Most Populous Countries
2007
2050
Country
Population (million)
Country
Population (million)
China
1,331
India
1,748
India
1,171
China
1,437
United States
307
United States
439
Indonesia
243
Indonesia
343
Brazil
191
Pakistan
335
Pakistan
181
Nigeria
285
Bangladesh
162
Bangladesh
222
Nigeria
153
Brazil
215
Russia
142
Congo, Dem Rep
189
Japan
128
Philippines
150
Population Reference Bureau
On January 1, 2011, as the baby
boomers begin to celebrate
their 65th birthdays, 10,000
people will turn 65 every day—
this will continue for 20 years.

Alliance for Aging Research
Dementia
Auguste Deter, the “first”
case
Goals









Epidemiology
Memory in typical aging
Mild cognitive impairment
Risk Factors for Dementia
Types of Dementia
Mental Status and functional Assessments
Laboratory Evaluations
Hierarchical Approach to Diagnosing Dementia
Treatment
Prevalence
Incidence of dementia
Liverpool, UK
Rochester, MN, USA (men)
Incidence of dementia (%)
30
Rochester, MN, USA (women)
20
10
0
65-74
75-79
80-84
Age group (years)
Incidence
Swedish data
Role of APOE
Rorsman et al (1986); Hofman et al (1991)
Prevalence of dementia in developing countries
 Problems with cross-cultural assessment of dementia
 language
 culture
 assessment
 differential morbidity and mortality
Chandra et al (1994)
Dementia
 Memory Impairment* PLUS




Aphasia - disorder of language
Agnosia - disorder of recognition
Apraxia - impaired execution of tasks
Executive Dysfunction - impaired abstraction,
sequencing, monitoring
 Asso AP, 1993 DSM 4th ed.
 McKhann G et al,Neurology 1984;34:939-944
Cognition
Dementia
Function
Behavior
Memory in normal aging vs. dementia
 Slow
 Accurate recall
 Remedied by cues e.g.
appointment calendars
and lists
 Stable
 Does not interfere with
function
 Slow
 Inaccurate recall
 Reminders fail
eventually, recall poor
despite cueing
 Progressive decline
 Interferes with function
Memory in normal aging vs. dementia
 Misplaces items
infrequently
 Independent retrieval
possible
 Can follow directions;
oral or verbal
 Capable of self-care
 Misplaces personal
items frequently
 Needs help from others
to find items
 Can hardly follow
directions even with
guide
 Gradually incapable of
self-care
Memory declines with age
* Education
* Cognitive
demand
* I.Q.
Memory
and
Cognition
Normal
MCI
Abnormal
Age
Memory System
Encoding
Registration
Retrieval
Dementia
Normal aging
Neurons
Courtesy of The National Institute on Aging
Neuron
Dendrites
Axon
Neurotransmitter
Molecules
Receptor
Synapse
Slide 14
Mild cognitive impairment
Cognitive decline accompanies normal ageing
Memory in health
Cognitive speed
Memory in dementia
0
20
30
40
Age
50
60
70
Definitions
Mild cognitive impairment has been classified in a
number of ways
 AAMI
=
Age-associated memory impairment
(most widely studied)
 MCI
=
Mild cognitive impairment
 BSF
=
Benign senile forgetfulness
Subjective memory loss
 Subjective memory loss does not predict dementia or mortality
 Factors associated with subjective memory loss
 mood state
 use of memory strategies
 personality factors
Study measurements
Best-fit equation
Jorm (1997)
Mild cognitive impairment
 Easy to recognize MCI ( a large intermediate
zone between the cognitively normal elderly and
those with dementia
 Impairment in at least 1 cognitive domain
(usually recent memory) but who function
independently in daily affairs.
Mild cognitive impairment (MCI)
 2 Variants
Recognized
− Amnesic type
Most common
 Preclinical manifestation of AD
 Most common - Impaired performance on
delayed recall

− Multiple cognitive domains - localized
impairment of other cognitive domains
Less common
 Signal non-AD clinical syndromes

Predicting which patients with MCI will become
demented
 Psychological tests




verbal recall
visuospatial recall
object function recognition task
object identification task
 Genetic tests
 ?APOE or other susceptibility loci
 Neuroimaging
  atrophy &  activation in hippocampal & parahippocampal areas
Risk factors and protective factors
Using epidemiology to understand aetiology
 Risk-modifying factors for AD
 age
 family history
 head injury
 vascular factors
 diabetes
 education
 depression
 dietary factors
 heavy metals
 maternal age
 smoking
Prevalence of dementia
Prevalence (%)
40
35
30
25
20
15
10
5
0
30-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95-99
Age group (years)
Definition of prevalence
Prevalence differences in Europe
Hofman et al (1991)
Age specific dementia
prevalence (Frangitioni, 99 &
Sahadevan, 08)
Prevalence of Dementia in USA
Ages 40-65
Ages 65-70
Ages 70-80
Age 80+
1 in 1000
1 in 50
1 in 20
1 in 5
Head injury
 Increases risk of AD (relative risk 1.8)
 Increases Ab deposition in the brain
 Increases tangle formation when repeated and severe
Mehta et al (1999); Nicoll et al (1995)
Vascular risk factors
 Hypertension
 Evidence of cardiac disease
 Peripheral atherosclerosis
. . . increase risk of AD
 What does this mean for vascular dementia?
Breteler et al (1994); Tariska et al (1997)
Education
 Low educational level increases risk of dementia and probably AD
 Demonstrated by prospective studies and the Nun Study
Snowdon et al (1996)
Diabetes
 Late-onset diabetes increases risk of AD
 Insulin resistance increases risk of AD
•
However. . .
both conditions are common in the elderly and
the relative risk is small
Stewart and Liolitsa (1999); Ott et al (1999)
Depression
 A history of depression occurs more often in those with dementia
 However. . .
both conditions are common in the elderly and
the relative risk is small
 Does depression herald dementia?
Jorm et al (1991)
Clinical features of
Dementia
Delirium versus dementia
The confused patient
 Confusion is “the inability to think with one's customary clarity and
coherence” (Lishman 1987)
 Primary causes of confusion include dementia and delirium
 Confusion also arises as a consequence of other events and
pathologies
 It may be the doctor and not the patient who is confused
DSM-IV: features of delirium
DSM-IV: features of dementia
DSM-IV: features of delirium
 Disturbance of consciousness with reduced ability to focus,
maintain or shift attention
 Change in cognition or perception not accounted for by dementia
 Short development period and fluctuating course
 Evidence of a general medical condition accounting for the
disturbance
American Psychiatric Association (1994)
DSM-IV: features of dementia
 Multiple cognitive deficits, including memory and at least one of
aphasia, apraxia, agnosia and executive planning
 Cognitive deficits give rise to significant impairment in social and
occupational functioning
 Deficits do not occur only during a delirium and cannot be
accounted for by depression
American Psychiatric Association (1994)
Delirium prevalence
 Increases with age; even in the community, prevalence in the
elderly is > 10% especially in those with polypharmacy, diabetes,
visual impairment and structural brain disease
 Prevalence in hospital populations is 10–40%; elderly frail with
recent falls and fractures are at particularly high risk
 Elderly in long-term care also at high risk; the risk is greater in
those with preexisting dementia or other physical illness requiring
nursing-home care
Community prevalence
Hospital prevalence
Nursing-home prevalence
Prevalence of delirium in the community
> 18 years
> 55 years
Prevalence of delirium (%)
> 85 years
14
12
10
8
6
4
2
0
Folstein et al (1991)
Prevalence of delirium in hospital settings
Prevalence of delirium (%)
40
30
20
10
0
Medical in-patients
(Levkoff et al 1992)
10%
Geriatric in-patients
(O'Keeffe and Lavan 1997)
18%
Orthopaedic in-patients
(Forman et al 1995)
36%
Prevalence of delirium in long-term settings
Prevalence of delirium (%)
50
40
30
20
10
0
All elderly in care or hospital
(Sandberg et al 1998)
44%
Intermediate-care home
(Rovner et al 1986)
9%
Nursing homes
(Sabin et al 1982)
25%
Clinical features of delirium
 Impairment of consciousness
 Disordered perception
 Abnormal thought content
 Altered mood
 Motor features
 Autonomic features
Lishman (1987)
Comparing delirium and dementia
Delirium
Alzheimer's disease
Patient 'confused'
Patient 'confused'
Patient agitated
Patient 'agitated'
Patient anxious (psychic and somatic)
Patient anxious (psychic and somatic)
Hallucinations
Hallucinations
Rapid onset
Gradual onset
Fluctuating
Stable
Marked diurnal variation
Waking at night or 'sundowning'
Severe attentional deficits
Wandering attention
Primary cortical
degenerative diseases
Natural history of Alzheimer's disease
 Onset
 Progression
gradual, probably imperceptible
slow and gradual, but not linear; progressive amnesia
most common
less than 10 years, on average, from diagnosis to death
 Duration
Cognitive function
Alzheimer’s disease
Vascular dementia
Dementia with Lewy bodies
Time
Clinical symptoms of AD
 Amnesia
 memory loss is early and invariable
 recent memory loss before remote memory
 Aphasia
 nominal dysphasia early
 both expressive and receptive dysphasia in moderate stages
 severely disrupted speech in late phases
 Apraxia
 functional difficulties, initially instrumental, subsequently basic activities of daily living
 ‘special’ dyspraxias, including topographical dyspraxia
 Agnosia
 difficult to assess, but probably more prevalent than often realised
 includes autoprosopagnosia (one cause of ‘mirror sign’)
 Behavioural and psychiatric symptoms (BPSD)




depression
psychotic features
personality change
activity disturbance
Natural history of dementia with Lewy bodies
(DLB)
 Onset
may be gradual, but may also be sudden; in retrospect,
onset may have been first diagnosed as delirium
fluctuating
some evidence suggests total duration of illness shorter
than for AD
 Progression
 Duration
Cognitive function
Alzheimer’s disease
Vascular dementia
Dementia with Lewy bodies
Time
Discovery of a ‘new’ disorder
Discovery of a ‘new’ disorder
 Dementia with Lewy bodies was recognised as a separate disorder only relatively
recently
 Basal Lewy bodies described in Parkinson’s disease
 Lewy was a co-worker of Alzheimer
 Cortical Lewy bodies (LBs) became apparent with immunocytochemical studies of
brain




traditional H&E staining does not reveal cortical LBs
staining with ubiquitin antibodies illuminates cortical LBs
ubiquitin is part of the non-specific cellular mechanism for degrading proteins
now recognised that LBs are composed principally of synuclein\
 Clinical study demonstrated that these patients had a typical triad of symptoms
 fluctuating cognitive state
 visual hallucinations
 Parkinsonism
 Associated features
 sensitivity to neuroleptic
Clinical symptoms of DLB
 Dementia with Lewy bodies is a disorder with a characteristic triad
of symptoms
 fluctuating confusion
 visual hallucinations
 parkinsonism
McKeith et al (1996)
Natural history of vascular dementia
 Vascular dementia is classically described as a disorder of
 sudden onset
 stepwise deterioration
 However, there are problems with the notion as
 vascular factors are risk factors for AD
 mixed disease is common (and may be more common than vascular dementia alone)
 relationship between degree of vascular damage and dementia is not direct
 progression in vascular dementia is similar to that in AD (although mixed disease may be
different from both by showing more rapid decline) (Bowler et al 1997)
 vascular dementia is found in many forms (Loeb and Meyer 1996)
Introduction to frontotemporal dementia (FTD)
 FTD is a collection of related disorders
 Some FTD cases are associated with or are secondary to motor
disorders
 frontotemporal degeneration with parkinsonism
 dementia and ALS (amyotrophic lateral sclerosis; motor neuron
disease)
Natural history of frontotemporal dementia
 Onset usually age 50–60 years
 Clinical onset is insidious
 Early stages dominated by




personality changes
changes in social conduct
loss of emotional warmth
progressive loss of speech
 Natural history is of a slow and progressive deterioration
Gustafson (1993); Neary et al (1998)
Clinical symptoms of FTD
 Neuropsychiatric symptoms




inertia and loss of motivation
loss of organisational abilities
lack of insight
restlessness
 Speech problems
 early loss of expressive speech
 stereotyped phrases
 late mutism and amimia
Cherrier et al (1997); Duara et al (1999); Neary et al (1998)
Clinical symptoms of FTD
 Compared with AD
 FTD: early non-cognitive behavioural changes with relatively spared
cognition
 AD: early cognitive changes with relatively preserved personality
and behaviour
 Compared with vascular dementia
 better digit span and constructional ability
 worse verbal fluency and abstractions
Levy et al (1996); Cherrier et al (1997)
Subcortical dementias
Clinical symptoms of subcortical dementias
 Bradyphrenia
 Perseveration
 Executive function deficits
 Language and visuospatial preservation
 Mild amnesia
 Social functioning often preserved
 Neurological symptoms of the primary disorder
Cummings (1994); Cummings and Benson (1984); Savage (1997)
Huntington's disease and dementia
4–7/100,000 population
Caused by triple-repeat expansion
(autosomal dominant)
Onset usually at age 30–45 years, but may
be 15–80 years
Characterised by choreiform movements,
depression, psychosis and dementia
CADASIL: cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy
 Migraine
 Strokes or stroke-like episodes
 Psychiatric symptoms (especially depression)
 Dementia
 MRI shows diffuse leukoencephalopathy with subcortical infarcts
 Caused by mutations in Notch3
 Onset age 20–40 years
Desmond et al (1999); Kalimo et al (1999)
Binswanger's disease
 Disputed entity
 onset age 50–70 years
 evidence of hypertension or systemic vascular disease
 progressive dementia (with predominant subcortical features)
 depression
 gait abnormalities (especially small stepping gait)
 rigidity
 neurogenic bladder
Cummings (1994); Pantoni and Garcia (1995)
Parkinson's disease and dementia
 Occurs in 20–40% patients
 Usually occurs after motor disorder
 Mild amnesia
 Severe slowing of thought
 Depression common
 Part of Lewy body disease spectrum
Elwan et al (1996); Hughes et al (1993)
Progressive supranuclear palsy (PSP)
(Steele–Richardson–Olszewski syndrome)
 Characteristic clinical features of PSP
 parkinsonism without tremor
 dementia, personality change, emotional incontinence, depression
 early postural instability with unheralded falls often misinterpreted
as lipothymia, epilepsy, cardiac attacks
 spastic and ataxic dysarthria
 vertical ocular gaze palsy with vertical saccades
 apraxia of lid movement and blepharospasm
 poor levodopa response
Progressive
Supranuclear
Palsy
Facial appearance
“Poker face”
Progressive
Supranuclear
Palsy
Retrocollis
(neck extension)
Paresis of vertical gaz
(Downward paresis)
Progressive
Supranuclear
Palsy
Characteristic clinical features of corticobasal
degeneration (CBGD)
 Asymmetrical motor dysfunction with parkinsonian (rigidity and
akinesia) and cortical features
 Unilateral/asymmetrical dyspraxia and cortical sensory loss
 Loss of control of the involved limb (‘alien limb’ phenomenon)
 Early and severe gait and balance problems
 Mild global cognitive decline with dysexecutive syndrome,
dysphagia and explicit learning deficits
 Clinical dementia may be the primary feature
 Myoclonus
Relative frequencies of the main dementias
Alzheimer’s disease
5%
Pure DLB 3%
5%
Vascular dementia
Dementia with Lewy bodies
Frontotemporal dementia
Other dementias
white matter dementias
subcortical (secondary) dementias
transmissible encephalopathies
DLB with
AD 12%
Mixed
vascular
dementia
and AD 10%
60%
Pure vascular
dementia 5%
Gearing et al (1995); Kosunen et al (1996); Nagy et al (1998)
Diagnosis and Assessment of Dementia
Diagnosis
Detecting cognitive impairment
Describing the syndrome
Making the diagnosis
Diagnosis: a team approach
Guidelines insist upon a multidisciplinary approach
clinical management is core to the treatment
APA (1997)
interdisciplinary team with key co-ordinator is optimal
Alzheimer Society of Canada (1992)
regularly reviewed individual care package important
RCGP (Haines and Katona) (1992)
home assessment should be available
RCPsych (UK) (1995)
alliance with the patient and family essential
APA (1997)
Clinical assessment
History
 informant
 family
 personal
Examination
 physical
 mental
Royal College of Psychiatrists (1999)
Investigations
 Routine investigations
 full blood count
 serum electrolytes
 glucose
 renal function
 liver function
 thyroid function tests
 vitamin B12/folate
 syphilis serology
 Neuroimaging
 CT
 MRI
 SPECT
 Special investigations
 PET
 CSF
MRI- AD
AD+CVD
FTD CT imaging
Vascular Dementia
Alzheimer’s Disease
Spect Scan
Regional distribution of atrophy in the common
dementias
 Alzheimer’s disease
predominantly parietal and temporal
 Frontotemporal dementia
predominantly frontal and temporal
 Dementia with Lewy bodies
as for AD, but with additional subcortical pathology
 Vascular dementia
vascular distribution
Executive
functions
Praxia
Language
Memory
Perceptuospatial
function
Functional regions
FTD
AD
ALZHEIMER’S DEMENTIA
DSM-IV Diagnostic Criteria for AD
 Memory deficit that can be demonstrated
objectively on cognitive testing.
 At least one other cognitive deficit such as
− aphasia , executive function impairment,,
agnosia , or apraxia
 Together, these cognitive deficits must result in
impairment in performance of daily activities.
DSM-IV Diagnostic Criteria for AD
 The course is characterized by gradual onset and
continuing cognitive decline.
 These deficits must represent a decline from a
previous higher level of functioning.
 There must not be any other neurological disease
that accounts for them.
NINCDS–ADRDA criteria for AD
 Criteria for clinical diagnosis of AD include
 dementia
 deficits in two or more areas of cognition
 progressive
 no disturbance of consciousness
 onset ages 40–90 years
 absence of other systemic or brain disease that could account for
the condition
Other (1)
Other (2)
Unlikely
Possible AD
Definite AD
McKhann et al (1984)
Other clinical features compatible with probable
AD (1)
 Progressive deterioration in specific cognitive areas (e.g. aphasia
or apraxia)
 Impaired function and altered behaviour
 Family history
 Normal or non-specific EEG changes
 Atrophy on CT
 Normal lumbar puncture
Other clinical features compatible with probable
AD (2)
 Plateau in progression
 Other neurological features late in disease
− gait disorder,
− myoclonus or abnormal primitive reflexes
− Seizures
 Normal CT
Features making the diagnosis of probable AD
unlikely
 Sudden apoplectic onset
 Focal neurological features
 Seizures or gait disturbance early in the disease
Clinical diagnosis of possible AD
 May be made on the basis of a dementia syndrome when there
are variations in onset, course or presentation in the absence of
other systemic or neurological disease sufficient to cause the
syndrome
 May be made in the presence of other disorder if the disorder is
not considered to be the cause of the dementia
 Should be used in research studies if a single, gradually
progressive, severe cognitive deficit is found in the absence of
any identifiable cause
Definite AD
May only be made in the presence of
a clinical diagnosis of probable AD
together with neuropathological
evidence of AD
Molecular pathogenesis of AD
Plaques (1)
tangles
plaques
Plaques (2)
 Primitive or diffuse plaque
 Mature or neuritic plaque
Tangles (1)
Neuropil
Threads /
Dystrophic
Neurites
Tangles (2)
 Early tangles progress to tombstone tangles
Tombstone tangle
Mature tangle
Early tangle
VASCULAR DEMENTIA
NINDS–AIREN criteria for probable vascular
dementia
 Dementia
 Cerebrovascular disease evident on history, examination or
imaging
 Two disorders must be related by
 onset of dementia within 3 months or
 abrupt, fluctuating or stepwise progression
Features of VaD
Uncertain
Possible VaD
Definite VaD
Roman et al (1993)
Clinical features supportive of vascular dementia
 Early gait disorder (marche à petit pas)
 Frequent falls
 Urinary incontinence or frequency early in disorder
 Pseudobulbar palsy
 Personality and mood changes
Features that make the diagnosis uncertain or
unlikely
 Early memory loss and progressive deterioration in the absence
of corresponding focal lesions on imaging
 Absence of focal neurological signs
 Absence of cerebrovascular lesions on CT or MRI
Possible vascular dementia
 Dementia with focal neurological signs, but where imaging is
missing
 Absence of clear temporal relationship between stroke and
dementia
 Subtle onset or variable course and evidence of relevant CVD
Definite vascular dementia
 Clinical criteria
 Histopathological evidence
 Absence of AD changes exceeding those expected by age
 Absence of other disorder capable of producing dementia
LEWY BODY DEMENTIA
Newcastle criteria for Dementia Lewy Body ( DLB)
 Progressive cognitive decline and two of three core features
 fluctuation
 visual hallucinations
 parkinsonism
Features supporting diagnosis
DLB less likely in the presence of
McKeith et al (1996)
Features supportive of the diagnosis of DLB
 Repeated falls
 Syncope
 Transient loss of consciousness
 Neuroleptic sensitivity
 Systemised delusions
 Hallucinations in other modalities
A diagnosis of DLB is less likely in the presence
of
 Stroke disease — evidence as focal neurological signs or on
imaging
 Other systemic or brain disease sufficient to cause the condition
FRONTO-TEMPORAL
DEMENTIA
Manchester and Lund criteria for Fronto-Temopral
Dementia (FTD)
 Core diagnostic features
 insidious onset and gradual progression
 early decline in social interpersonal conduct
 early impairment in regulation of personal conduct
 early emotional blunting
 early loss of insight
Behavioural
Language
Physical signs
Investigations
Neary et al (1998)
Supportive diagnostic features: behavioural
disorder
 Decline in personal hygiene
 Mental rigidity and inflexibility
 Distractibility and impersistence
 Hyperorality and dietary changes
 Perseverative behaviour
 Utilisation behaviour
Supportive diagnostic features: speech and
language
 Altered speech output: aspontaneity or pressure
 Echolalia
 Perseveration
 Mutism
Supportive diagnostic features: physical signs
 Primitive reflexes
 Incontinence
 Akinesia, rigidity, tremor
 Low and labile blood pressure
Investigations
 Neuropsychology:
− significant impairment on frontal lobe tests
− Language deficits
− absence of severe amnesia, aphasia or visuospatial
deficits
 Prominent frontal and/or anterior temporal atrophy
on neuroimaging
Assessment scales
Why use scales in dementia assessment?
Reliability and validity
Standardisation
Multidisciplinary working
Quantification
Domains assessment using scales
 Cognition
 Behaviour
 Function
 Global
 Carers
 Services
Memory
Attention
Language
Visual Memory
Verbal memory
Visuoconstruction
Visuomotor Speed
Executive function
Cognition
Assessment of cognition in dementia
Scales for:
 primary care
 secondary care
 research
 specific cognitive deficits
 psychometric testing
 screening
 monitoring change
Screening scales
Which screening scales are suitable for
use in primary care?
AMT
MMSE
clock drawing test
AD-8
TYM
Abbreviated Mental Test Score (AMTS)
 Subject interview
 3-minute assessment
 10 items
 Range 0–10
 Score < 7-8 suggests dementia
Qureshi and Hodkinson (1974)
Mental Test Score (MTS) / Abbreviated Mental Test
Score
ORIGINAL TEST ITEMS
Score
Name
Age
Time (to nearest hour)
Time of day
Name and adress for five-minute recall
(this should be repeated by the patient to ensure it has been heard
correctly)
Mr John Brown
42 West Street
Gateshead
Day of week
Date (correct day of month)
Month
Year
Place: Type of place (i.e. hospital)
Name of hospital
Name of ward
Name of town
0/1
0/1
0/1
0/1
0/1/2
0/1/2
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
Qureshi and Hodkinson (1974)
Mental Test Score (MTS) / Abbreviated Mental Test
Score
ORIGINAL TEST ITEMS
Score
Recognition of two persons (doctor, nurse, etc.)
Date of birth (day and month sufficient)
Place of birth (town)
School attended
Former occupation
Name of wife, sibling or next of kin
Date of First World War (year sufficient)
Date of Second World War (year sufficient)
Name of present Monarch
Name of present Prime Minister
Months of year backwards
Count 1-20
Count 20-1
Total
0/1/2
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1/2
0/1/2
0/1/2
-34
Qureshi and Hodkinson (1974)
Mental Test Score (MTS) / Abbreviated Mental Test
Score
ABBREVIATED MENTAL TEST SCORE
1.
2.
Age
Time (to nearest hour)
Address for recall at end of test – this should be repeated by the
3.
patient to ensure it has been heard correctly: 42 West Street
4.
Year
5.
Name of hospital
6.
Recognition of two persons (doctor, nurse, etc)
7.
Date of birth
8.
Year of First World War
9.
Name of present Monarch
10. Count backwards 20-1
(each question scores one mark)
Quresi and Hodkinson (1974)
Mini-Mental State Examination (MMSE)
 Subject interview
 10-minute assessment
 30 items
 Range 0–30
 Score < 24-25 suggests dementia
 Assessment of orientation, registration, attention and calculation,
recall, language and visual construction
Folstein et al (1975)
Mini-Mental State Examiniation (MMSE)
Max score
Score
ORIENTATION
5
What is the (year) (season) (date) (month) (day)?
5
Where are we: (state) (county) (town) (hospital) (floor)?
REGISTRATION
3
Name 3 objects: (1 second to say each). Then ask the patient all three
after you have said them. Give 1 point for each correct answer. Then
repeat them until the patient learns all 3. Count trials and record.
Number of trials
ATTENTION AND CALCULATION
5
Serial 7s. 1 point for each correct. Stop after 5 answers. If the patient
refuses, spell ”world” backwards.
RECALL
3
Ask for 3 objects repeated above. Give 1 point for each correct.
The copyright in the Mini Mental State Examination is wholly owned by the Mini Mental Ilc, a Massachusetts limited
company.
© 1975, 1988 Mini Mental Ilc.
Folstein et al (1975)
Mini-Mental State Examiniation (MMSE)
Max score
Score
LANGUAGE
9
Name a pencil; name a watch. (2 points)
Repeat the following: ”No ifs, ands or buts.” (1 point)
Follow a three-stage command: ”Take this paper in your right hand, fold it in half,
and put it on the floor.” (3 points)
Read and obey the following: ”Close your eyes.” (1 point)
Write a sentence. (1 point)
Copy a design. (1 point)
Total Score
Assess level of consciousness along a continuum
Alert
Drowsy
Stupor
Coma
The copyright in the Mini Mental State Examination is wholly owned by the Mini Mental Ilc, a Massachusetts limited
company.
© 1975, 1988 Mini Mental Ilc.
Folstein et al (1975)
MMSE Modification
 Modifications were made for Singapore populations:
−
−
−
−
For “season” substitute “time of day”
For “state” substitute “region of Singapore”
For “county” substitute “nearby housing estate”
For “no ifs ands or buts” substitute “44 stone lions”
Montreal Cognitive Assessment (MoCA)

Subject interview

10-minute assessment

30 items

Range 0–30

Score < 26 suggests MCI and AD

Designed to be more sensitive to mild cognitive deficits than
MMSE (Sensitivity MoCA 90% vs MMSE 18%) (Nasreddine, et
al, 2005).
Consists of 8 cognitive subtests: visuospatial /executive,
naming, memory, attention, language, abstraction, delayed
recall, orientation.

Alzheimer’s Disease Assessment Scale cognitive
section (ADAS–cog)
 Subject interview
 30–45-minute assessment
 11 sections on cognition
 70-point scale
Rosen et al (1984)
ADAS-cog
Cognitive items
1. Spoken language ability
2. Comprehension of spoken language
3. Recall of test instructions
4. Word-finding difficulty
5. Following commands
6. Naming: objects, fingers
High:
1
2
3
4
Fingers:
Thumb
Medium:
1
2
3
4
Pinky
Index
Low:
1
2
3
4
Middle
Ring
American Psychiatric Association (1984)
ADAS-cog
7. Construction: drawing
Figures correct
Closing in:
1
Yes
2
3
4
3
4
No
8. Ideational praxis
Step correct:
1
2
5
9. Orientation
Day
Year
Person
Time of day
Date
Month
Season
Place
10. Word recall: mean error score
11.
Word recognition: mean error score
Cognition total
American Psychiatric Association (1984)
ADAS-cog
Non-cognitive items
12. Tearful
13. Appear / reports depressed mood
14. Concentration, distractibility
15. Uncooperative to testing
16. Delusions
17. Hallucinations
18. Pacing
19. Increased motor activity
20. Tremors
21. Increase / decrease appetite
Non-cognition total
American Psychiatric Association (1984)
ADAS-cog
Total scores
Cognitive behaviour
Non-cognitive behaviour
Word recall
Word recognition
Total
Rating
x = not assessed
0 = not present
1 = very mild
2 = mild
3 = moderate
4 = moderately severe
5 = severe
American Psychiatric Association (1984)
ADAS-cog
Spoken language – quality of speech, NOT quantity
Comprehension – do NOT include responses to commands
Do NOT include finger or object naming
Score
0 – 5 steps correct
1 – 4 steps correct
2 – 3 steps correct
3 – 2 steps correct
4 – 1 steps correct
5 – cannot do one step correct
American Psychiatric Association (1984)
ADAS-cog
Name fingers of dominant hand and high / medium / low frequency
objects
0 = all correct; one finger incorrect and / or one object incorrect
1 = two-three fingers and / or two objects incorrect
2 = two or more fingers and three-five objects incorrect
3 = three or more fingers and six-seven objects incorrect
4 = three or more fingers and eight-nine objects incorrect
Ability to copy circle, two overlapping rectangles, rhombus and cube
American Psychiatric Association (1984)
ADAS-cog
Five components in sending self a letter
1 = difficulty or failure to perform one component
2 = difficulty and / or failure to perform two components
3 = difficulty and / or failure to perform three components
4 = difficulty and / or failure to perform four components
5 = difficulty and / or failure to perform five components
Date, month, year, day of week, season, time of day, place and person
Non-cognitive behaviour is evaluated over preceding week to interview
American Psychiatric Association (1984)
Function
Instrumental Activities of Daily Living Scale (IADL)
 Interview with carer
 10-minute assessment
 8 items
Lawton and Brody (1969)
Instrumental Activities of Daily Living Scale (IADL)
A.
Ability to use telephone
1.
Operates telephone on own initiative – looks up and dials numbers, etc
2.
Dials a few well-known numbers
3.
Answers telephone, bud does not dial
4.
Does not use telephone at all
B.
Shopping
1.
Takes care of all shopping needs independently
2.
Shops independently for small purchases
3.
Needs to be accompanied on any shopping trip
4.
Completely unable to shop
The Gerontological Society of America (1969)
Instrumental Activities of Daily Living Scale (IADL)
C.
Food preparation
1.
Plans, prepares and serves adequate meals independently
2.
Prepares adequate meals if supplied with ingredients
3.
Heats, serves and prepares meals, or prepares meals, but does not maintain
adequate diet
4.
Needs to have meals prepared and served
D.
Housekeeping
1.
Maintains house alone or with occasional assistance (e.g. ’heavy work domestic help’)
2.
Performs light daily tasks such as dishwashing, bedmaking
3.
Performs light daily tasks, but cannot maintain acceptable level of cleanliness
4.
Needs help with all home maintenance tasks
5.
Does not participate in any housekeeping tasks
The Gerontological Society of America (1969)
Instrumental Activities of Daily Living Scale (IADL)
E.
Laundry
1.
Does personal laundry completely
2.
Launders small items- rinses stockings, etc
3.
All laundry must be done by others
F.
Mode of transport
1.
Travels independently on public transport or drives own car
2.
Arranges own travel via taxi, but does not otherwise use public transport
3.
Travels on public transport when accompanied by another
4.
Travel limited to taxi or automobile with assistance of another
5.
Does not travel at all
The Gerontological Society of America (1969)
Instrumental Activities of Daily Living Scale (IADL)
G.
Responsibility for own medications
1.
Is responsible for taking medication in correct dosages at correct time
2.
Takes responsibility if medication is prepared in advance in separate dosage
3.
Is not capable of dispensing own medication
H.
Ability to handle finance
1.
Manages financial matters independently (budgets, writes cheques, pays rent, bills, goes
to bank), collects and keeps track of income
2.
Manages day-to-day purchases, but needs help with banking, major purchases, etc
3.
Incapable of handling money
The Gerontological Society of America (1969)
Basic Activities of Daily Living Scale (BADL)
Physical self-maintenance scale
A.
Toilet
1.
Cares for self at toilet completely, no incontinence
2.
Needs to be reminded, or needs help in cleaning self, or has rare (weekly, at most)
accidents
3.
Soiling or wetting while asleep not more than once a week
4.
Soiling or wetting while asleep more than once a week
5.
No control of bowels or bladder
B.
Feeding
1.
Eats without assistance
2.
Eats with minor assistance at mealtimes and / or with special preparation of food, or
help in cleaning up after meals
3.
Feeds self with moderate assistance and is untidy
4.
Requires extensive assistance for all meals
5.
Does not feed self at all and resists efforts of others to feed him
The Gerontological Society of America (1969)
Basic Activities of Daily Living Scale (BADL
C.
Dressing
1.
Dresses, undresses and selects clothes from own wardrobe
2.
Dresses and undresses self with minor assistance
3.
Needs minor assistance in dressing and selecting clothes
4.
Needs major assistance in dressing, but cooperates with efforts of others to help
5.
Completely unable to dress self and resists efforts of others to help
D.
Grooming (neatness, hair, nails, face, clothing)
1.
Always neatly dressed, well groomed without assistance
2.
Grooms self adequately with occasional minor assistance (e.g. shaving)
3.
Needs moderate and regular assistance or supervision in grooming
4.
Needs total grooming care, but can remain well groomed after help from others
5.
Actively negates all efforts of others to maintain grooming
The Gerontological Society of America (1969)
Basic Activities of Daily Living Scale (BADL
E.
Physical ambulation
1.
Goes about grounds or city
2.
Ambulates within residence or about one block’s distance
3.
Ambulates with assistance of (check one): (
1
2
) cane, (
) walker, (
) wheelchair
Gets in and out without help
Needs help in getting in and out
4.
Sits unsupported in chair or wheelchair, but cannot propel without help
5.
Bedridden more than half the time
F.
Bathing
1.
Bathes self (tub, shower, sponge bath) without help
2.
Bathes self with help in getting in and out of tub
3.
Washes face and hands only, but cannot bathe rest of body
4.
Does not wash self, but is cooperative with those who bathe him
5.
Does not wash self and resists efforts of others to keep him clean
The Gerontological Society of America (1969)
ADCS-ADL Assessment Tool
 The commonly used assessment tool was developed by the Alzheimer’s
Disease Cooperative Study
 Used to assess a person’s functional ability
 Physical functioning is usually measured by the ability to
accomplish basic activities of daily living (ADL)
 Other components of functional well-being measured are their
higher functional abilities
Online scale: http://www.medafile.com/cln/ADCSADL.htm
In the past 4 weeks, did subject use a household appliance to do
chores?
Yes 
No
Don’t Know
If yes, ask about all of the following , and check those that were used:
 Washer
_ Dryer
_ Dishwasher  Toaster
_Range

Microwave
_Vacuum
_Toaster Oven
_Food Processor
_Other_________________
If yes, for the most commonly used appliances, which best describes
how {s}
usually used them:
4  without help, operating more than on-off controls if needed
3 _ without help, but operated only on/ off controls
2 _ with supervision, but no physical help
1 _ with physical help
Global assessment
Functional Assessment Staging (FAST)
 Clinician-rated scale
 30-minute assessment; 2-minute rating
 7 major stages
 16 substages
Reisberg (1988)
Functional Assessment Staging (FAST)
Yes
Months1
No.
1.
No difficulties either subjectively or objectively
2.
Complains of forgetting location of objects; subjective work difficulties
3.
Decreased job functioning evident to co-workers, difficulty in
travelling to new locations
4.
Decreased ability to perform complex tasks (e.g. planning dinner for
guests, handling finances, marketing)
5.
Requires assistance in choosing proper clothing
6a. Difficulty putting clothing on properly
6b. Unable to bathe properly; may develop fear of bathing
6c.
Inability to handle mechanisms of toileting (e.g. forgets to flush,
doesn’t wipe properly)
6d. Urinary incontinence
6e. Faecal incontinence
Note: Functional staging score = highest ordinal value; 1Number of months FAST stage deficit has been noted
© 1984 by Barry Reisberg, M.D.
Reisberg (1988)
Functional Assessment Staging (FAST)
Yes
Months1
No.
7a.
Ability to speak limited (1 to 5 words only)
7b.
All intelligible vocabulary lost
7c.
Non-ambulatory
7d.
Unable to sit up independently
7e.
Unable to smile
7f.
Unable to hold head up
TESTER:
COMMENTS:
Note: Functional staging score = highest ordinal value; 1Number of months FAST stage deficit has been noted
© 1984 by Barry Reisberg, M.D.
Reisberg (1988)
Clinical Dementia Rating (CDR)
 Clinician-rated scale
 Extensive assessment; 2-minute rating
 6 domains
 4 stages in each domain
Hughes et al (1982)
Clinical Dementia Rating (CDR)
Impairment
None
Questionable
Mild
Moderate
Severe
0
0.5
1
2
3
Memory
No memory loss
or slight
inconstant
forgetfulness
Consistent slight
forgetfulness;
partial recollection
of events; ’benign
forgetfulness’
Moderate
memory loss;
more marked for
recent events;
defect interferes
with everyday
activities
Severe memory
loss; only highly
learned material
retained; new
material rapidly
lost
Severe memory
loss; only
fragments
remain
Orientation
Fully orientated
Fully orientated
except for slight
difficulty with time
relationships
Moderate
difficulty with
time
relationships;
orientated for
place at place at
examination;
may have
geographic
disorientation
elsewhere
Severe difficulty
with time
relationships;
usually
disorientated to
time, often to
place
Orientated to
person only
Rating: Score only as decline from previous usual level due to cognitive loss, not impairment due to other factors
Hughes et al (1982)
Clinical Dementia Rating (CDR)
Impairment
Judgement
and problem
solving
None
Questionable
Mild
Moderate
Severe
0
0.5
1
2
3
Solves everyday
problems and
handles business
and financial
affairs well;
judgement good
in relation to past
performance
Slight impairment
in solving
problems
similarities and
differences
Moderate
difficulty in
handling
problems
similarities and
differences;
social judgement
usually impaired
Severely
impaired in
handling
problems,
similarities and
differences;
social
judgement
usually
impaired
Unable to make
judgements or
solve problems
Rating: Score only as decline from previous usual level due to cognitive loss, not impairment due to other factors
Hughes et al (1982)
Clinical Dementia Rating (CDR)
Impairment
Community
affairs
None
Questionable
Mild
Moderate
Severe
0
0.5
1
2
3
Independent
function at usual
level in job,
shopping, and
volunteer and
social groups
Slight impairment
in these activities
Unable to
function
independently at
these activities,
although may
still be engaged
in some;
appears normal
to casual
inspection
No pretence of independent function
outside of home
Appears well
enough to be
taken to
functions
outside a
family home
Appears too ill to
be taken to
functions outside
a family home
Rating: Score only as decline from previous usual level due to cognitive loss, not impairment due to other factors
Hughes et al (1982)
Clinical Dementia Rating (CDR)
Impairment
Home and
hobbies
Personal care
None
Questionable
Mild
Moderate
Severe
0
0.5
1
2
3
Life at home,
hobbies and
intellectual
interests well
maintained
Life at home,
hobbies and
intellectual
interests
slightly
impaired
Mild but definite
impairment of
function at
home; more
difficult chores
abandoned;
more
complicated
hobbies and
interests
abandoned
Only simple
chores
preserved;
very restricted
interests,
poorly
maintained
Severe memory
loss; only
fragments
remain
Needs prompting
Requires
assistance in
dressing,
hygiene,
keeping of
personal
effects
Severe difficulty
with time
relationships;
usually
disorientated to
time, often to
place
Fully capable of self-care
Rating: Score only as decline from previous usual level due to cognitive loss, not impairment due to other factors
Hughes et al (1982)
Quality of life
Progressive Deterioration Scale (PDS)
 Clinician-rated scale
 Extensive assessment; 15-minute rating
 11 domains
Progressive Deterioration Scale (PDS)
DeJong et al (1989)
Summary of content areas for the Progressive
Deterioration Scale (PDS)
Extent to which patient can leave immediate neighbourhood
Ability to safely travel distances alone
Confusion in familiar settings
Use of familiar household implements
Participation / enjoyment of leisure / cultural activities
Extent to which patient does household chores
Involvement in family finances, budgeting, etc
Interest in doing household tasks
Travel on public transport
Self-care and routine tasks
Social function / behaviour in social settings
Reprinted by permission of the publisher from Clinical Therapeutics, 11, 545-54. Copyright 1989 by Excerpta Medica Inc.
DeJong et al (1989)
Burden interview
 Carer self-report
 20-minute rating
 29 items
Zarit et al (1980)
Burden interview
1.
I feel resentful of other relatives who could, but do not, do things for my spouse
2.
I feel that my spouse makes requests which I perceive to be over and above what s/he needs
3.
Because of my involvement with my spouse, I don’t have enough time for myself
4.
I feel stressed between trying to give to my spouse as well as to other family responsibilities, job, etc
5.
I feel embarrassed over my spouse’s behaviour
6.
I feel guilty about my interactions with my spouse
7.
I feel that I don’t do as much for my spouse as I could or should
8.
I feel angry about my interactions with my spouse
9.
I feel that, in the past, I haven’t done as much for my spouse as I could have or should have
10. I feel nervous or depressed about my interactions with my spouse
The Gerontological Society of America (1980)
Burden interview
11. I feel that my spouse currently affects my relationships with other family members and friends in a
negative way
12. I feel resentful about my interactions with my spouse
13. I am afraid of what the future holds for my spouse
14. I feel pleased about my interactions with my spouse
15. It’s painful to watch my spouse age
16. I feel useful in my interactions with my spouse
17. I feel my spouse is dependent
18. I feel strained in my interactions with my spouse
19. I feel that my health has suffered because of my involvement with my spouse
20.
I feel that I am contributing to the wellbeing of my spouse
The Gerontological Society of America (1980)
Burden interview
21. I feel that the present situation with my spouse doesn’t allow me as much privacy as I’d like
22. I feel that my social life has suffered because of my involvement with my spouse
23. I wish that my spouse and I had a better relationship
24. I feel that my spouse doesn’t appreciate what I do for him / her as much as I would like
25. I feel uncomfortable when I have friends over
26. I feel that my spouse tries to manipulate me
27.
I feel that my spouse seems to expect me to take care of him / her as if I were the only one s/he could
depend on
28. I feel that I don’t have enough money to support my spouse in addition to the rest of our expenses
29. I feel that I would like to be able to provide more money to support my spouse than I am able to now
The Gerontological Society of America (1980)
TREATMENT
Neurons
Courtesy of The National Institute on Aging
Neuron
Dendrites
Axon
Neurotransmitter
Molecules
Receptor
Synapse
Slide 14
 Acetylcholinestarase inhibitors
− Donepezil ( Aricept) 5mg, 10mg
− Rivastigmine (exelon) patch 4.5mg, 10mg
−
tab 1.5mg, 3mg, 4.5mg
− Galantamine (reminyl) 4mg,8mg,12mg
 NMDA receptors antagonist
* N-methyl-D-aspartate receptor
− Memantine 10mg, 20mg
Desirable properties
Competitive inhibition
Reversible inhibition
Low toxicity
Few drug interactions
Long active half-life
Selectivity
McKeith (1999)
Outcome targets
Cognition
Global measures
Function
Behaviour
Quality of life
Health economics
Leber (1990)
Cholinergic transmission
Muscarinic receptor
Nicotinic receptor
ACh
ACh metabolites
Glutamate
Glutamatergic receptors
5
6
Second
messengers
2
8
4
1
Neuronal
firing
3
AChE
7
Correcting cholinergic loss in AD
Muscarinic receptor
Nicotinic receptor
ACh
ACh metabolites
4
1
3
Choline
Lecithin
Acetyl
CoA
AChE
AChEIs
2
NMDA RECEPTOR
ANTAGONIST
Learning and glutamatergic transmission
Glutamate
Magnesium
Learning
Rest
Ca2+
Ca2+
Signal
Noise
Signal
detected
Noise
Pathological activation of NMDA-receptors
Glutamate
Magnesium
Pathological activation of
NMDA-receptors
Impairment of plastic
processes
Rest
Learning
Chronic
neurodegeneration
Ca2+
Ca2+
Ca2+
Signal not
detected
Damaged
neuron
Signal
Noise
Noise
Signal
Mechanism of action of memantine (1)
 Both memantine and magnesium allow the physiological
activation of the NMDA-receptor due to their:
 voltage dependency
 rapid unblocking kinetics
BUT
 Memantine does not leave the NMDA-receptor channel as easily as
magnesium following tonic low level activation of NMDA-receptors
 Memantine’s voltage-dependency is not as pronounced as
magnesium’s
Mechanism of action of memantine (2)
Pathological activation of
NMDA-receptors
Possible neuroprotection
by memantine
Rest
Rest
Memantine improves
plastic processes
Learning
M
Ca2+
Glutamate
Magnesium
M Memantine
M
Ca2+
Ca2+
Signal
detected
Signal
Noise
Noise
Noise
?Choice of treatment
Choice of Treatment
 Is the patient demented?
− No evidence of efficacy in MCI studies
 What is the cause of dementia?
− Limited efficacy studies in FTD
 What is the stage of dementia?
− Limited evidence for efficacy of memantine in early dementia
− Limited evidence for efficacy of AChEIs in late dementia
 What are the symptoms to be targeted?
− Efficacy for cognition, global scales
− Preservation of ADL
− Prevention of emergent behavioral problems
 What other issues need to be addressed?
− Dysphagia
− cost
Alzheimer’s is not just
a little memory loss.
It eventually kills,
but not before it takes
everything away.