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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 Scientist Stanford / 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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SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Dec 22, 2015

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Page 1: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 2: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 3: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 4: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 5: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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.

Page 6: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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?“

Page 7: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Cognitive ContinuumCognitive Continuum

Mild CognitiveMild CognitiveImpairmentImpairment

NormalNormal

DementiaDementia

CP926864- 35

Page 8: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Mild Cognitive Impairment

NormalNormal MCIMCI ADAD

00 0.50.5 11

CDR CDR (clinical dementia rating scale)(clinical dementia rating scale)3004153-1

Page 9: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 10: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 11: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 12: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 13: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 14: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

No Testing:

What happens without screening?

Total Population Risk=P

P

Have ADNo effective intervention

Do not have AD

P’

Helena Kraemer, 2003

Page 15: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 16: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 17: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

$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

Page 18: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 19: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 20: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 21: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 22: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 23: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 24: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 25: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 26: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 27: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 28: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 29: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 30: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 31: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 32: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 33: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Miech et al., 2002

Cache County, probability of incident dementiaCircles – femalesSquares - malesOpen – ApoE-e44Gray – ApoE-e4/xBlack – ApoE-ex/x

Page 34: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)))

Page 35: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 36: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 37: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

d f

or

De

me

nti

a S

cre

en

Benefit: $5,000 - 0Benefit: $10,000 - 0Benefit: $25,000 - 0Benefit: $100,000 - 0Benefit: cure = $240,000

Page 38: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

st

Ju

sti

fie

d f

or

De

me

nti

a S

cre

en

meanApoE 4/4ApoE 3/4ApoE 3/3

Page 39: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

CSF-Aβ42 (protein decline)

Amyloid imaging(ligand increase)

FDG-PET

MRI hipp

CSF-tau

Cognition

Function

ADNIADCS

Page 40: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 41: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 42: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 43: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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.

Page 44: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Ashford et al., 1989

Page 45: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Ashford et al., 1989

Page 46: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

AD all (easiest to hardest at p=.5)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

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

Page 47: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

AD all (easiest to hardest at p=.5)

0.00

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DISABILITY ("time-index" year units)

ITE

M IN

FO

RM

AT

ION

PENCAPWATCLOCAPETAREDORIGHCITYFOLDSENTCOUNPHRALEVESEASYEARALAPMONTADDRDRAWDAYASPEL_1DATEAPPLPENNTABL

Page 48: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

TES

T IN

FOR

MA

TIO

N

Page 49: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 50: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 51: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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.

Page 52: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 53: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Animals named in 30 seconds (mms>19)

0

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0 5 10 15 20 25

number of animals named

pe

rce

nt

of

tota

l

Normal Controls, n=386

Mild Alzheimer Patients, n=380JW Ashford, MD PhD, 2001

Page 54: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Animals named in 1 min (mms>19) - CERAD data set

0

2

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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

Page 55: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 56: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 57: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

BRIEF ALZHEIMER SCREEN (Normal vs Mild AD, MMS>19)

9

20

1413

1211

10

9

6

7

8

2627

25

0

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0 10 20 30 40 50 60 70 80 90 100

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

Page 58: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Brief Alzheimer Screen (BAS) ROC for Univ. Kentucky ADRC Clinic Cases

Schmitt et al., 2006

Page 59: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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.

Page 60: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 61: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 62: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 63: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 64: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

Japanese MCIS vs. Biomarkers

Cho et al., 2009

Page 65: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 66: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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!!

Page 67: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 68: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 69: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 70: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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%)

Page 71: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 72: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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+)

Page 73: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 74: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 75: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 76: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 77: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 78: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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)

Page 79: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 80: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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.

Page 81: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

ADNI data, 2008

Page 82: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 83: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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

Page 84: SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D. Clinical Professor (affiliated) Department of Psychiatry & Behavioral.

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?