screening tools for mci (mild cognitive impairment) j. wesson ashford, m.d., ph.d. clinical...
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SCREENING TOOLS FOR MCI(mild cognitive impairment)
J. Wesson Ashford, M.D., Ph.D.
Clinical Professor (affiliated) Department of Psychiatry & Behavioral Sciences
Stanford University
Senior Research ScientistStanford / VA Aging Clinical Research
Stanford University and VA Palo Alto Health Care System
International Conference on Alzheimer’s disease
July 12, 2010
Slides at: www.medafile.com (Dr. Ashford’s lectures)
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Disclosures for Dr. Ashford• Alzheimer’s Association
– Member, Northern California Branch Scientific Advisory Board
• Alzheimer’s Foundation of America– Medical Advisory Board member– Chair, Memory Screening Advisory Board
• Journal of Alzheimer’s Disease– Clinical Editor
• Developing a memory test:– MemTrax – for computers, internet, audience presentations– Partner with HAPPYneuron
• Consultant for Orasi, Inc.– Developing MEG test for AD
• Share owner in Satoris, Inc.– Developing proteomics test for AD
• Share owner, consultant for Neurotez, Inc– Developing Leptin as a treatment for AD
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Screening Tools for MCI(outline of presentation)
• Definition of Mild Cognitive Impairment (MCI)• Dementia signs without social impairment
• Is it “cost-worthy” to screen for MCI?• Estimate based on benefits, costs, incidence, sensitivity, specificity
• Understanding the progression of Alzheimer’s disease• Gompertz Hazard Curve in early AD pathological changes, genetics
• Central concept of change over time – Gompertz Survival Curve
• Existing cognitive tools for MCI screening• MMSE, BAS, MIS, MCIS, episodic memory tests, MemTrax
• Biomarkers for MCI screening• Genetics, CSF, blood, brain scanning, EEG/ERP/MEG
• Future directions for MCI screening• Longitudinal assessment
• MemTrax – quick, fun games for precise memory measurement
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A. Multiple Cognitive Deficits 1. Memory Impairment
Especially new learning, a prominent early symptom
2. Other Cognitive Impairment: Aphasia, apraxia, agnosia, or executive
dysfunction
B. Deficits sufficiently severe to impair Social/Occupational functioning
C. Course Shows Gradual Onset And Decline Must represent a decline from a previous level of functioning
D. Deficits Are Not Due to:1. Other CNS Conditions2. Substance Induced Conditions
E. Do Not Occur Exclusively during DeliriumF. Not Due to Another Psychiatric Disorder
Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994)
Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994)
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Petersen: J Int Med, 2004Petersen: J Int Med, 2004
Mild Cognitive ImpairmentMild Cognitive Impairment
CP1265413-4
Non-amnestic MCINon-amnestic MCISingle domainSingle domain
Non-amnestic MCINon-amnestic MCISingle domainSingle domain
YesYes
NoNo
Non-amnestic MCINon-amnestic MCINon-amnestic MCINon-amnestic MCI
Single non-memorySingle non-memorycognitive domaincognitive domain
impaired?impaired?
Single non-memorySingle non-memorycognitive domaincognitive domain
impaired?impaired?NoNo
Non-amnestic MCINon-amnestic MCIMultiple domainMultiple domain
Non-amnestic MCINon-amnestic MCIMultiple domainMultiple domain
Amnestic MCIAmnestic MCISingle domainSingle domainAmnestic MCIAmnestic MCISingle domainSingle domain
YesYes
Cognitive complaintCognitive complaintCognitive complaintCognitive complaint
Not normal for ageNot normal for ageNot dementedNot demented
Cognitive declineCognitive declineEssentially normal functional activitiesEssentially normal functional activities
YesYes
Amnestic MCIAmnestic MCIAmnestic MCIAmnestic MCI
MCIMCIMCIMCI
Memory impaired?Memory impaired?Memory impaired?Memory impaired?
MemoryMemoryimpairment only?impairment only?
MemoryMemoryimpairment only?impairment only? NoNo
Amnestic MCIAmnestic MCIMultiple domainMultiple domainAmnestic MCIAmnestic MCI
Multiple domainMultiple domain
1/3 AD,1/3 not,1/3 both.
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What’s the Difference?Normal Aging
Occasional loss of memory for words and names.
Slowed processing speed.
Difficulty sustaining attention when faced with competing environmental stimuli.
No functional impairment.
MCI
Memory impairment beyond that expected for age, increasing over last six to 12 months.
Other cognitive functions generally unimpaired.
Daily function not significantly impaired.
Not demented.
Source: Dr. Pierre Tariot, University of Rochester Medical Center. “What is on the Horizon for Alzheimer’s Disease Research?“
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Cognitive ContinuumCognitive Continuum
Mild CognitiveMild CognitiveImpairmentImpairment
NormalNormal
DementiaDementia
CP926864- 35
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Mild Cognitive Impairment
NormalNormal MCIMCI ADAD
00 0.50.5 11
CDR CDR (clinical dementia rating scale)(clinical dementia rating scale)3004153-1
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Estimate MMSE as a function of time
0
5
10
15
20
25
30
-10 -8 -6 -4 -2 0 2 4 6 8 10
Estimated years into illness
MM
SE
scor
e
AAMI / MCI/ early AD -- DEMENTIA
ALZHEIMER’S DISEASE COURSE
Ashford et al., 1995
The best model to fit the progression,both mathematically and biologically,is the Gompertz survival curve (99.7% fit to mean changes over time):
S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
(calculated from the CERAD data set)
(Time-Index Scale)
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Time (years)
Pro
gre
ssio
nPresymptomatic MCI Clinical Dementia
CDR 0.5 CDR 1 CDR 2 CDR 3
Neuropsychological
/Functional Status
AD Pathological Burden
Threshold for
Clinical Detection
Adapted from Daffner & Scinto, 2000
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Is it worth screening for Alzheimer’s disease or MCI?
“If there was treatment for AD, I'd recommend screening, but there is no disease-modifying therapy."
Anonymous Alzheimer expert -2008
“All older adults benefit from memory screening because it detects cognitive problems before memory loss is noticeable.”
Anonymous Alzheimer expert -2008
Healthy Aging, 2008; repost, 2010“Memory Screening: Is it Worth It?”
http://healthy-aging.advanceweb.com
http://healthy-aging.advanceweb.com/Patient-Resource-Center/Disease-Management-and-Prevention/Memory-Screening-Is-it-Worth-It.aspx
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Alzheimer's Disease Is Under-diagnosed
• Early AD 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%–50% of cases remain undiagnosed
– Diagnoses are missed at all levels of severity: mild, moderate, severe
• Undiagnosed AD patients often face avoidable social, financial, and medical problems
• Early diagnosis and appropriate intervention may lessen disease burden
– Early treatment may substantially improve overall course
• No definitive laboratory test for diagnosing AD exists
– Efforts to develop biomarkers, early recognition by brain scan
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Why MCI Screening Is Important to Consider
• Cognitive impairment is disruptive to human well-being and psychosocial function
• Cognitive Impairment is potentially a prodromal condition to dementia and Alzheimer’s disease (AD)
• Dementia is a very costly condition to individuals and society
• With the aging of the population, there will be a progressive increase in the proportion of elderly individuals in the world
• Screening will lead to better care
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No Testing:
What happens without screening?
Total Population Risk=P
P
Have ADNo effective intervention
Do not have AD
P’
Helena Kraemer, 2003
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Testing: What happens with testing?
Total Population
No ADAD
Unnecessary intervention OK No effective intervention Effective intervention
$ Testing $Testing $ Testing $ Testing$ Intervention $ Intervention
Iatrogenic Damage? Clinical Wash Clinical Wash Clinical Gain
Major(?) Loss Minor (?) Loss Minor(?) Loss Major(?) Gain Some gain
False Positive True Negative False Negative True Positive
PP’
SeSe’
SpSp’
Helena Kraemer, 2003
Specificity = Sp Sensitivity = Se
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Factors for Deciding whethera Screening Test is Cost-Effective
1) Benefit of a true positive screen
2) Benefit of a true negative screen
3) Cost of a false positive screen
4) Cost of a false negative screen
5) Incidence of the disease (in population)
6) Test sensitivity (in population)
7) Test specificity (in population)
8) Test cost
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$W = Cost–Worthiness Calculation $W > ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T
• BENEFIT– $B = benefit of a true positive diagnosis
• Earlier diagnosis may mean proportionally greater savings• Estimate: (100 years – age ) x $1000• Save up to $50,000 (e.g., nursing home cost for 1 year)
– (after treatment cost deduction at age 50, none at age 100)– (cost-savings may vary according to your locale)
– True negative = real peace of mind (no money)
• COST– $C = cost of a false positive diagnosis
• $500 for further evaluation– (time, stress of suspecting dementia)
– False negative = false peace of mind (no price)
• I = incidence (new occurrences each year, by age)• Se = sensitivity of test = True positive / I• Sp = specificity of test = True negative / (1-I) = (1-False positive/(1-I)• $T = cost of test, time to take (Subject, Tester)
Kraemer, Evaluating Medical Tests, Sage, 1992
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Benefits of Early Alzheimer Diagnosis:Social
• Undiagnosed AD patients face avoidable problems – Social, financial
• Early education of caregivers– 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– Caregiver burden, blame, denial
• Promote safety– Driving, compliance, cooking, etc.
• Patient’s and family’s right to know– Especially about genetic risks
• Promote advocacy– For research and treatment development
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Benefits of Early Alzheimer Diagnosis
Medical
• Early diagnosis and treatment and appropriate intervention may:– improve overall course substantially
– lessen disease burden on caregivers / society
• Specific treatments now available for dementia (anti-cholinesterases, memantine)
– Improve cognition
– Improve function (ADLs)
– Delay conversion from Mild Cognitive Impairment to AD
– 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
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Benefits of Early Treatment ofAlzheimer’s Disease
• Neurophysiological pathways in patients with AD are still viable and are a target for treatment
• Opportunity to reduce from a higher level: – Functional decline– Cognitive decline– Caregiver burden
Need to estimate net benefit monetarily
(key factor in determining case for screening)Estimate benefit = (100 years – age ) x $1000
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Estimated Age-related Benefitof Early Alzheimer Treatment
0
10000
20000
30000
40000
50000
50 60 70 80 90 100
AGE
Dol
lar
savi
ngs
from
de
laye
d nu
rsin
g ho
me
plac
emen
t
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Value of Diagnosis versus Time-Index
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
-10 -8 -6 -4 -2 0 2 4 6 8 10
Estimated years into illness(TimeIndex Scale)
Re
lati
ve
va
lue
of
de
tec
tio
n
Value across continuum
Value at transition
Value early
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Cost of False-Positive Screen
• Referral of normal individual for further testing– (more specific testing)
• Value of individual’s time
• Cost of additional testing
• Estimate cost = $500 per false-positive screen
• This does not and should not include the cost of untoward results of misdiagnosis, medication side-effects, or malpractice – quality management should address these
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Other Benefits and Costs of Screening
• Benefit of true-positive screen = intangible– Peace of mind – Plan further into future
• Cost of false-negative screen = wash– Delay in diagnosis and treatment– No different from current condition
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INCIDENCE OF MCI(Hazard per year)
Based on estimate of 4 million AD patients with dementia in US in 2000, with an incidence that doubles every 5 years, illness duration of 8 years.
Assume average of 5 years from onset of MCI to onset of dementia
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U.S. mortality, dementia, MCI rate by age (mortality = 2000 CDC / 2000 census)
0.0001
0.0010
0.0100
0.1000
1.0000
0 10 20 30 40 50 60 70 80 90 100
Age (years)
Haz
ard
/ y
ear
Males, 2t = 8.2yrs
Females, 2t = 7.5 yrs
dementia incidence, 2t = 5 yrs
MCI incidence, 2t = 5yrs
JW Ashford, MD PhD, 2003; See: Raber et al., 2004 (Incidence for a to a + 1 year)
The Gompertz survival curve explains 99.7% of male and female mortalityVariance between 30 and 95 y/o:
U(t) = Ro * exp (alpha * t)
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Dementia rate, assume Td = 5 yrs
0.0001
0.001
0.01
0.1
1
10
100
1000
50 60 70 80 90 100
Age (years)
Haz
ard
/ y
ear
mean rate
APOE 4/4 (x7.5)
APOE 3/4 (x2)
APOE 3/3 (x0.6)
Early onset (x200)
Using the Gompertz equationto model rate of dementiaincrease with age:
U(t) = Ro * exp (alpha * t)
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MCI rate, assume Td = 5 yrs
0.0001
0.001
0.01
0.1
1
10
100
1000
50 60 70 80 90 100
Age (years)
Ha
zard
/ y
ea
r
mean rateAPOE 4/4APOE 3/4APOE 3/3Early Onset
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Probability of Dementia Onset
0
0.01
0.02
0.03
0.04
0.05
0.06
50 60 70 80 90 100
Age
pro
bab
ility
/ yr
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
Using Gompertz equationsto model probability of dementia with age:
D(t) = U(t) * S(t)
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Probability of MCI Onset
0
0.01
0.02
0.03
0.04
0.05
0.06
50 60 70 80 90 100
Age
pro
bab
ility
/ yr
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
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Probability of Dementia Onset
0
0.01
0.02
0.03
0.04
50 60 70 80 90 100
Age (single mortality correction)
pro
b/
yr
* l
ive p
op
ula
tio
n APOE 4/4-MAPOE 4/4-FAPOE 3/4-MAPOE 3/4-FAPOE 3/3-MAPOE 3/3-F
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Probability of MCI Onset
0
0.01
0.02
0.03
0.04
50 60 70 80 90 100
Age (single mortality correction)
pro
b/
yr
* l
ive p
op
ula
tio
n
APOE 4/4-MAPOE 4/4-FAPOE 3/4-MAPOE 3/4-FAPOE 3/3-MAPOE 3/3-F
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Miech et al., 2002
Cache County, probability of incident dementiaCircles – femalesSquares - malesOpen – ApoE-e44Gray – ApoE-e4/xBlack – ApoE-ex/x
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Probability Not Demented
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
50 60 70 80 90 100
Age
Pro
po
rtio
n o
f p
op
ula
tio
n
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
Using a Gompertz survivalcurve to model probability of not having dementia with age:S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
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Probability Not MCI
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
50 60 70 80 90 100
Age
Pro
po
rtio
n o
f p
op
ula
tio
n
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
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Cost-Worthy Test EvaluationBenefit = $50,000 - 0; False Pos = $500
-100-50
050
100150200250300350400450500550600
50 55 60 65 70 75 80 85 90 95
AGE
Cos
t Jus
tifie
d fo
r D
emen
tia S
cree
n .8, .8
.9, .9
.95, .95
1,1
Se, Sp
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Cost-Worthy Test EvaluationSensitivity = 0.9, Specificity = 0.9
-$200$0
$200$400$600$800
$1,000
50 55 60 65 70 75 80 85 90 95
AGE (years)
Co
st
Ju
sti
fie
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or
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en
Benefit: $5,000 - 0Benefit: $10,000 - 0Benefit: $25,000 - 0Benefit: $100,000 - 0Benefit: cure = $240,000
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Cost-Worthy Dementia ScreeningSe=0.9; Sp=0.9
Benefit = $25,000 - 0; False Pos = $500
-1000
100200300400500600
50 55 60 65 70 75 80 85 90 95
AGE
Co
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Ju
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or
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meanApoE 4/4ApoE 3/4ApoE 3/3
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CSF-Aβ42 (protein decline)
Amyloid imaging(ligand increase)
FDG-PET
MRI hipp
CSF-tau
Cognition
Function
ADNIADCS
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Critical Factors for Developing Cost-Effective Screening
1) Develop benefit of a true positive screen- Need effective disease slowing treatments
2) Define value of genetic testing- Need to recognize central role of APOE genotype
3) Determine sensitivity and specificity of tests- Parameters must apply to population
4) Need to determine cost-worthiness- This must be determined for each test
5) Specific tests must be optimally sequenced- Frequent cognitive screens triggering biomarker tests
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Need to Develop Better Screening and Early Assessment Tools
• Trait factors – determine at 50 y/o to plan screening– Genetic vulnerability testing (or family history)– Vulnerability factors (education, occupation, head injury, blood pressure)
• State factors (begin annually at appropriate age)– Early recognition (10 early warning signs), ADLs– Screening tools (6th vital sign in elderly)
• Brief clinical screens vs. computerized tests• Tests need to assess likely level of function
– Detecting early change over time• Measuring rate, predicting progression
• Positive diagnostic tests– CSF – amyloid levels low (early), tau levels elevated (MCI)– Brain scan – PET – f-DG, f-DDNP, f-amyloid ligands (early)– Dementia severity tested on “time-index” continuum
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Alzheimer's Disease Top 10 Warning Signs (not early)
1. Recent memory changes affecting daily life2. Challenges in problem solving and planning3. Difficulty performing familiar tasks4. Disorientation to time and/or place5. Difficulty understanding visual images and/or spatial
relationships6. Problems with spoken and written language (eg,
paraphasia, agraphia)7. Misplacing things8. Poor judgment9. Withdrawal from activities (eg, social, work)10.Changes in personality and/or mood
Alzheimer's Association. 10 Signs of Alzheimer's. Available at: http://www.alz.org/alzheimers_disease_10_signs_of_alzheimers.asp. Accessed April 20, 2009.
Need a Top 10 Early Warning Signs
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Challenges With the Mini-Mental State Examination• Mini-Mental State Exam (MMSE)
– Folstein MF, et al. J Psychiatr Res. 1975;12:189-198.
• Several items do not provide adequate information
• Adds noise rather than discrimination between demented and nondemented individuals, particularly in early AD, MCI
• Poor range for measuring change– Large standard error of measurement
• Poor power for assessing medication benefit
• Inadequate screening tool
• Too long– Better, shorter tests are available
• Copyright is being enforced (test is not free)Ashford JW. Aging Health. 2008;4:399-432.
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Ashford et al., 1989
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Ashford et al., 1989
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AD all (easiest to hardest at p=.5)
0
0.1
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1
-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10
DISABILITY ("time-index" year units)
PR
OB
AB
ILIT
Y C
OR
RE
CT
PENCILAPPL-REPWATCLOCATIONPENY-REPTABL-REPCLOS-ISRIT-HANDCITYFOLD-HLFSENTENCECOUNTYNO-IFSFLOORSEASONYEARPUT-LAPMONTHADDRESSDRAW-PNTDAYSPEL_ALLDATEAPPL-MEMPENY-MEMTABL-MEM
Mini-Mental State Exam items
MMSEitems
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AD all (easiest to hardest at p=.5)
0.00
0.02
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0.10
0.12
0.14
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-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10
DISABILITY ("time-index" year units)
ITE
M IN
FO
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AT
ION
PENCAPWATCLOCAPETAREDORIGHCITYFOLDSENTCOUNPHRALEVESEASYEARALAPMONTADDRDRAWDAYASPEL_1DATEAPPLPENNTABL
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AD all
0.00
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-4 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10
DISABILITY SCALE
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T IN
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Implications of Item Characteristic Curves
for Patient Testing• REMOVE POOR ITEMS, ESPECIALLY THOSE THAT ADD NOISE
• SELECT ITEMS THAT BETTER PERTAIN TO FOCUS OF STUDY
• MAXIMIZE INFORMATION OBTAINED PER MINUTE OF TESTING
• DECREASE VARIABILITY IN TEST
• IMPROVE ACCURACY, PRECISION
• DEVELOP BETTER SCREENING TESTS
• ON-LINE COMPUTATION - WWW.MEDAFILE.COM
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Relatively Brief Cognitive and Memory Tests
Ashford JW. Aging Health. 2008;4:399-432.
Name of Test Author
Animal Naming in 1 minute
Rey Auditory Verbal Learning Test
Abbreviated Mental Test
Halstead, 1943
Rey, 1958
Hodkinson, 1972
Short Portable Mental Status Questionnaire (SPMSQ) Pfeiffer, 1975
Clifton Assessment Procedures for the Elderly-Cognitive Assessment Scale (CAPE-CAS)
Pattie, 1981
Blessed 6-Item Katzman, 1983
Visual memory, category fluency, temporal orientation Eslinger, 1985
Short Test of Mental Status Kokmen, 1987
Delayed Word Recall test (DWR) Knopman, 1989
Memory Impairment Screen Buschke, 1999
Three Words–Three Shapes Weintraub, 2000
General Practitioner Assessment of Cognition (GP-COG) Brodaty, 2002
6-Item Screener Callahan, 2002
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Relatively Brief Cognitive and Memory Tests (cont.)
Ashford JW. Aging Health. 2008;4:399-432.
Name of Test Author
Efficient Office-Based Assessment of Cognition Karlawish, 2003
Mini-Cog Borson, 2003
Rapid Dementia Screening Test (RDST) Kalbe, 2003
Brief Alzheimer Screen (BAS) Mendiondo, 2003
Short Cognitive Evaluation Battery (SCEB) Robert, 2003
AB Cognitive Screen)(ABCS) Molloy, 2005
Quick & Easy (Q&E) Dash, 2005
Mild Cognitive Impairment Screen (MCIS) Shankle, 2005
Blessed Memory Test/Category Fluency Kilada, 2005
10-Item Free Recall With Serial Position Effect Analysis Tractenberg, 2005
From Ashford, 2008 - Aging Health. (2008) 4(4):399-432.
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Screening tools tested for MCI• 3-word memory +clock draw (MiniCog, Borson) + FAQ (Functional
Activity Questions) – Steenland et al., 2008
• 3-word memory + temporal orientation + “spell WORLD backwards” + category naming – BAS (Brief Alzheimer Screen) – Mendiondo et al., 2003 – (only test based on item construct validity)
• 4-word memory (deep encoding – MIS, Buschke) + Isaacs Set Test (category fluency) – Chogard et al., 2008
• 5-word memory, 4 sets – Gialaouzidis, 2010
• 10-word memory with computation (MCIS) – Shankle et al.
• Internet tools:– Test Your Memory – 10 skill assessment – Brown et al., 2010
– Computer Self Test – 6 cognitive domains – Canon, Dougherty, 2010
– Memtrax – Computer Memory Game – Ashford et al., 2006• WWW.MEMTRAX.COM
• WWW.MEMTRAX.NET
Note: word memory is American tradition; name & address memory is English tradition
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Animals named in 30 seconds (mms>19)
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0 5 10 15 20 25
number of animals named
pe
rce
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tota
l
Normal Controls, n=386
Mild Alzheimer Patients, n=380JW Ashford, MD PhD, 2001
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Animals named in 1 min (mms>19) - CERAD data set
0
2
4
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0 10 20 30 40
number of animals named
pe
rce
nt
of
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Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380
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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
Mendiondo, Ashford, Kryscio, Schmitt., J Alz Dis 5:391, 2003
www.medafile.com/bas.htm
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0
10
20
30
40
50
60
70
80
90Pe
rcen
t of V
alid
atio
n Sa
mpl
e
3-22 23 24 25 26 27-39
BAS Score
Mild AD
Control
JW Ashford, MD PhD, 2001
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BRIEF ALZHEIMER SCREEN (Normal vs Mild AD, MMS>19)
9
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25
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False Positive Rate (%) (1-Specificity)
Tru
e P
osi
tiv
e R
ate
(%
) (
Se
nsi
tiv
ity)
animals 1 m AUC = 0.868
animals 30 s AUC = 0.828
MMSE AUC = 0.965
Date+3 Rec AUC = 0.875
BAS AUC = 0.983
JW Ashford, MD PhD, 2003
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Brief Alzheimer Screen (BAS) ROC for Univ. Kentucky ADRC Clinic Cases
Schmitt et al., 2006
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Spearman Correlations Between Neuropsychological and MRI Volumetric Data
Grey Mat. White Mat. Right Hipp. Left Hippo. Right Ento Left Ento
MIS
Controls 0.18 0.112 0.185 0.243 –0.085 –0.205
MCI –0.022 –0.213 0.430a 0.378 0.156 0.21
AD –0.100 0.033 0.192 0.23 –0.012 –0.061
FCSRT learning
Controls 0.25 0.249 0.048 0.252 –0.214 –0.152
MCI –0.044 –0.243 0.469a 0.383 0.374a 0.424a
AD –0.032 –0.224 –0.091 0.211 –0.074 –0.168
FCSRT delayed
Controls 0.161 0.136 0.028 0.233 –0.325 –0.295
MCI –0.010 –0.267 0.554b 0.424a 0.426a 0.407a
AD –0.205 –0.126 0.286 0.451a 0.104 0.081
Abbreviations: AD, Alzheimer Disease; ento, entorhinal; hipp., hippocampus; mat., matterFCSRT, Free and Cued Selective Reminding Test; MIS, Memory Impairment Screen;a Significant correlations are flagged with P < .05.b Significant correlations are flagged with P < .001.
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The MCIS For Clinical Practice & Research
Takes 10 Minutes
Accuracy1-4 is:
96-97% for Normal vs. Mild Cognitive Impairment.
99% for Normal vs. Mild Dementia.
Improves Signal:Noise Ratio by 100% over standard scoring methods5.
16 culturally unbiased, equivalent wordlists randomly selected without replacement in each patient to minimize test-retest effects5.
Available in English, Spanish and Japanese.
Adopted in all Medicare regions.
1Shankle et al. PNAS. 20052Trenkle et al. J. Alz. Dis. 2007.3Cho et al. Jap. J. Exp. Med. 2007.4Tabara et al. Hypertension Research. 2009.5Shankle et al. Alz. & Dementia, 2009.
www.mccare.com
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1Kendall & Stuart, The Advanced Theory of Statistics. 1961.2Shankle et al. PNAS. 2005
Developing The Measurement Technology: Memory PatternsRaw CWL Data Matrix
of Recalled and Forgotten Words(eg: 0010101101)
Correspondence Analysis1
(Multivariate Gaussian-Distributed Optimal Patient
& Word Score Vectors)
• Logistic Regression • ROC Curve Analysis• Age-Specific Prevalence
Classification algorithm &Memory Performance Index
(MPI) scaling
1This method explains the maximum possible amount of the raw data’s variance for the class of linear methods.
In contrast to FA & PCA, Correspondence analysis accounts for differences due to heterogeneous samples.
Optimal Scores Vary By: List Position Exposure Frequency Delay Being Recalled or Not
Item Responses Are Usually Scored As 0 or 1: All Items Have Equal Value
Wordlist Memory Task: 4 Trials
Word 1Word 2 Word 3 Word 4 Word 5 Word 6Word 7 Word 8 Word 9Word
10
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Wordlist Development1 million common nouns.Frequency, range, and diversity of usage statistics paralleled CERAD and ADAS-Cog Wordlists
600 nouns met these criteria
Constructed 10-word lists that met the following requirements Each word: could be used only once.could only have 1 or 2 syllableshas unique letter or sound.has no homonyms or antonyms in list.has low associability with all other list words.Each target list word can be matched on all above criteria with a word in
its accompanying distracter list.
16 Wordlists Met All Above Criteria(Subjects Must Be Tested 9 Times Before They See The Same Wordlist
Twice)
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MCIS Performance Summary MCIS Performance Summary Study Comparisons ROC Accuracy Sensitivity Specificity
Normal vs. MCI* (3 Validation Studies)1,2,3 96-97% 94-96% 88-100%
Normal vs. MCI Due To Alzheimer’s Disease1,2 99% 98% 92%
Normal vs. MCI Due To Non-Alzheimer’s Disease1,2 96% 91% 88%
Normal vs. Mild Dementia1 99% 96% 99%
Normal vs. Asymptomatic CI (Primary Care Sample)2 93% 86% 99%
Positive Predictive Value for MCI1,2 86-100%
Negative Predictive Value for Normal Aging1,2 96-99%
Within-Subject Inter-Rater Reliability: Office Staff vs Neuropsych. (Cronbach alpha)2 0.87 ± 0.07
Validity compared to Clinical Diagnosis (Kappa statistic)2 0.92 ± 0.09
False Negative Rate Based on Long-Term Care Claims After 3 years exposure: N=250,0004 0.008-0.095%
*The underlying etiologies of the MCI syndrome in the primary care, community and academic samples included Alzheimer’s disease, Lewy Body disease, Parkinson’s disease, Frontal Temporal Lobe dementia, normal pressure hydrocephalus, cerebrovascular disease, alcohol dependence, traumatic brain injury, metabolic disorders, and depressive pseudo-dementia.
1Shankle et al. PNAS: 2005. 2Trenkle et al. J. Alz Dis: 2007. 3Cho et al. Am J. Alz Dis Other Dem. 2008. 4Cohen et al. National Underwriter, 2009.
Psychometric Properties
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Japanese MCIS vs. Biomarkers
Cho et al., 2009
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Comparing Standard Recall & MCIS Scoring Method (MPI)
Delayed, Immediate or Total Free RecallR2 = 23.4-26.9% of variance explained
MPI ScoreR2 = 55.5% of variance explained
Regression of Recall Scores or MCIS Scoring Method (MPI) Score AgainstAge, Gender, Education, Race, Method of Administration & Wordlist Used1
N=121,481 Applicants for Long-Term Care Insurance: Ages 20-100
1Shankle et al. Alz. And Dementia. 5; 2009: 295-306.
Effect sizes (Cohen’s d) were as follows: Effect of Race, gender, and wordlist on MPI Score were negligible (<0.02) Effect of Education & phone vs. in-person testing on MPI Score were small
(0.02-0.05) Effect of Age on MPI Score was large (0.68) Effect of all covariates on Free Recall scores was negligible or small (<
0.09)
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Time to Administer Available Short Screening Tests
Top cognitive tests studied for BRIEF SCREENING for MCI
• Brief Alzheimer Screen 2 – 3 min• Mini-cog + FAQ 5 - 8 min• MIS + Isaacs Set Test 4 – 6 min• MCIS 10 min
A suitably accurate cognitive test for MCI is not available.
Because on variability between individuals, MCI screening requires longitudinal assessment!!
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Need to Develop More Sensitive and Specific Tools for MCI
• Genetic vulnerability testing (trait risk)– APOE genotype + age is among the best currently
• Improve awareness of vulnerability factors, ask the “right questions” of the patient or informant (education, occupation, head injury)
• Early recognition “10 warning signs”– Activities of daily living (ADLs), behavior changes, forgetting
• Increase suspicion and use available screening tools (while new and better tools/tests are developed)– "6th vital sign" in elderly
• Utilize current diagnostic tests that can best identify probable AD– Cerebrospinal fluid: tau levels, amyloid levels
– Brain scan, PET scan: f-2DG, f-DDNP, f-amyloid-ligands
• More routine use of mild dementia severity assessments
• Detect early change over time– Measure rate of change, predict progression
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Memory / MCI / Dementia Screening Test
• Need test for cognitive screening of patients for early Alzheimer’s disease
• Test needs to be on multiple platforms– Doctor’s offices– Best if computerized for rapid, objective assessment– Internet-based testing – CD-ROM distribution– Kiosk administration (eg, drug stores, shopping malls)
• Test needs to be very brief (~1-minute)• Multiple test-forms needed so it can be repeated often (quarterly)• Annual screening annually after age 50 years
– Repeated every 3 months for individuals over 65 years or with concerns/risk factors
– Variety of versions allow daily testing as an exercise
• Any change over time needs to be detected• The test should be free (or cost very little)
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MEMTRAX - Memory Test(For Dementia Screening, Cognition Assessment)
Test to screen patients for dementia, AD: Subjects are asked to respond to images that are repetitions of previously shown images.– Computerized test (computer or web - 3 minutes)– KIOSK administration (clinic check-in)– Group administration (Power-Point – 6 minutes)
• On the paper & pencil version, each slide is shown for 5 seconds. The test-taker is ask to fill in the circle next to the number for a repeated slide. After a practice set, the 50-slide test takes 4 minutes and 10 seconds.
• For the computerized test, each image is shown for 3 seconds, and the subject pushes the space bare to indicate recognition of a repeated picture.
• Estimate level (based on 2,000 patients, caregivers)– >90% very good– 80-90% good– 70-80% consider mild cognitive impairment– <70% dementia
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MEMTRAX Memory Test
116 subjects – mostly elderly normals, some young, some dementia patientsFalse positive errors (false recognition) – 33(64);6(58);47(27)—4,18,23,34(1);1,2,8(0)
- mean – 8.3% (sd-14.5%) errors per itemFalse negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3)
- second presentation (#15): mean- 10.5% (sd-6.2%) errors per item- third presentation (#10) mean – 5.7% (sd-2.5%) errors per item- second 10 vs. same third 10: 10.5% (sd-3.4%) vs 6.6% (sd-2.5%)
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Performance in 116 subjects
0
5
10
15
20
25
0 5 10 15 20 25
Number False negative
Num
ber
Fals
e po
siti
ve
Probable Normal
? fronto-temporaldementia
? MCI
? dementia
RandomPerformance
Regression
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True Negative Performance
y = -0.0352x + 25.564
R2 = 0.039
y = -0.0597x + 27.24
R2 = 0.141
1213141516171819202122232425
40.0 50.0 60.0 70.0 80.0 90.0 100.0
Age (years)
Nu
mb
er
Co
rre
ct
Male true-
Female true-
Linear (Male true-)
Linear (Female true-)
True Positive Performance
y = -0.0438x + 27.029
R2 = 0.0617
y = -0.0418x + 26.746
R2 = 0.0605
1213141516171819202122232425
40.0 50.0 60.0 70.0 80.0 90.0 100.0
Age (years)
Nu
mb
er
Co
rre
ct
Male true+
Female true+
Linear (Male true+)
Linear (Female true+)
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CONCLUSIONS on MEMTRAX
• A short, computerized test provides a measure of cognitive function, including memory and attention, on a robust continuum, establishing a baseline of cognitive function and potentially predicting the presence of dementia– Computerized version – 2-3 minutes, fun game, provides reaction
time measure– Paper&Pencil, with PowerPoint slide show, can be given to a
large audience
• Testing for reliability and validity are Classical Test Theory concepts– Modern Test Theory examines performance across individual
items on a continuum • (varied by first repeat vs second repeat, number of slides
between first show and first repeat, etc.– Analysis for maximum likelihood level of cognition (both
recognition and attention), provides information about dementia probability
– Information about visuo-spatial and language function is available
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MEMTRAX - Memory Test(to detect AD onset)
• New test to screen patients for AD: – World-Wide Web – based testing– CD-distribution– KIOSK administration (grocery stores, drug stores)
• Determine level of ability / impairment• Test takes about 1-minute• Test can be repeated often (e.g., weekly, quarterly)• Any change over time can be detected• Experimental tests at: www.medafile.com• Social network tests at: www.memtrax.net
• Clinical test at: www.memtrax.com
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Comprehensive Screening Plan• At age 50 years: initial screen, review risks
– Review dementia family history – strongly consider APOE genotyping– Review of systems, vital signs– Brief cognitive evaluation – establish baseline for longitudinal assessment– Complete blood count (CBC), B12, cholesterol– Begin yearly assessments if high risk
• At age 55–60 years: follow-up assessments– Review of systems, vital signs– Brief cognitive evaluation using longitudinal measures!!– CBC, B12, cholesterol
• At age 65 years and older: begin annual assessments– Review of systems, vital signs– Brief cognitive evaluation watching longitudinal changes– CBC, B12, cholesterol
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Secondary Screen:Specific Testing
• More cognitive testing
• Complete orientation testing
• Test ability to name animals and vegetables in 1 minute
• Ask for recall of 10 items after distraction
• Test praxis
• Draw clock, cube
• Talk with a knowledgeable informant
• Ask questions about activities of daily living
• Ask questions about depression, sleep
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Potential AD BiomarkersPotential AD BiomarkersProbably not cost-worthy as screening tests,Probably not cost-worthy as screening tests,but may be useful for secondary screeningbut may be useful for secondary screening
• Blood, urine ABlood, urine Aββ40? A40? Aββ42? Neuritic threads?42? Neuritic threads?– Most studies suggest not helpful, may be wrongMost studies suggest not helpful, may be wrong
• Protein levels in blood – Leptin, ProteomicsProtein levels in blood – Leptin, Proteomics– Lower Leptin predicts MCI progression to dementiaLower Leptin predicts MCI progression to dementia
• CSF: CSF: AAββ4040? ? AAββ4242? Others ? Others AAββ species? species?– Possibly highly predictivePossibly highly predictive
• CSF: CSF: tau, p-tautau, p-tau– Assess active disease progression.Assess active disease progression.
• EEG/MEG/ERPEEG/MEG/ERP• NeuroimagingNeuroimaging
– Structural (volumetric assessments)Structural (volumetric assessments)– Functional (FDG-PET, SPECT)Functional (FDG-PET, SPECT)– Specific protein imaging (PET)Specific protein imaging (PET)
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Serum Leptin levels and cognition in the elderly
78
MiId
Mod
erat
e
Nor
mal
Sev
ere
10
20
Lept
in (
ng/m
l)
Data: Satoris, Inc.
AD
In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009)
Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001)
In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009)
Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001)
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Correlation networks of Alzheimer disease (AD) signature proteins in plasma of controls without dementia and patients with AD.
PROTEOMICS:Expression patterns of Alzheimer disease (AD) signature proteins discriminate between plasma samples from patients with AD and controls.Britshgi & Wyss-Coray, 2009
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0
100
200
300
400
500
600
700
AD Patients Control Patients
CSF in Alzheimer’s Disease, both MCI and Dementia patients:
Low Aβ and High Tau
Aβ Tau
Co
nce
ntr
atio
n (
pg
/mL
)
Sunderland T, et al. JAMA. 2003;289:2094-2103.
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ADNI data, 2008
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ADNI Data – CSF ABeta, total tau
Comparison p-value
33 vs 34 <.0001
33 vs 44 <.0001
34 vs 44 0.08
Normal vs MCI 0.57
Normal vs Mild AD 0.15
MCI vs Mild AD 0.20
Comparison p-value
33 vs 34 0.07
33 vs 44 0.67
34 vs 44 0.99
Normal vs MCI 0.05
Normal vs Mild AD <.01
MCI vs Mild AD 0.06
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ADNI CSF Data – total tauNumber of participants that provided CSF at baseline Ages +std of participants that provided CSF at baseline
CSF tau levels ± std
APOE genotype
Normal MCI Mild AD
33 67 (72%) 82 (44%) 29 (31%)
34 24 (26%) 81 (44%) 42 (45%)
44 2 (2%) 22 (12%) 22 (24%)
APOE genotype
Normal MCI Mild AD
33 75.8 ± 5.0 75.4 ± 8.4 76.3 ± 8.6
34 75.8 ± 6.0 73.9 ± 6.7 75.6 ± 6.6
44 77.0 ± 1.4 72.2 ± 6.0 69.8 ± 7.0
APOE genotype
Normal MCI Mild AD
3367.8 ± 26.9
83.6 ± 40.8 123.8 ± 68.6
3481.8 ± 42.6
122.4 ± 72.7 113.3 ± 42.0
44 71.0 ± 2.8 110.6 ± 45.9 128.9 ± 53.1
APOE genotype
Normal MCI Mild AD
33 212.4 ± 48.4 189.1 ± 59.8 168.8 ± 52.3
34 156.0 ± 47.8 148.4 ± 42.4 139.0 ± 27.2
44 126.0 ± 2.8 119.8 ± 23.5 116.2 ± 22.3
CSF ABeta levels ± std
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Future directions for MCI screening
• Successful treatments for MCI
• APOE genotyping – routine at 50 y/o
• Preventive measures based on genetics
• Longitudinal assessment of memory
• Computer games to monitor cognition– quick, fun, inexpensive
• Can beta-amloid deposition be controlled by mental, physical exercises, better sleep?