Transcript DIAGNOSIS OF AZLHEIMER’S DISEASE

Screening for
Mild Cognitive Impairment and
Alzheimer's Disease:
Relevance of Age and APOE genotype
Memory & Aging Center Team
University of California, San Francisco
May 21, 2004
J. Wesson Ashford, M.D., Ph.D.
Stanford / VA Alzheimer’s Center
VAMC, Palo Alto, California
Slides at: www.medafile.com/MCIscra.ppt
Dementia Definition
• Multiple Cognitive Deficits:
– Memory dysfunction
• especially new learning, a prominent early
symptom
– At least one additional cognitive deficit
• aphasia, apraxia, agnosia, or executive
dysfunction
• Cognitive Disturbances:
– Sufficiently severe to cause impairment of
occupational or social functioning and
– Must represent a decline from a previous level of
functioning
DIAGNOSTIC CRITERIA FOR DEMENTIA
OF THE ALZHEIMER TYPE
(DSM-IV, APA, 1994)
A. DEVELOPMENT OF MULTIPLE COGNITIVE DEFICITS
B.
C.
D.
F.
G.
1. MEMORY IMPAIRMENT
2, OTHER COGNITIVE IMPAIRMENT
THESE IMPAIRMENTS CAUSE DYSFUNCTION IN
IN SOCIAL OR OCCUPATIONAL ACTIVITIES
COURSE SHOWS GRADUAL ONSET AND DECLINE
DEFICITS ARE NOT DUE TO:
1. OTHER CNS CONDITIONS
2. SUBSTANCE INDUCED CONDITIONS
DO NOT OCCUR EXCLUSIVELY DURING DELIRIUM
ARE NOT DUE TO OTHER PSYCHIATRIC DISORDER
BIOPSYCHOSOCIAL SYSTEMS AFFECTED BY AD
NEUROPLASTIC MECHANISMS AFFECTED AT ALL LEVELS
(Ashford, Mattson, Kumar, 1998; Teter, Ashford, 2002)
• SOCIAL SYSTEMS
• INSTRUMENTAL ADLs - EARLY
• BASIC ADLs - LATE
• PSYCHOLOGICAL SYSTEMS
• PRIMARY LOSS OF SHORT-TERM MEMORY
– LEARNING PROCESSES – CLASSICAL, OPERANT
• LATER LOSS OF LEARNED SKILLS
• NEURONAL MEMORY SYSTEMS
• CORTICAL GLUTAMATERGIC STORAGE
• SUBCORTICAL
– (acetylcholine, norepinephrine, serotonin)
• CELLULAR PLASTIC PROCESSES
– APP metabolism – early, broad cortical distribution
– TAU hyperphosphorylation – late, focal effect, dementia related
NEUROPATHOLOGY OF AD
• Senile plaques
• beta-amyloid protein (? Primary problem)
• Neurofibrillary tangles
• hyper-phosphorylated tau (loss of synapses,
dementia)
• Neurotransmitter losses
• Acetylcholine (Ach) – major loss of nicotinic
receptors
• Norepinephrine, serotonin, glutamate,
GABAss
• Inflammatory responses
New Neuropath Mechanisms
• Amyloid PreProtein (APP - ch21) (early changes)
– metabolism occurs on cholesterol “rafts”
• Cholesterol transport by APOE (ch 19), provides,
removes
– alpha-secretase vs beta/gamma secretase metabolism
– influence toward alpha-secretase by Acetylcholine
– gamma-secretase (PreSenilin genes, ch14,1)
– break down - Insulin Degrading Enzyme (ch10), etc.
– prevention of fibril formation by melatonin
• Tau hyperphosphorylation (relation to dementia)
– glycogen-synthase-kinase (GSK) 3-beta
– inhibition by Ach, lithium, valproic acid
Differential Diagnosis: Top Ten
(commonly used mnemonic device: AVDEMENTIA)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Alzheimer Disease (pure ~40%, + mixed~70%)
Vascular Disease, MID (5-20%)
Drugs, Depression, Delirium
Ethanol (5-15%)
Medical / Metabolic Systems
Endocrine (thyroid, diabetes), Ears, Eyes, Environ.
Neurologic (other primary degenerations, etc.)
Tumor, Toxin, Trauma
Infection, Idiopathic, Immunologic
Amnesia, Autoimmune, Apnea, AAMI
VA – consider PTSD, Gulf War Syndrome
Alzheimer’s Disease
versus
Dementia
– 50 - 70% of dementias are due to AD
– Probable AD - 30% of cases, 90% neuropath - correct
– 20% have other contributing diagnoses
– Possible AD - 40% of cases, 70% are AD at neuropath
– 40% have other contributing diagnoses
– Unlikely AD - 30% of cases, 30% are AD at neuropath
– 80% have other contributing diagnoses
– Alzheimer’s disease is a pathological condition
– Dementia is a clinical condition frequently caused by AD
• The AD dementia has some characteristics and some heterogeneity
UNDERLYING CONTINUUM OF
ALZHEIMER SEVERITY
(unidimensional)
• CROSS-SECTIONAL MEASURES
– DEMENTIA SEVERITY (cognitive, ADL)
• COGNITIVE SCALE SCORE
• Z-SCORE
• PRINCIPAL COMPONENT ANALYSIS
– BRAIN ATROPHY, DYSFUNCTION
– AUTOPSY MEASURES: plaques, tangles
– TIME TO DEATH
• LONGITUDINAL MEASUREMENT
– TIME INTO THE DISEASE PROCESS
• CONSIDERABLE HETEROGENEITY IN DISEASE
PRESENTATION AND BRAIN DISTRIBUTION
MILD COGNITIVE IMPAIRMENT
CRITERIA (Amer. Acad. Neurology)
(Petersen et al., 2001 – Neurology 56:1133)
1. Memory complaint, preferably
corroborated by an informant
2.
3.
4.
5.
Objective memory impairment
Normal general cognitive function
Intact activities of daily living
Not demented
- Earlier descriptions by:
Jonker, Hooyer, 1990
Flicker, Ferris, Reisberg, 1991
Zaudig, 1992
MILD COGNITIVE IMPAIRMENT
ISSUES IN DEFINITION
(Petersen et al., 2001 – Neurology 56:1133)
Study
Mean Criteria
Age
Annual
conversion
rate to AD %
Mayo
81
MCI
12
Toronto
74
Memory Impairment
14
Columbia
66
Questionable dementia
15
MGH
72
CDR 0.5
Seattle
74
Isolated memory loss
12
NYU
71
GDS 3
25
6
ALZHEIMER’S DISEASE
Estimate MMSE as a function of time
MMSE score
30
25
20
15
10
5
0
-10
-8
-6
-4
-2
0
2
4
6
8
10
Estimated years into illness
AAMI / MCI
DEMENTIA
Ashford et al., 1995
Age-Associated Memory Impairment
vs
Mild Cognitive Impairment
• Memory declines with age – need to consider relative to
APOE genotype!
• Age - related memory decline corresponds with atrophy of
the hippocampus
• Older individuals remember more complex items and
relationships
• Older individuals are slower to respond
• Memory problems predispose to development of
Alzheimer’s disease
• Thus --- screening for MCI / early AD must consider age!
– And should consider APOE genotype!
Early Recognition of AD: Consensus Statement
(AAGP, AGS, Alzheimer’s Association)
• AD continues to be missed as diagnosis
• AD is unrecognized and under-reported
– patients do not realized
– families tend to compensate
• Effective treatment and management
techniques are available
– (AChEIs FDA approved)
– Several other approaches are beneficial
Small et al., JAMA, 1997
AD is Underdiagnosed
• Early Alzheimer’s disease is subtle – it is easy for
family members and physicians to miss the initial
signs and symptoms
• Less than half of AD patients are diagnosed
– Estimates are that 25% to 50% of cases remain
undiagnosed
• Undiagnosed AD patients often face avoidable
social, financial, and medical problems
• Early diagnosis and appropriate intervention may
lessen disease burden
• No definitive laboratory test for diagnosing AD exists
Evans DA. Milbank Quarterly. 1990; 68:267-289
AD Can Be Readily Diagnosed
McKhann G et al. Neurology. 1984;34:939-944.
Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164.
• A diagnosis of Alzheimer’s disease can be
made with a high degree of certainty
• Using NINCDS-ADRDA criteria, accuracy in
autopsy-verified cases is approximately 90%
• Diagnosis is a 2-step process:
– Detection through screening
– Confirmation through patient history and
physical, caregiver interview, brain imaging,
and appropriate laboratory studies
Assessment
History Of The Development Of The Dementia
–
–
–
–
–
–
•
•
•
•
Ask the Patient What Problem Has Brought Him to See You
Ask the Family, Companion about the Problem
Specifically Ask about Memory Problems
Ask about the First Symptoms
Enquire about Time of Onset
Ask about Any Unusual Events Around the Time of Onset,
e.g., stress, trauma, surgery
– Ask about Nature and Rate of Progression
Physical Examination
Neurological Examination
Laboratory Tests
Neuropsychological / Cognitive Assessment
RELATIVE RISK FACTORS
FOR ALZHEIMER’S DISEASE
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•
•
•
•
•
•
•
•
Family history of dementia
Family history – Downs
Family history - Parkinson’s
Maternal age > 40 years
Head trauma (with LOC)
History of depression
History of hypothyroidism
History of severe headache
NSAID use or statin use
3.5 (2.6 - 4.6)
2.7 (1.2 - 5.7)
2.4 (1.0 - 5.8)
1.7 (1.0 - 2.9)
1.8 (1.3 - 2.7)
1.8 (1.3 - 2.7)
2.3 (1.0 - 5.4)
0.7 (0.5 - 1.0)
0.2 (0.05 – 0.83)
Roca, 1994, t’Veldt, 2002
NEUROPSYCHOLOGICAL
TESTING (WAIS, WECHSLER)
•
•
•
•
•
•
•
•
MEMORY: SHORT-TERM, REMOTE
VERBAL FUNCTION, FLUENCY
VISUO-SPATIAL FUNCTION
ATTENTION
EXECUTIVE FUNCTION
ABSTRACT THINKING
ACCOUNT FOR EDUCATION
ACCOUNT FOR PRIOR DISFUNCTIONS
BRIEF CLINICAL TOOLS FOR
COGNITIVE ASSESSMENT
•
•
•
•
•
•
•
•
•
MINI-MENTAL STATE EXAM
CLOCK DRAWING
ANIMAL NAMING (1 minute)
MATTIS DEMENTIA RATING SCALE
ALZHEIMER’S DISEASE
ASSESSEMENT SCALE (ADAS)
ACTIVITIES OF DAILY LIVING
GLOBAL CLINICAL SCALE
CLINICAL DEMENTIA RATING SCALE
GLOBAL DETERIORATION SCALE / FAST
Justification for Brain Scan in
Dementia Diagnosis
• Differential Diagnosis: Tumor, Stroke, Subdural
Hematoma, Normal Pressure Hydrocephalus,
Encephalomalacia
• Confirmation of atrophy pattern
• Estimation of severity of brain atrophy
• MRI shows T2 white matter changes
– Periventricular, basal ganglia, focal vs confluent
– These may indicate vascular pathology
• SPECT, PET - estimation of regions of
physiologic dysfunction, areas of infarction
• Helps family to visualize problem
Etiology
• Age (initial genesis vs response to stress)
– Bigger factor than for mortality (a = 5 yrs vs 7.5 or 8.2 yrs)
– Degree of natural vulnerability of neuroplastic (memory) systems
– Stressor response (pathology - vulnerability during activity of
repair mechanisms): trauma (head injury), vascular (stroke),
surgery, loss, grief, etc.
• Genetics (neuroplasticity related - amyloid and cell membrane)
– Familial, early onset: APP (21), PS (14, 1) (less than 5%)
– Late onset: APOE e4 (ch19) (?50% - 90% of AD)
• relation to brain cholesterol metabolism? – cell membranes
• APOE e2 may be most protective
– many other candidate genes
• Relation to vascular factors, cholesterol, BP
• Education (more reserve)
– (? design – larger brain vs better development vs protection – wiser choices)
• Environment - diet, exercise, smoking
Genes and Alzheimer’s disease
(60% - 80 % of causation)
(all known genes relate to bamyloid)
• Familial AD (onset < 60 y/o) (<5%)
– Presenilin I, II (ch 14, 1)
– APP (ch 21)
• Non-familial (late onset)
– APOE
•
•
•
•
Clinical studies suggest 40 – 50% due to e4
If e2 is considered, may be 95% of causation
Population studies suggest 10 – 20% cause
Evolution over last 300,000 to 200,000 years
– At least 20 other genes
APO-E genotype and AD risk
46 Million in US > 60 y/o //// 4 Million have AD
(data from Saunders et al., 1993; Farrer et al., 1997)
G enT
% pop
% AD
#pop
#AD
risk If a ll U S
E 2 /2
1%
0 .1 %
0 .5 M .0 0 4 M 0 .8 %
E 2 /3
12 %
4%
E 3 /3
.4 M
5 .5 M
.1 8 M 3 .2 %
1 .5 M
60%
3 5 % 2 7 .6 M
1 .4 M 5 .1 %
2 .3 M
E 3 /4
21%
42%
9 .6 M
1 .7 M
18%
8 .2 M
E 4 /4
2%
16%
.9 M
.6 M
67%
3 0 .7 M
JW Ashford, MD PhD, 2003
Are we ready to do genetic testing
to predict AD?
• The family members want it
– They consider recommendations against genetic testing
to be “paternalistic”
• Family members can make more powerful financial
decisions based on this knowledge than the relevance of
insurance companies implementing changes in actuarial
calculations
• Those at risk can seek more frequent testing
– This is the best opportunity for early recognition
• Those at risk will be better advocates for research
• Specific preventive treatments can be developed for each
genetic factor
U.S. Census 2000 by age
www.census.gov
Males,
138,053,563
Females,
143,368,343
2,500,000
2,250,000
# people
2,000,000
1,750,000
1,500,000
1,250,000
Total = 281,421,906
>60 = 45,809,291
>65 = 35,003,844
>85 = 4,251,678
>100=
62,545
1,000,000
750,000
500,000
250,000
0
0
10
20
30
40
50
Age
JW Ashford, MD PhD, 2003
60
70
80
90 100
U.S. mortality by age - 1999
www.cdc.gov
Males, 1,175,460
45,000
Number of people
40,000
Females, 1,215,939
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
0
10
20
30
40
50
Age
JW Ashford, MD PhD, 2003
60
70
80
90
100
U.S. mortality rate by age
1999 CDC / 2000 census
Males, 2t = 8.2yrs
Females, 2t = 7.5 yrs
Alzheimer incidence
Yearly Hazard
1.0000
0.1000
0.0100
0.0010
0.0001
0
JW Ashford, MD PhD, 2003
10
20
30
40 Age 50
60
70
80
90
100
Proportion of population
Probability Not Demented
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
50
60
70
80
Age
JW Ashford, MD PhD, 2003
90
100
# / yr
U.S.
Alzheimer Incidence
(4 million / 8yr)
male=170,603
16000
14000
12000
10000
8000
6000
4000
2000
0
female=329,115
50
60
70
80
Age
JW Ashford, MD PhD, 2003
90
100
JW Ashford, MD PhD, 2003
(Incidence for a to a + 1 year)
Proportion of population
Probability Not Demented
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
50
60
70
80
Age
JW Ashford, MD PhD, 2003
90
100
Proportion / Year
U.S. AD Incidence by APOE
(proportion of cases)
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
4/4
3/4
3/3
50
JW Ashford, MD PhD, 2000
60
70
Age
80
90
100
prob/ yr * live population
Probability of Dementia Onset
APOE 4/4-M
APOE 4/4-F
APOE 3/4-M
APOE 3/4-F
APOE 3/3-M
APOE 3/3-F
0.04
0.03
0.02
0.01
0
50
60
70
80
90
Age (single mortality correction)
JW Ashford, MD PhD, 2003
100
Why Diagnose AD Early?
• Safety (driving, compliance, cooking, etc.)
• Family stress and misunderstanding (blame, denial)
• Early education of caregivers of how to handle
patient (choices, getting started)
• Advance planning while patient is competent (will,
proxy, power of attorney, advance directives)
• Patient’s and Family’s right to know
• Specific treatments now available
– May slow underlying disease process
– May delay nursing home placement longer if started
earlier
Need for Better Screening
and Early Assessment Tools
• Genetic vulnerability testing (trait risk)
• Vulnerability factors (education, occupation, head
injury)
• Early recognition (10 warning signs)
• Screening tools (6th vital sign in elderly)
• Positive diagnostic tests
– CSF – tau levels elevated, amyloid levels low
– Brain scan – PET – DDNP, Congo-red derivatives
• Mild Dementia severity assessments
• Detecting early change over time
– predicting progression, measuring rate
Need for a Brief Screening Test for
Alzheimer’s Disease
• Recent evidence of benefits of anticholinesterase agents in the treatment
of mild Alzheimer’s disease
– Improvement of cognition
– Slowing of progression
Alzheimer Warning Signs
Top Ten
Alzheimer Association
1. Recent memory loss affecting job
2. Difficulty performing familiar tasks
3. Problems with language
4. Disorientation to time or place
5. Poor or decreased judgment
6. Problems with abstract thinking
7. Misplacing things
8. Changes in mood or behavior
9. Changes in personality
10. Loss of initiative
Available Screening Tests
• MMSE
10 -- 15 min
• Too long
• 7-Minute Screen
7 – 10 min
• Too complex
• Clock Drawing Test
2 – 4 min
• Not sensitive
• Mini-cog
3 – 5 min
• Complex scoring, unclear adequacy
• Memory Impairment Screen
4 min
• Need for slightly shorter, easier test
• (a suitably accurate test that takes less than
2 minutes is not available)
Anim als nam ed in 1 m in (m m s>19) - CERAD data set
12
percent of total
10
8
6
4
2
0
0
10
20
30
num ber of anim als nam ed
Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380
40
Animals name d in 30 se conds (mms>19)
16
14
percent of total
12
10
8
6
4
2
0
0
5
10
15
number of animals named
Normal Controls, n=386
JW Ashford, MD PhD, 2001
Mild Alzheimer Patients, n=380
20
25
Animal naming ROCs
(AUC 15: 0.74; 30: 0.83; 45: 0.86; 60: 0.87)
100
90
80
13
70
Sensitivity (% )
15
14
.
17
8
11
10
7
12
60
16
9
animals in 15 secs
11
8
50 10
40
animals in 30 secs
6
animals in 45 secs
7
animals in 60 secs
5
30
20
10
0
0
10
20
30
40
50
60
False Positive Rate (%)
70
80
90
100
Brief Alzheimer Screen (BAS)
• Repeat these three words: “apple, table, penny”.
• So you will remember these words, repeat them again.
• What is today’s date?
• D = 1 if within 2 days.
• Spell the word “WORLD” backwards
• S = 1 point for each word in correct order
• “Name as many animals as you can in 30 seconds, GO!”
• A = number of animals
• “What were the 3 words I asked you to repeat?” (no prompts)
• R = 1 point for each word recalled
BAS = 3 x R + 2/3 x A + 5 x D + 2 x S
Percent of Validation Sample
90
80
Mild AD
70
Control
60
50
40
30
20
10
0
3-22
JW Ashford, MD PhD, 2001
23
24
25
BAS Score
26
27-39
Mendiondo et al., 2004
BRIEF ALZHEIMER SCREEN
(Normal vs Mild AD, MMS>19)
20
True Positive Rate (%) (Sensitivity)
100
27
90
26
25
80
14
13
12
11
10
70
9
60
8
animals 1 m
AUC = 0.868
animals 30 s
AUC = 0.828
MMSE
AUC = 0.965
20
Date+3 Rec
AUC = 0.875
10
BAS
AUC = 0.983
50
40
97
30
6
0
0
10
20
30
40
50
60
70
80
False Positive Rate (%) (1-Specificity)
JW Ashford, MD PhD, 2003
90 100
CONCLUSIONS on the BAS
• A single cut-off score provides reasonable sensitivity and
specificity for the diagnosis of AD within 2 – 3 minutes
• Two cut-off points divide the population into 3 tiers
– the first cut-off indicates a low likelihood of dementia
– the second indicates a high likelihood of dementia
– the remaining group falls into a ‘gray area’ in need of
closer scrutiny, follow-up, and more extensive testing
• A suitably short screen can be administered yearly to
individuals over 60 y/o as a 6th vital sign
• Next direction – use of IRT to locate level of impairment
BLT/Ashford Memory Test
(to detect AD onset)
• New test to screen patients for AD:
– World-Wide Web – based testing,
– CD-distribution
– KIOSK administration
•
•
•
•
•
•
Determine level of ability / impairment
Test takes about 1-minute
Test can be repeated often (e.g., quarterly)
Any change over time can be detected
Test is at: www.ibaglobal.com/BLT
For info, new tests, see: www.medafile.com,
www.brainlane.net