Transcript DIAGNOSIS OF AZLHEIMER’S DISEASE

Screening Elderly Clinic Patients
for Early Dementia:
Psychological Tests, Brain Scans,
Genetic Tests, and CSF Biomarkers
J. Wesson Ashford, M.D., Ph.D.
Stanford / VA Alzheimer’s Center
VAMC, Palo Alto, California
May 16, 2005
Stanford University Medical Center
Slides at: www.medafile.com (Dr. Ashford’s lectures)
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
Differential Diagnosis: Top Ten
(easy mnemonic device: AVDEMENTIA)
1.
2.
3.
4.
5.
6.
7.
Alzheimer Disease (pure ~40%, + mixed~70%, ? dLbd)
Vascular Disease, MID (5-20%)
Drugs, Depression, Delirium
Ethanol (5-15%)
Medical / Metabolic Systems
Endocrine (thyroid, diabetes), Ears, Eyes, Environ.
Neurologic (other primary degenerations, fronto-temporal, consider diffuse Lewy body dementia, Parkinson
component)
8. Tumor, Toxin, Trauma
9. Infection, Idiopathic, Immunologic
10. Amnesia, Autoimmune, Apnea, AAMI
Adapted from Yesavage, 1979
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
AD Can Be Readily
Diagnosed
• 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 (test vs. family concern)
– Confirmation through patient history and physical,
caregiver interview, brain imaging, and appropriate
laboratory studies
McKhann G et al. Neurology. 1984;34:939-944.
Kazee AM et al. Alzheimer Dis Assoc Disord. 1993;7:152-164.
Ashford JW et al, Psychiaric Annals, 1996;26:262-268.
AD is Under-diagnosed
• Early Alzheimer’s disease is subtle, the diagnosis continues to be missed
– it is easy for family members to avoid the problem and compensate for
the patient
– physicians tend 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
– Diagnoses are missed at all levels of severity: mild, moderate, severe
• No definitive laboratory test for diagnosing AD exists
– Efforts to develop biomarkers, early recognition by brain scan
Evans DA. Milbank Quarterly. 1990; 68:267-289
Reasons to Diagnose Alzheimer’s Disease Early
Social / financial
• Undiagnosed AD patients often face avoidable social and financial
problems
• 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)
• Reduce family stress and misunderstanding (blame, denial)
• Promote safety (driving, compliance, cooking, etc.)
• Patient’s and Family’s right to know, especially about genetic risks
• Opportunity to reduce caregiver burden
• Promote advocacy for research and treatment development
Reasons to Diagnose Alzheimer’s Disease Early
Medical
• Early diagnosis and appropriate intervention may lessen
disease burden and early treatment may improve overall
course substantially
– Neurophysiological pathways in patients with AD are still
viable and are a target for treatment
• Specific treatments now available
(anti-cholinesterases, memantine)
– Improve cognition
– Improve function (ADLs)
– Delay conversion to AD from Mild Cognitive Impairment
– Slow underlying disease process, the sooner the better
– Decreased development of behavior problems
– Delay nursing home placement, possibly over 20 months
– Delay nursing home placement longer if started earlier
Benefits of Treatment of AD With
Acetylcholinesterase Inhibitors
• AChEIs may improve, maintain, or slow the decline of cognitive,
behavioral, and functional performance in patients with mild-tomoderate AD
• Delay of treatment leads to loss of potential benefit
• AChEIs may delay nursing home placement over 20 months, and
potentially much more when started early.
• AChEIs have demonstrated consistent efficacy and safety in
maintaining cognitive function, as measured by ADAS-cog in patients
with mild-to-moderate AD for up to 1 year – relative to placebo!!
Donepezil1
Rivastigmine2
Galantamine3
38 weeks
38–42 weeks
52 weeks
1. Rogers SL et al. Eur Neuropsychopharmacol. 2000;10:195-203. 2. Farlow M et al. Eur Neurol. 2000;44:236-241.
3. Raskind MA et al. Neurology. 2000;54:2261-2268.
Recent Findings about
Donepezil
• Petersen et al., 2005: for Mild Cognitive Impairment
patients with an E4 allele, conversion to AD in 36
months:
• placebo = 76%
• donepezil = 23%
• Hashimoto et al., 2005: slowing of annual
hippocampal atrophy:
– APOE4 (1 or 2)
• control = 5.6%
• donepezil = 4.2%
– No APOE4
• control = 4.4%
• donepezil = 3.2%
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
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 realize
– families tend to compensate
• Effective treatment and management
techniques are available
– (AChEIs, memantine FDA approved)
– Several other approaches are beneficial
Small et al., JAMA, 1997
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
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!
ALZHEIMER’S DISEASE COURSE
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/ early AD -- DEMENTIA
Ashford et al., 1995
100%
90%
80%
Percentage
70%
60%
AD
MCI
Non-Affected
50%
40%
30%
20%
10%
Markov Chain model
Age
84
82
80
78
76
74
72
70
68
66
64
62
60
0%
Yesavavage et al., 2002
Dementia 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
Brain Scan
LABORATORY TESTS (routine)
• BLOOD TESTS
– electrolytes, liver, kidney function tests, glucose
– thyroid function tests (T3, T4, FTI, TSH)
– vitamin B12, folate (consider homocysteine)
– complete blood count, ESR
– VDRL, HIV (if indicated)
• EKG (if indicated)
• CHEST X-RAY (if indicated)
• URINALYSIS
• ANATOMICAL BRAIN SCAN – CT (cheaper ?), MRI
– Scripps = $880 (min); Modesto = $6,600
(max)
SPECIAL LABORATORY TESTS
• FUNCTIONAL BRAIN IMAGING
(SPECT, PET – Medicare will pay special
cases)
• EEG, Evoked Potentials (P300)
• REACTION TIMES (slowed in the elderly,
especially when complex response is required
• CSF ANALYSIS - ROUTINE STUDIES
– ELEVATED TAU (future possible)
– DECREASED AMYLOID (future possible)
• HEAVY METAL SCREEN (24 hr urine)
• GENOTYPING
– APO-LIPOPROTEIN-E (for supporting dx)
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
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
• ---(NOT A SCREENING TEST!!!)
Need to Develop Better Screening
and Early Assessment Tools
•
•
•
•
•
Genetic vulnerability testing (trait risk)
Vulnerability factors (education, occupation, head injury)
Early recognition (10 warning signs), ADLs
Screening tools (6th vital sign in elderly)
Positive diagnostic tests
– CSF – tau levels elevated, amyloid levels low
– Brain scan – PET –
• NFTs: DDNP
• Amyloid: Thioflavin-S, 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
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
Time to Administer Available Short
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)
MMSE
items
AD all (easiest to hardest at p=.5)
Mini-Mental State Exam items
PROBABILITY CORRECT
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
-4 -3 -2 -1
0
1
2
3
4
5
6
7
8
DISABILITY ("time-index" year units)
9 10
PENCIL
APPL-REP
WATC
LOCATION
PENY-REP
TABL-REP
CLOS-IS
RIT-HAND
CITY
FOLD-HLF
SENTENCE
COUNTY
NO-IFS
FLOOR
SEASON
YEAR
PUT-LAP
MONTH
ADDRESS
DRAW-PNT
DAY
SPEL_ALL
DATE
APPL-MEM
PENY-MEM
TABL-MEM
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
Dementia Screening Test
Requirements
•
Need test to screen patients for Alzheimer’s disease
•
Test needs to be on multiple platforms:
•
Test needs to be very brief (about 1-minute)
•
Multiple test forms needed so it can be repeated often (quarterly)
•
Screening should be done yearly after age 50, and repeated every 3
months for individuals over 65 years of age or with concerns
•
Any change over time needs to be detected
•
The test cost should be nominal
–
–
–
–
–
Doctor’s offices
Best if computerized for rapid, objective assessment
World-Wide Web – based testing,
CD-distribution
KIOSK administration – drug stores, shopping malls
MEMTRAX - 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
• Free test is at: www.medafile.com
Issues in Screening
• ROC analysis provides independent values for how the screening test
values affect the normal and patient populations, then plots their
relationship with respect to each other (specificity vs sensitivity
respectively) – data must be derived from the represented population!!!
• The value of the test must be calculated with respect to the risk of the
disease, in the specific population to which it is being applied
– Risk is affected by age, genotype, many other factors
– Accounting for a priori probability is Bayesian analysis
• The cost of the applying the test and the costs of false positive and false
negative results as well as the benefits of correct positive and negative
results must be assessed
• Alzheimer’s disease is not a dichotomous diagnosis in early stages, but
a continuum, which would be better assessed with a probabilistic
statement, that would be better calculated from Item Response Theory
• Item Response Theory and Factor Analysis allow combination of many
test component items
Kraemer, 1992; Ashford & Schmitt, 2001
Control: What happens without screening?
Total Population
Risk=P
P’
Do not have AD
P
Have AD
No effective intervention
Helena Kraemer, 2003
Testing: What happens with testing?
Total Population
P’
P
AD
No AD
Sp’
Sp
Unnecessary intervention
$ Testing
$ Intervention
$Testing
Se
Se’
OK
No effective intervention
$ Testing
Effective intervention
$ Testing
$ Intervention
Iatragenic Damage?
Clinical Wash
Clinical Wash
Clinical Gain
Major(?) Loss
Minor (?) Loss
Some gain
Minor(?) Loss
Major(?) Gain
Helena Kraemer, 2003
Cost – Benefit Calculation
•
•
•
•
•
I = incidence
P = Total Population
X = cost of test, time to take (subject, ? Tester)
Se = sensitivity of test = 1- False negative (Fn)
Sp = specificity of test = 1- False positive (Fp)
Cost:
–
–
–
–
–
Total cost of test = P*X
Fp = $1000 * P * (1-I) * (1-Sp) (+false hope)
Tn = 0 (real peace of mind)
Fn = false peace of mind
Tp = (-$49,000 * P * I * Se) => $50,000 = NH cost/1year
• Avg Person Benefit= 49000*I*Se -X -1000*(1-I)*(1-Sp)
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
Cost-Benefit Analysis per Individual
COST: brain scan - $1000, CSF - $100, Computer memory test - $10
Benefit: $50,000 approximate savings by nursing home placement delay
cost
incidence
(age)
Sp
1
0.99
0.99
0.99
0.9
0.9
Se
1
0.99
0.9
0.8
0.9
0.8
10
0.001
62
39
28.52
24.1
19.2
-65.8
-70.7
10
0.005
73
235
222.6
201
176
111
86.5
10
0.01
76
480
465.2
421
372
332
283
10
0.05
89
2440
2406
2186
1941
2100
1855
100
0.001
62
-51
-61.5
-65.9
-71
-156
-161
100
0.005
73
145
132.6
111
86.1
21
-3.5
100
0.01
76
390
375.2
331
282
242
193
100
0.05
89
2350
2316
2096
1851
2010
1765
1000
0.001
62
-951
-961
-966
-971
-1056
-1061
1000
0.005
73
-755
-767
-789
-814
-879
-904
1000
0.01
76
-510
-525
-569
-618
-658
-707
1000
0.05
89
1450
1416
1196
951
1110
865
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)
GenT %pop %AD
#pop
E2/2
0.5M .004M 0.8%
.4 M
5.5M .18M 3.2%
1.5 M
1% 0.1%
risk If all US
E2/3
12 %
E3/3
60%
35% 27.6M 1.4M 5.1%
2.3 M
E3/4
21%
42%
8.2 M
E4/4
2%
16%
JW Ashford, MD PhD, 2003
4%
#AD
9.6M 1.7M 18%
.9M
.6M 67%
30.7M
Number of people/yr
Dementia rate, for Td = 5 yrs
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
presenilin
1000
100
10
1
0.1
0.01
0.001
0.0001
50
J. W. Ashford, 2004
60
70
80
Age
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
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
presenilin
50
60
70
80
Age
J. W. Ashford, 2004
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
60
70
Age
80
Raber, Huang, Ashford, 2004, Neurobiol Aging. 25:641-650
90
100
Genes and Alzheimer’s disease
(60% - 80 % of causation)
(all known familial 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 (apo-lipo-protein-E)
•
•
•
•
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
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
RELATIVE RISK FACTORS
FOR ALZHEIMER’S DISEASE
•
•
•
•
•
•
•
•
•
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
Summary Requirements for
Screening Test Evaluation
• Sensitivity, specificity for the population to which test is to be
applied – values change with level of disease being screened
• Portion of population at risk
– Risks according to age, gender, genotype, family hx, education, etc.
• Cost of test -$1, $10, $100, $1000
– Need brief screen to replace MMSE (ASAP) - $10 Medicare allowance
• Costs of false positive, false negative tests
• Benefits of true positive, true negative
– Longevity is increasing over time, needs to be factored in.
• Cascaded tests – preliminary screen, confirmatory exam
• Longitudinal tests may provide much more reliable information
• Different tests for clinic (cascaded), research (outcomes)
– Clinic: brief screen, brain scan; Research: CSF - is disease stopped?
• Benefit to society relative to other societal needs.
Future Directions for
Alzheimer’s Disease
• Need more precise assessment of cognition
from normal to severe dementia
• Need to use Item Response Theory and
Computerized Adaptive Testing
• Screening tests need to be widely used, that
implement computer administration
• Test analyses need to be risk/benefit-related
• Better tests will lead to better treatments
• Better treatments will lead to prevention
THE TOP TEN TREATMENTS
FOR PREVENTING ALZHEIMER’S DISEASE
www.medafile.com
1. Take blood pressure regularly, assure systolic pressure is always < 130.
2. Watch your cholesterol; if cholesterol is above 200, talk to your clinician about
treatment. Consider “statin” medications. Increase dietary intake of omega-3-fatty
acids.
3. Exercise your body, mind, and spirit regularly. Physical exercise best 10-30 mins
after each meal for 10-30 minutes, 3 times per day. Maximize your education. Do
mental puzzles (like crossword puzzles). Stay active.
4. Physically protect your brain. Wear your car seat-belt. Wear a helmet when riding a
bicycle or participating in activity where you might hit your head.
5. Decrease your risk of type II diabetes. Monitor your fasting blood sugar yearly. Keep
your BMI (Basal Metabolic Index) in the optimal range (19-25) by controlling food
intake and exercise. If you have diabetes, make sure that blood sugar is optimally
controlled.
1.
6. Consult your clinician about pains (treat arthritis with ibuprofen, sulindac, or indocin).
7. Take your vitamins daily (folate - 400mcg, B12 - 25mcg, C - 250 mg, and E -
200iu's). Check yearly that your homocysteine levels are low and no signs of B12
deficiency.
8. Discuss sex-hormone replacement therapy with your clinician.
9. For sleep difficulty, try 3 - 6 milligrams of melatonin at bedtime.
Future Developments
to Prevent AD
• Anti-cholinesterase treatments to prevent AD
– May need to be started early at very low doses
• NMDA receptor modulators (memantine)
– Early treatment may prevent neuroplastic neuron damage
• Immunologic therapy to eliminate beta-amyloid
– Preliminary trials appear to remove deposits
• Prevention of beta-amyloid-42
– Certain NSAIDs may prevent formation
• Medication to prevent tau hyperphosphorylation
– Lithium and valproic acid may be helpful
• Specific treatments for APOE modulation
– This may be related to statin effects