consequences on protein function.
Mutations in PABPC1L and RPE65 were observed in additional unrelated patients but not
control subjects. The functions of the encoded proteins are not well characterized but are
involved in RNA splicing in developing neurons, translation, retinal regeneration and olfaction.
In conclusion, pair-wise exome-sequencing is an efficient method to identify novel gene
mutations in familial PD that enhances traditional linkage efforts in disease gene mapping.
a see abstract by Lin, Evans et al.
b see www.geopd.org
Alexandru Hanganu (Canada)
Mild Cognitive Impairment in Parkinson’s disease is linked with extensive cortical thinning
during longitudinal analysis
Mild Cognitive Impairment in Parkinson’s disease is linked with extensive cortical thinning
during longitudinal analysis
Alexandru Hanganu1, Christophe Bedetti1,2, Clotilde Degroot1, Béatriz Mejia-Constain1, AnneLouise Lafontaine3, Sylvain Chouinard4, Oury Monchi1,5
1Centre de Recherche de l’Institut Universitaire de Gériatrie de Montréal, Montreal, QC, Canada
2Centre d’Études Avancées en Médicine du Sommeils, Hôpital du Sacré Cœur de Montréal,
Montreal, QC, Canada
3Movement Disorders Unit, McGill University Health Center, Montreal, QC, Canada
4Centre Hospitalier de l’Université de Montréal, Unité des troubles du movement André
Barbeu, Montreal, QC, Canada
5University of Montreal, Department of Radiology, Montreal, QC, Canada
2
Objective: We performed a longitudinal study in patients with Parkinson’s disease (PD) with
and without mild cognitive impairment (MCI) at the beginning of the study and tested whether
cortical thickness in the MCI group would reveal significantly more changes over time than the
non-MCI patients.
Methods: We included 33 non-demented PD patients at the early stages of the disease who
were studied twice 20 months apart. On each session (Time 1 and Time 2) they participated in
an MRI investigation and a comprehensive neuropsychological assessment. Based on the Time
1 neuropsychological assessment, patients were divided in two groups: MCI positive and MCI
negative. The construction of cortical surface was based on MPRAGE 3T images, using
FreeSurfer 5.1 image analysis suite. Images underwent a standard pre-processing and analyzing
procedure according with FreeSurfer longitudinal stream. (Reuter et al. 2010). Misclassification
of tissue types was corrected by minimal manual adjustment. Cortical thickness was computed
as the shortest distance between the grey/white boundary and gray/cerebrospinal fluid
boundary at each vertex on the tessellated surface (Fischl et al. 2000). Analysis of longitudinal
data was performed using the linear mixed effects model included in FreeSurfer (Bernal-Rusiel
et al. 2013).
Results: The intergroup analysis revealed increased cortical thinning in PD-MCI compared with
PD non-MCI in the right supplementary motor area (SMA), ventral premotor cortex, left middle
temporal gyrus, supramarginal gyrus and lingual cortex. The intragroup results showed bigger
clusters of cortical thinning in PD-MCI in occipital lobe and premotor cortex bilaterally, as well
as right SMA, middle temporal gyrus and precuneus cortex. On the other hand, the PD non-MCI
group exhibited smaller clusters in the right occipital cortex, supramarginal gyrus and superior
temporal gyrus. Our results suggest that the early presence of MCI in PD patients is indicative of
faster neural degradation.
Maryka Quik (USA)
Nicotine and nicotinic receptor drugs reduce L-dopa-induced dyskinesias in a nonhuman
primate model of Parkinson's disease
Nicotine and nicotinic receptor drugs reduce L-dopa-induced dyskinesias in a nonhuman
primate model of Parkinson's disease
Maryka Quik1, Danhui Zhang1, F. Ivy Carol2, Michael Decker3, Tanuja Bordia1
1SRI, Menlo Park, CA, USA
2RTI International, Research Triangle Park, NC, USA
3AbbVie, Inc, North Chicago, IL, USA
3
Objective: Although L-dopa is one of the primary therapies for Parkinson's disease, it can lead
to disabling dyskinesias for which there is little treatment. Nicotine has recently been shown to
decrease L-dopa-induced dyskinesias (LIDs) in several parkinsonian animal models. The goal of
the current study was to identify the optimal nicotine treatment regimen for reducing LIDs in
nonhuman primates and to test if nicotine improved LIDs in both L-dopa-primed and L-dopa
naïve monkey. In addition, we investigated the effectiveness of the nicotinic receptor drugs
varenicline and ABT-089, which acts selectively in the brain thus minimizing side effects.
Methods: Monkeys were given MPTP until parkinsonian. Nicotine or nicotinic receptor drugs
were then given to L-dopa-naïve or L-dopa primed monkeys, with L-dopa (10 mg/kg) gavaged
twice daily. Dyskinesias were scored every 30 min. Parkinsonism was also measured.
Results: Nicotine was given to nonhuman primates in the drinking water before L-dopa
treatment was started and also to animals with pre-existing dyskinesias. Nicotine decreased
LIDs by 60-70% after several weeks of treatment in both the L-dopa-naïve and L-dopa primed
animals. The beneficial effect of nicotine was consistently observed for the entire course of the
study, which lasted up to 23 weeks. Nicotine did not worsen parkinsonism. We also tested the
effect of the nicotinic receptor drugs varenicline, which has been approved for use in humans
as a smoking cessation aid, and ABT-089, which has been evaluated in phase 2 clinical trials for
other indications. Both ABT-089 and varenicline reduced dyskinesias by about 50%. The effect
of these drugs persisted for the entire length of the study (several months). These combined
data suggest that treatment with nicotine and nicotinic receptor drugs has potential as a
successful antidyskinetic therapy for L-dopa-treated Parkinson's disease patients. These studies
were supported by NIH grant NS59910
Ryan Duncan (USA)
Balance differences between people with and without freezing of gait in Parkinson disease
Balance differences between people with and without freezing of gait in Parkinson disease
Ryan P. Duncan1, Abigail L. Leddy2, MSCI, James T. Cavanaugh, , Leland E. Dibble4, Terry D. Ellis5,
K. Bo Foreman4, Matthew P. Ford6, and Gammon M. Earhart1
1Washington University, Saint Louis, MO, USA
2Rehabilitation Institute of Chicago, Chicago, IL, USA
3University of New England, Portland, ME, USA
4University of Utah, Salt Lake City, UT, USA
5Boston University, Boston, MA, USA
6University of Alabama at Birmingham, Birmingham, AL, USA
4
Objective: To determine whether balance impairments differ between groups of people with
PD who either have or do not have a history of freezing of gait (FOG), taking into account
differences in disease severity, disease duration and age. Balance was assessed using the
Balance Evaluation Systems Test (BESTest) total and section scores, Mini-BESTest total score,
and Berg Balance Scale (BBS) total score.
Methods: Balance of 78 participants (58% male; mean age ± SD = 68.1 ± 9.3 years; H&Y
frequency (stage(n)): I(5), II(30), II.5(28), III(8), IV(7)) with PD was assessed using the BESTest,
Mini-BESTest, and the BBS. Participants completed the FOG
Questionnaire; those reporting a score greater than one on item three were classified as
freezers. The Movement Disorder Society-Unified Parkinson Disease Rating Scale subsection III
(MDS-UPDRS III) was administered to measure motor symptom severity. Analyses of covariance
were used to determine differences between freezers and non-freezers in BESTest total and
section scores, Mini-BESTest total score, and BBS total score, using a PD severity composite
score (MDS-UPDRS III score, years since diagnosis, and age) as a covariate (α=0.05).
Results: Thirty-two (41.0%) participants were classified as freezers. After accounting for disease
severity and duration as well as age, freezers had significantly lower BESTest (F(1,76)=7.33;
p=0.008) and Mini-BESTest (F(1,76)=12.26; p=0.001) total scores compared to non-freezers.
There were no differences in BBS scores for freezers compared to non-freezers (p=0.27). With
respect to the individual BESTest sections, freezers had significantly lower scores on sections IV
(postural responses) (F (1,76)=14.39; p<0.001) and VI (stability in gait) (F(1,76)=9.16; p=0.003)
than non-freezers. In conclusion, regardless of motor symptom severity, years since diagnosis,
and age, freezers had more severe balance impairment than non-freezers as measured by the
BESTest and Mini-BESTest. Physical therapists should consider addressing postural response
and stability in gait problems in PD patients with FOG.
5
Day 2- October 3rd
Moderator: Oscar Gershanik
Martinj van der Eijk (The Netherlands)
Patient-centered care in the Parkinson centers of excellence: a multicenter study
Patient-centered care for PD patients in the Parkinson centers of excellence: a multicenter
study
Martijn van der Eijk1, Marjan J. Faber2, Peter N. Schmidt3, Marten Munneke1, Michael S.
Okun3,4, Bastiaan R. Bloem5
1Radboud University Nijmegen Medical Centre; Nijmegen Centre for Evidence Based Practice;
Department of Neurology, Nijmegen, The Netherlands
2Radboud University Nijmegen Medical Centre, Scientific Institute for Quality of Healthcare (IQ
healthcare), Nijmegen, The
Netherlands
3National Parkinson Foundation, Miami, Florida
4University of Florida, Center for Movement Disorders and Neurorestoration, Gainesville,
Florida
5Radboud University Nijmegen Medical Centre; Donders Center for Brain, Cognition
and Behaviour; Department of Neurology, Nijmegen, The Netherlands
Objective: Patient experience questionnaires are increasingly recognized as an essential part of
quality of care assessment. We developed and validated the Dutch Patient‐Centeredness
Questionnaire for PD (PCQ-PD). Here we describe the validation of the English PCQ-PD and its
initial application to a representative patient sample from American and Canadian Parkinson
centers of excellence.
Methods: First, the PCQ-PD was translated from Dutch into English, based on a forwardbackward translation process. Second, the applicability was evaluated by an expert consultation
round with 17 center directors. Third, the questionnaire was pre-tested within cognitive
interviews with professionals (n=7), patients (n=6) and caregivers (n=6). Fourth, psychometric
validation was performed in a multicenter study within 20 centers. Data-analysis focused on
psychometric properties of the questionnaire and the level of patient-centeredness by
calculating scores for overall patient-centeredness [0-3], subscale experiences [0-3] and quality
improvement scores [0-9].
6
Results: 972 PD patients completed the questionnaire (mean 49 per center, range 37-58). After
the validation procedure, the PCQ-PD addressed 44 items in six subscales of patientcenteredness. The internal consistency, expressed in Cronbach’s α per subscale, ranged from
0.677 to 0.889. The mean overall patient-centeredness score was 2.09 (SD 0.44). The ‘providing
information’ subscale received the lowest experiences ratings (Δ1.62, SD 0.62). ‘Were you
informed about what your health professionals discussed with each other regarding your
treatment?’ obtained the highest quality improvement score (4.61). Centers differed
significantly on the overall patient-centeredness score and information-, collaboration-,
accessibility-, and patient-involvement subscales (p<.001). Centers had comparable scores on
the empathy- and emotional support subscales. The PCQ-PD is a valid instrument to measure
patient-centeredness in PD care in America and Canada. Psychometric properties of the
instrument were good. Application of the PCQ-PD revealed the level of patient-centeredness in
the centers of excellence. The main outcome was a compelling call for the provision of
information.
Andrew Vo (Canada)
Recasting the role of dorsal striatum in learning and decision-making: A study in Parkinson’s
disease
Recasting the role of dorsal striatum in learning and decision-making: A study in Parkinson’s
Disease
Andrew Vo1,2, Nole Hiebert1,3, Ken N. Seergobin1, Stephanie Solcz1, Adrian M. Owen1,2,3, Allison
Partridge1, Penny A. MacDonald1,2,3,4
1Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
2Department of Psychology, University of Western Ontario, London, Ontario, Canada
3Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario,
Canada
4Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario,
Canada
Objective: Changes to cognitive functions are now recognized in Parkinson’s disease (PD). Our
aim was to investigate learning and decision-making in PD, as well as the effect of dopaminergic
medication on these separate cognitive processes.
7
Methods: In Session 1, 36 PD patients and 36 age-matched, healthy control participants learned
to associate abstract images to key-press responses through trial-and-error based on feedback.
Half of the PD patients learned these stimulus-response relations ON medication whereas the
other half learned associations OFF medication. In Session 2, on a separate day, patients and
controls were asked to select key-press responses associated with abstract images learned in
Session 1. No feedback was provided, precluding new learning. Half of the PD patients
performed response selections ON whereas the other half performed selections OFF
medication. For each ON and OFF group in Session 2, an equal number of participants had
learned stimulus-response relations ON as OFF medication, to reduce carry-over effects from
learning efficiency in Session 1.
Results: PD patients learned stimulus-response associations significantly more poorly ON
relative to OFF medication in Session 1. Further, learning was impaired in PD patients ON
medication relative to controls, though no differences in learning arose between PD patients
OFF medication and controls. In contrast, PD patients ON and OFF medication performed keypress responses based on previous learning equally well in Session 2. ON medication PD
patients performed equivalently to controls, however, OFF medication PD patients performed
these decisions more poorly than controls. In PD, learning is unimpaired but decision-making
seems deficient at baseline. Dopaminergic medication worsens learning stimulus-response
associations. At present there is incomplete understanding of cognitive impairments in PD and
the effect of dopaminergic medication on cognition. Our results help to anticipate these
concerns and guide medication strategies, taking into account motor and cognitive symptoms,
and individual patient priorities.
Elisaveta Sokolov (UK)
Non-motor clinical staging using the non-motor symptoms scale and motor correlation in an UK
cohort of Parkinson’s
Non-motor clinical staging using the non-motor symptoms scale and motor correlation in an
UK cohort of Parkinson’s
Sokolov E2,3, Moon T3, Martinez-Martin P4, Ray Chaudhuri K.1,2
1King’s College London, National Parkinson Foundation Centre of Excellence and Regional
Movement Disorders Unit, UK
2 National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre and
Dementia Unit at South London and Maudsley NHS Foundation Trust and [Institute of
Psychiatry] King’s College London, UK
8
3 Guys
& St Thomas NHS Foundation Trust, London, UK
National Centre of Epidemiology Alzheimer Disease Research Unit and CIBERNED, Alzheimer
Center Reina Sofia Foundation, Carlos III Institute of Health, Madrid, Spain
4
Objective: We recently described a novel grading system of people with Parkinson’s (PwP)
using the non motor symptoms scale (NMSS) and assessing NMS burden (NMSB staging), the
stages ranging from no NMS (stage 0) to severe burden of NMS (NMSS > 71, stage 4). 1 In this
unselected UK cohort of 517 cases, we provide a clinical categorization of cases after allocating
each case to the NMSB staging system.
Methods: Retrospective and prospective data on 517 cases have been collected in the UK for
the validation studies of NMSS as well as an ongoing NMS natural history study. All cases were
staged as per NMSB and clinical association with motor staging (Hoehn and Yahr) and other
parameters were assessed.
Results: Only 1 of 517 patients (0.19%) reported no NMS (NMSB stage 0). 154 (30%) were at
stage 2 moderate level of NMS and had a mean age of 68± 12yrs with a median HY stage of 2, a
relatively mild motor stage. However, 23% had severe NMSB stage while HY score was
moderate at a median of 2, while 21% had very severe NMSB stage with HY score median of
2.5, not be considered as advanced Parkinson’s from the motor perspective. Amongst the
NMSB stages 3 and 4, several NMS dominant endophenotypes were recognised (sleep
dominant, fatigue dominant for example) from a clinical perspective.
Conclusions: This study outlines the importance of including NMS assessments, now formalized
by the NMSB staging as part of a clinical process to implement holistic care of the multi-morbid
PwP.
Reference: Chaudhuri KR,1 Rojo JM,2 Schapira AHV3, Brooks DJ,4 Stocchi F, Odin P et al. A
proposal for a comprehensive gradation of Parkinson’s disease severity combining motor and
non-motor assessments: meeting the unmet need. PLOS One. February 2013 | Volume 8 | Issue
2 | e57221
9
Ariadna Recasens Ibabe (Spain)
Lewy body fractions from patients with Parkinson’s disease initiate synuclein-dependent
neurodegeneration in mice and non-human primates
Lewy body fractions from patients with Parkinson’s disease initiate α-synuclein-dependent
neurodegeneration in mice and non-human primates
Ariadna Recasens1, Benjamin Dehay2, Jordi Bové1, Iria Carballo-Carbajal1, Sandra Dovero2, Ana
Pérez3, Pierre-Olivier Fernagut2, Javier Blesa4, Annabelle Parent1, Celine Perier1, Isabel Fariñas3,
José A. Obeso4, Erwan Bezard2 and Miquel Vila1,5,6,
1Neurodegenerative Diseases Research Group, Vall d’Hebron Research Institute (VHIR)-Center
for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona,
Spain
2Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293,
Bordeaux, France
3Department of Cell Biology, University of Valencia, Valencia, Spain
4Basal Ganglia and Movement Disorders Unit, Center for Applied Medical Research (CIMA),
University of Navarra, Pamplona, Spain
5Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona
(UAB), Barcelona, Spain
6Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
Objective: Mounting evidence indicate that neuropathological -synuclein lesions may selfpropagate and spread progressively throughout the brain of Parkinson’s disease (PD) patients
by a cell-to-cell transmission mechanism, thereby contributing to the extension and progression
of the disease process. While synthetic α-synuclein fibrils can lead to α-synuclein pathology in
mouse brain, the physiopathological significance of disease-associated, Lewy body (LB)-linked
human α-synuclein is unknown.
Methods: Here, we stereotaxically inoculated -synuclein-containing LB fractions derived from
nigral post-mortem PD samples into the substantia nigra or striatum of wild-type mice and nonhuman primates (NHP).
Results: In mice, a single LB nigral injection resulted in progressive nigrostriatal
neurodegeneration starting at striatal dopaminergic terminals. At the onset of LB-induced
denervation, endogenous murine α-synuclein adopted a pathological conformation and
accumulated within nigral neurons. LB-induced pathogenic effects required both human αsynuclein present in LB fractions and host expression of α-synuclein. In NHP, striatal or nigral LB
10
injections caused nigrostriatal degeneration and accumulation of pathological α-synuclein in
anatomically interconnected regions. Our study unravels a pathogenic prion-like species-barrier
crossing effect of human-derived pathological α-synuclein.
Day 3- October 4th
Moderator: Eduardo Tolosa
Bin Hu (Canada)
Concurrent Arm Swing-Stepping (CASS) test for dual task-related movement in-coordination
and hesitation in Parkinson’s disease
Concurrent arm swing-stepping (CASS) test for dual task-related movement incoordination
and hesitation in Parkinson’s disease
Taylor Chomiak1, Alexandra Cihal1, Terry Clark1, Ranjit Ranawaya2, and Bin Hu1
1DCN and Hotchkiss Brain Institute and University of Calgary, Calgary, AB, Canada
2Movement Disorders Clinic-Alberta Health Services, Calgary, AB, Canada
Objective: Parkinson’s disease (PD) patients frequently show gait and balance impairments
while simultaneously performing parallel tasks under sustained and divided attention. In this
study we have developed a simple dual task by asking patients to perform concurrent arm
swing and on-the-spot stepping (CASS). Our initial aim was to examine whether CASS can reveal
deficits in movement initiation and coordination, and whether the detected deficits were
associated with self-assessment of fall risk.
Methods: The study included a total of thirty-three PD patients (mean age: 66.6 years, SD 9.5;
mean disease duration: 8.1 years, SD 5.9) who were first instructed to swing their arms and
then to initiate the secondary task of leg stepping. We defined a lack of arm-leg coordination as
arm swing and leg stepping occurring on the ipsilateral, instead of the contralateral side. Gait
hesitations were scored as follows: no-hesitation (0 sec), slight hesitation (<5 sec), and large
hesitation/freezing (>5 sec). The Falls Efficacy Scale-International (FES-I) was used to assess fallrelated self-efficacy.
Results: We found 78.8% patients showed some degree of deficits in coordination across three
trials, whereas gait hesitation and/or freezing occurred significantly less (36.4%; p<0.01).
Furthermore, multilevel regression analysis controlled for age, gender, and disease duration
revealed that CASS-related hesitation/freezing, but not coordination, was a significant predictor
11
of FES-I score (p<0.01), with R2 increasing by 33.3% after adding the hesitation variable but not
the coordination variable (2.0%; p>0.05). Our results indicate that CASS can be used as a simple
clinical test to reveal dual task-related movement incoordination, gait hesitation and/or
freezing, as well as their relationship with self-reported functional efficacy in PD patients.
Acknowledgments: CIHR, Parkinson Alberta Society, and Dr. Sarah Furtado and the Movement
Disorders Clinic-Alberta Health Services.
Ianai Fishbein (USA)
Altered Alpha Synuclein degradation and augmentation of Parkinson disease phenotype in a
transgenic mouse model
Altered Alpha Synuclein degradation and augmentation of Parkinson disease phenotype in a
transgenic mouse model
Ianai Fishbein1, Yien-Ming Kuo1, Robert Nussbaum1,
1UCSF, Institute of Human Genetics, San Francisco, CA, USA
Objective: The involvement of the protein α-Synuclein (Snca) in the pathogenesis of Parkinson's
disease (PD) has been well documented. Heterozygous carriers of Gaucher disease mutations,
who are otherwise healthy, have an increased risk for PD. Since mutations in the gene encoding
for the Glucocerebrosidase (GBA) enzyme are known to reduce degradation of some proteins in
the lysosome, it has been suggested that reduced Snca degradation might facilitate its
accumulation and aggregation. In this study we investigated the half-life of Snca in neurons. We
also asked how it might be affected by a Gaucher mutation, and what impact that would have
in vivo in a PD mouse model.
Methods: We used cultured primary cortical neurons generated from mice expressing wildtype
mouse Snca, wildtype human Snca or A53T Snca, in a background of either wildtype Gba or
heterozygosity for the p.L444P Gba mutation. We also tested these double transgenic mice for
behavioral and biochemical PD related phenotypes.
Results: We found that Snca is very stable, with a t1/2 = ~60 hours for both the wildtype and
A53T human protein in culture, while the mouse protein had an even greater t 1/2 of ~140 hours.
Heterozygosity for the Gaucher mutation reduced Gba activity by ~40%, reduced Snca
degradation and triggered accumulation of the protein in culture. This mutation also prompted
the augmentation of motor and gastrointestinal deficits found in the A53T mouse model of PD,
albeit only when mice reached an advanced age. This study demonstrates that heterozygosity
12
for mutations in Gba interferes with Snca degradation and contributes to accumulation of the
protein. We have a created a mouse model for the interaction between GBA mutations and
synucleinopathies, thereby strengthening the Gba enzyme as a potential therapeutic target for
PD.
Daniel Levesque (Canada)
Unilateral 6-OHDA lesion and Dopa administration in Nur77 knockout rats reveal an important
role of this transcription factor in Parkinson’s disease and its treatment
Unilateral 6-OHDA lesion and Dopa administration in Nur77 knockout rats reveal an
important role of this transcription factor in Parkinson’s disease and its treatment
Daniel Lévesque1, Joanie Baillargeon2, Claude Rouillard2
1 Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada
2Neuroscience, CRCHUL and Fac. of Medicine, Psychiatry and Neuroscience, Laval University,
Quebec, QC, Canada
Objective: Nur77 (Nr4a1) is a transcription factor of the nuclear receptor family that is
associated with neuroadaptation pathways triggered by perturbation of dopamine (DA)
neurotransmission. We have previously shown that DA denervation and repeated L-Dopa
treatment modulate Nur77 mRNA expression patterns in the striatum. However, the exact role
of this transcription factor in Parkinson’s disease (PD) and L-Dopa treatment is still unknown. In
the present study, we investigated the role of Nur77 in a newly developed rat knockout model
(FHH-Nr4a1m1Mcwi, nonsense mutation, Y130stop).
Methods: We performed unilateral 6-hydroxydopamine (6-OHDA) lesions in wild type and
Nur77 knockout rats. Daily L-Dopa treatments (6.25 mg/kg, benserazide 15 mg/kg) were
maintained for 21 days. Circling behavior and Abnormal Involuntary Movement (AIM) scores
were measured five times. We also evaluated the effect of striatal Nur77 overexpression using
an adeno-associated viral construct in this PD model. In addition, we quantified the effect of
the neurotoxin on DA cells using stereology (TH
immunoreactivity).
Results: Nur77 knockout rats showed a dramatic reduction in both L-Dopa-induced circling and
AIM scores. On the other hand, Nur77 striatal overexpression tended to increase these
behavioral measures. Moreover, the effect of 6-OHDA injections on TH immunoreactivity was
reduced in Nur77 knockout, compared to wild type rats. Thus, these results suggest that Nur77
plays an important role in L-Dopa-induced dyskinesia as well as in DA cell loss in this PD model.
Supported by the Michael J. Fox Foundation (MJFF) for Parkinson’s disease.
13
Rob Skelly (UK)
Does a specialist Parkinson’s unit improve outcomes for hospitalised Parkinson’s patients?
Does a specialist unit improve outcomes for hospitalised patients with Parkinson’s disease? A
prospective study
Rob Skelly, Lisa Brown, Apostolos Fakis, Lindsey Kimber, Charlotte Downes, Fiona Lindop, Clare
Johnson, Caroline Bartliff, Nin Bajaj
Royal Derby Hospital, Derby, UK
Objective: Suboptimal management of Parkinson’s Disease (PD) medication in hospital may
lead to avoidable complications and increased length of stay. We introduced an in-patient PD
unit for those admitted urgently with general medical problems. We explored the effect of the
unit on medication management, length of stay and patient experience.
Methods: We conducted a single-center prospective feasibility study. The unit’s core features
were defined following consultation with patients and professionals: specially trained staff,
ready availability of PD drugs, guidelines, and care led by a geriatrician with specialty PD
training. We compared patient outcomes before and after introduction of the unit. Mandatory
staff training comprised four one-hour sessions: PD symptoms; medications; therapy;
communication and swallowing. Most medication was prescribed using an electronic
Prescribing and Administration system (iSOFT). A patient experience survey was administered.
Results:
General
Ward
Care
PD Unit
care
20
24
81 (7584)
81 (7384)
0.611
16 (80%)
16
(67%)
0.498
pvalue
Baseline
characteristics
Number
Age – median
(Interquartile
range)
Gender: male –
no. (%)
14
Stage
(% Hoehn-Yahr 4
and 5)
6 (30%)
14
(58%)
0.160
PD medication
doses given (%
of all prescribed
doses)
1,827
(82%)
1,307
(86%)
0.022
PD medication
given on time
[within 30
minutes of
scheduled time]
(%)
949
(44%)
904
(60%)
<0.001
Patients with any
PD medication
prescription
error(s) (%)
12 (67%)
11
(46%)
0.221
Length of stay –
days: median
(IQR)
13 (9 27)
9 (5-16)
0.043
Patient
experience –
overall
experience of
care (higher
scores better):
median (IQR)
(n=31)
3 (2-3)
3 (3-4)
0.016
Outcomes
Discussion: If replicated and generalisable to other hospitals, reductions in length of stay would
lead to significant cost savings. The apparent improved outcomes with Parkinson’s unit care
merit further investigation. We hope to test the hypothesis that specialized units are costeffective and improve patient care using a cluster-randomized controlled trial design.
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About The World Parkinson Congress
The World Parkinson Congress is the only international meeting of its kind, where crosspollination of the entire spectrum of Parkinson’s disease – researchers, clinicians, people with
Parkinson’s, allied health professionals and care partners -- come together. Designed to be
inspiring and rejuvenating, the WPC provides an opportunity for people with Parkinson’s, those
who care for them and those working to find a cure the world over, to meet and share their
experiences.
About the World Parkinson Coalition
The World Parkinson Coalition Inc. is a New York-based charitable organization dedicated to
providing an international forum for the latest scientific discoveries, medical practices and
caregiver initiatives related to Parkinson's disease. By bringing physicians, scientists, allied
health professionals, caregivers and people with Parkinson's together, WPC Inc. hopes to create
a worldwide dialogue to expedite the discovery of a cure and best treatment practices for this
devastating disease. For more information: www.worldpdcongress.org
PARKINSON SOCIETY CANADA Hosts the World at WPC 2013
Parkinson Society Canada is the national voice of Canadians living with Parkinson’s disease. A
charitable organization founded in 1965, its vision is a better life with a brighter future for
Canadians living with Parkinson’s today, a world without Parkinson’s tomorrow. Parkinson
Society Canada, with a network of partners including Parkinson Society Québec, funds discovery
research and provides education, support, and advocacy on behalf of over 100,000 Canadians
living with Parkinson’s. For more information: www.parkinson.ca.
-
30 -
Contact:
Catherine Pouliot
catherine.pouliot@edelman.com
O:514-315-1986
C: 514-817-9741
Manon Desrosiers
manon.desrosiers@edelman.com
O:514-315-1971
C: 514-224-5444
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