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)
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
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
Diagnostic Criteria For Dementia Of
The Alzheimer Type
(DSM-IV, APA, 1994)
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 Conditions
2. Substance Induced Conditions
E. Do Not Occur Exclusively during Delirium
F. Not Due to Another Psychiatric Disorder
Mild Cognitive Impairment
Cognitive complaint
1/3 AD,
1/3 not,
1/3 both.
Not normal for age
Not demented
Cognitive decline
Essentially normal functional activities
MCI
Memory impaired?
Yes
Yes
No
Amnestic MCI
Non-amnestic MCI
Memory
impairment only?
Single non-memory
cognitive domain
impaired?
Amnestic MCI
Single domain
No
Amnestic MCI
Multiple domain
Yes
Non-amnestic MCI
Single domain
No
Non-amnestic MCI
Multiple domain
CP1265413-4
Petersen: J Int Med, 2004
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?“
Cognitive Continuum
Normal
Mild Cognitive
Impairment
Dementia
CP926864- 35
Mild Cognitive Impairment
Normal
0
MCI
AD
0.5
1
CDR (clinical dementia rating scale)
3004153-1
ALZHEIMER’S DISEASE COURSE
Estimate MMSE as a function of time
(calculated from the CERAD data set)
MMSE score
30
25
20
15
10
The best model to fit the progression,
both mathematically and biologically,
is the Gompertz survival curve
(99.7% fit to mean changes over time):
5
0
S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
-10
-8
-6
-4
-2
0
2
4
6
8
10
Estimated years into illness
(Time-Index Scale)
AAMI / MCI/ early AD -- DEMENTIA
Ashford et al., 1995
Presymptomatic
MCI
Clinical Dementia
CDR 0.5 CDR 1
CDR 2
CDR 3
Neuropsychological
Progression
/Functional Status
Threshold
for
Clinical
Detection
Time (years)
Adapted from Daffner & Scinto, 2000
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
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
Why MCI Screening Is
Important to Consider
• Cognitive impairment is disruptive to human wellbeing 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
No Testing:
What happens without screening?
Total Population
Risk=P
P’
Do not have AD
P
Have AD
No effective intervention
Helena Kraemer, 2003
Testing: What happens with testing?
Helena Kraemer, 2003
Total Population
P’
Specificity = Sp
Sensitivity = Se
P
AD
No AD
Sp’
Sp
Unnecessary intervention
$ Testing
$ Intervention
$Testing
Se
Se’
OK
No effective intervention
$ Testing
Effective intervention
$ Testing
$ Intervention
Iatrogenic Damage?
Clinical Wash
Clinical Wash
Clinical Gain
Major(?) Loss
Minor (?) Loss
Some gain
True Negative
Minor(?) Loss
Major(?) Gain
False Negative
True Positive
False Positive
Factors for Deciding whether
a 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
$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
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
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
Benefits of Early Treatment of
Alzheimer’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
Dollar savings from
delayed nursing home
placement
Estimated Age-related Benefit
of Early Alzheimer Treatment
50000
40000
30000
20000
10000
0
50
60
70
80
AGE
90
100
Value of Diagnosis versus Time-Index
Value across continuum
Value at transition
Value early
Relative value of detection
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
-10
-8
-6
-4
-2
0
2
4
Estimated years into illness
(TimeIndex Scale)
6
8
10
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
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
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
U.S. mortality, dementia, MCI rate
by age (mortality = 2000 CDC / 2000 census)
Males,
1.0000
2t = 8.2yrs
Fem ales, 2t = 7.5 yrs
Hazard / year
dem entia incidence, 2t = 5 yrs
MCI incidence, 2t = 5yrs
0.1000
The Gompertz survival curve explains
99.7% of male and female mortality
Variance between 30 and 95 y/o:
0.0100
U(t) = Ro * exp (alpha * t)
0.0010
0.0001
0
10
20
30
40
50
60
70
80
90 100
Age (years)
JW Ashford, MD PhD, 2003; See: Raber et al., 2004
(Incidence for a to a + 1 year)
Dementia rate, assume Td = 5 yrs
mean rate
Hazard / year
1000
APOE 4/4 (x7.5)
100
APOE 3/4 (x2)
Using the Gompertz equation
to model rate of dementia
increase with age:
U(t) = Ro * exp (alpha * t)
APOE 3/3 (x0.6)
10
Early onset (x200)
1
0.1
0.01
0.001
0.0001
50
60
70
80
Age (years)
90
100
MCI rate, assume Td = 5 yrs
mean rate
APOE 4/4
APOE 3/4
APOE 3/3
Early Onset
1000
Hazard / year
100
10
1
0.1
0.01
0.001
0.0001
50
60
70
80
Age (years)
90
100
Probability of Dementia Onset
probability / yr
0.06
mean rate
APOE 4/4
0.05
APOE 3/4
APOE 3/3
0.04
0.03
0.02
Using Gompertz equations
to model probability of
dementia with age:
D(t) = U(t) * S(t)
0.01
0
50
60
70
80
Age
90
100
Probability of MCI Onset
0.06
probability / yr
mean rate
APOE 4/4
0.05
APOE 3/4
APOE 3/3
0.04
0.03
0.02
0.01
0
50
60
70
80
Age
90
100
prob/ yr * live population
Probability of Dementia Onset
APOE 4/4-M
APOE 4/4-F
APOE 3/4-M
APOE 3/4-F
APOE 3/3-M
APOE 3/3-F
0.04
0.03
0.02
0.01
0
50
60
70
80
90
Age (single mortality correction)
100
prob/ yr * live population
Probability of MCI Onset
0.04
APOE 4/4-M
APOE 4/4-F
APOE 3/4-M
APOE 3/4-F
APOE 3/3-M
APOE 3/3-F
0.03
0.02
0.01
0
50
60
70
80
90
Age (single mortality correction)
100
Cache County, probability
of incident dementia
Circles – females
Squares - males
Open – ApoE-e44
Gray – ApoE-e4/x
Black – ApoE-ex/x
Miech et al., 2002
Proportion of population
Probability Not Demented
1
0.9
0.8
mean rate
0.7
APOE 4/4
0.6
APOE 3/4
APOE 3/3
0.5
0.4
Using a Gompertz survival
curve to model probability of
not having dementia with age:
S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
0.3
0.2
0.1
0
50
60
70
80
Age
90
100
Proportion of population
Probability Not MCI
1
0.9
0.8
mean rate
0.7
APOE 4/4
0.6
APOE 3/4
0.5
APOE 3/3
0.4
0.3
0.2
0.1
0
50
60
70
80
Age
90
100
Cost Justified for
Dementia Screen
Cost-Worthy Test Evaluation
Benefit = $50,000 - 0; False Pos = $500
600
550
500
450
400
350
300
250
200
150
100
50
0
-50
-100
Se, Sp
.8, .8
.9, .9
.95, .95
1,1
50 55 60 65 70 75 80 85 90 95
AGE
Cost Justified for
Dementia Screen
Cost-Worthy Test Evaluation
Sensitivity = 0.9, Specificity = 0.9
$1,000
$800
$600
$400
$200
$0
-$200
50 55 60 65 70 75 80 85 90 95
AGE (years)
Benefit: $5,000 - 0
Benefit: $10,000 - 0
Benefit: $25,000 - 0
Benefit: $100,000 - 0
Benefit: cure = $240,000
Cost Justified for
Dementia Screen
Cost-Worthy Dementia Screening
Se=0.9; Sp=0.9
Benefit = $25,000 - 0; False Pos = $500
600
500
400
300
200
100
0
-100
50 55 60 65 70 75 80 85 90 95
AGE
mean
ApoE 4/4
ApoE 3/4
ApoE 3/3
FDG-PET
MRI hipp
CSF-Aβ42
(protein decline)
Amyloid imaging
(ligand increase)
Cognition
Function
CSF-tau
ADNI
ADCS
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
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
Alzheimer's Disease Top 10
Warning Signs (not early)
1.
2.
3.
4.
5.
Recent memory changes affecting daily life
Challenges in problem solving and planning
Difficulty performing familiar tasks
Disorientation to time and/or place
Difficulty understanding visual images and/or spatial
relationships
6. Problems with spoken and written language (eg,
paraphasia, agraphia)
7. Misplacing things
8. Poor judgment
9. Withdrawal from activities (eg, social, work)
10. Changes in personality and/or mood
Need a Top 10 Early Warning Signs
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.
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.
Ashford et al., 1989
Ashford et al., 1989
MMSE
items
AD all (easiest to hardest at p=.5)
Mini-Mental State Exam items
PROBABILITY CORRECT
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
-4 -3 -2 -1
0
1
2
3
4
5
6
7
8
DISABILITY ("time-index" year units)
9 10
PENCIL
APPL-REP
WATC
LOCATION
PENY-REP
TABL-REP
CLOS-IS
RIT-HAND
CITY
FOLD-HLF
SENTENCE
COUNTY
NO-IFS
FLOOR
SEASON
YEAR
PUT-LAP
MONTH
ADDRESS
DRAW-PNT
DAY
SPEL_ALL
DATE
APPL-MEM
PENY-MEM
TABL-MEM
PENC
AP
WATC
LOCA
PE
TA
REDO
RIGH
CITY
FOLD
SENT
COUN
PHRA
LEVE
SEAS
YEARA
LAP
MONT
ADDR
DRAW
DAYA
SPEL_1
DATE
APPL
PENN
TABL
AD all (easiest to hardest at p=.5)
0.16
ITEM INFORMATION
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
-4
-3
-2
-1
0
1
2
3
4
5
6
7
DISABILITY ("time-index" year units)
8
9
10
AD all
TEST INFORMATION
0.60
0.50
0.40
0.30
0.20
0.10
0.00
-4
-3 -2
-1
0
1
2
3
4
5
DISABILITY SCALE
6
7
8
9
10
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
Relatively Brief Cognitive and
Memory Tests
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
Ashford JW. Aging Health. 2008;4:399-432.
Relatively Brief Cognitive and
Memory Tests (cont.)
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,
Ashford JW. Aging Health.
2008;4:399-432.
2008 - Aging Health. (2008) 4(4):399-432.
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
Animals name d in 30 se conds (mms>19)
16
14
percent of total
12
10
8
6
4
2
0
0
5
10
15
number of animals named
Normal Controls, n=386
JW Ashford, MD PhD, 2001
Mild Alzheimer Patients, n=380
20
25
Anim als nam ed in 1 m in (m m s>19) - CERAD data set
12
percent of total
10
8
6
4
2
0
0
10
20
30
num ber of anim als nam ed
Normal Controls, CS = 1, n = 386
Alzheimer patients, CS = 0, n = 380
40
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
www.medafile.com/bas.htm
Mendiondo, Ashford, Kryscio, Schmitt., J Alz Dis 5:391, 2003
Percent of Validation Sample
90
80
Mild AD
70
Control
60
50
40
30
20
10
0
3-22
JW Ashford, MD PhD, 2001
23
24
25
BAS Score
26
27-39
BRIEF ALZHEIMER SCREEN
(Normal vs Mild AD, MMS>19)
20
True Positive Rate (%) (Sensitivity)
100
27
90
26
25
80
14
13
12
11
10
70
9
60
8
animals 1 m
AUC = 0.868
animals 30 s
AUC = 0.828
MMSE
AUC = 0.965
20
Date+3 Rec
AUC = 0.875
10
BAS
AUC = 0.983
50
40
97
30
6
0
0
10
20
30
40
50
60
70
80
False Positive Rate (%) (1-Specificity)
JW Ashford, MD PhD, 2003
90 100
Brief Alzheimer Screen (BAS) ROC for Univ. Kentucky ADRC Clinic Cases
Schmitt et al., 2006
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
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
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
FCSRT learning
Controls
FCSRT delayed
Controls
Abbreviations: AD, Alzheimer Disease; ento, entorhinal; hipp., hippocampus; mat., matter
FCSRT, 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.
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. 2005
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.
2Trenkle
www.mccare.com
Developing The Measurement Technology: Memory Patterns
Raw CWL Data Matrix
of Recalled and
Forgotten Words
(eg: 0010101101)
Correspondence Analysis1
(Multivariate GaussianDistributed 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
Word 1 Word 2 Word 3 Word 4 Word 5 Word 6 Word 7 Word 8 Word 9 Word 10
Wordlist Memory Task: 4 Trials
1Kendall
2Shankle
& Stuart, The Advanced Theory of Statistics. 1961.
et al. PNAS. 2005
Wordlist Development
1 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 syllables
has 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)
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%
*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.
Psychometric Properties
86-100%
Positive Predictive Value for MCI1,2
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%
1Shankle
2Trenkle
3Cho
4Cohen
et al. PNAS: 2005.
et al. Am J. Alz Dis Other Dem. 2008.
et al. J. Alz Dis: 2007.
et al. National Underwriter, 2009.
Japanese MCIS vs. Biomarkers
Cho et al., 2009
Comparing Standard Recall & MCIS Scoring Method (MPI)
Regression of Recall Scores or MCIS Scoring Method (MPI) Score Against
Age, Gender, Education, Race, Method of Administration & Wordlist Used1
N=121,481 Applicants for Long-Term Care Insurance: Ages 20-100
Delayed, Immediate or Total Free Recall
R2 = 23.4-26.9% of variance explained
R2
MPI Score
= 55.5% of variance explained
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)
1Shankle
et al. Alz. And Dementia. 5; 2009: 295-306.
Time to Administer Available
Short Screening Tests
Top cognitive tests studied for BRIEF SCREENING for MCI
•
•
•
•
Brief Alzheimer Screen
Mini-cog + FAQ
MIS + Isaacs Set Test
MCIS
2 – 3 min
5 - 8 min
4 – 6 min
10 min
A suitably accurate cognitive test for MCI is not available.
Because on variability between individuals, MCI
screening requires longitudinal assessment!!
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
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)
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
MEMTRAX Memory Test
116 subjects – mostly elderly normals, some young, some dementia patients
False 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 item
False 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%)
Performance in 116 subjects
Probable Normal
Number False positive
25
? fronto-temporal
dementia
? MCI
20
15
? dementia
10
Random
Performance
Regression
5
0
0
5
10
15
20
Number False negative
25
Number Correct
True Negative Performance
25
24
23
22
21
20
19
18
17
16
15
14
13
12
40.0
y = -0.0352x + 25.564
2
R = 0.039
y = -0.0597x + 27.24
R2 = 0.141
Male trueFemale trueLinear (Male true-)
Linear (Female true-)
50.0
60.0
70.0
80.0
90.0
100.0
Age (years)
Number Correct
True Positive Performance
25
24
23
22
21
20
19
18
17
16
15
14
13
12
40.0
y = -0.0438x + 27.029
2
R = 0.0617
y = -0.0418x + 26.746
2
R = 0.0605
Male true+
Female true+
Linear (Male true+)
Linear (Female true+)
50.0
60.0
70.0
Age (years)
80.0
90.0
100.0
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
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
www.medafile.com
Social network tests at: www.memtrax.net
Clinical test at: www.memtrax.com
• Experimental tests at:
•
•
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
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
Potential AD Biomarkers
Probably not cost-worthy as screening tests,
but may be useful for secondary screening
• Blood, urine Aβ40? Aβ42? Neuritic threads?
–
Most studies suggest not helpful, may be wrong
• Protein levels in blood – Leptin, Proteomics
–
Lower Leptin predicts MCI progression to dementia
• CSF: Aβ40? Aβ42? Others Aβ species?
–
Possibly highly predictive
• CSF: tau, p-tau
–
Assess active disease progression.
• EEG/MEG/ERP
• Neuroimaging
–
–
–
Structural (volumetric assessments)
Functional (FDG-PET, SPECT)
Specific protein imaging (PET)
Serum Leptin levels and cognition in the elderly
AD
20
Severe
Moderate
MiId
10
Normal
Patients with AD have
lower serum leptin levels
compared to controls,
independent of BMI
(Power et al., 2001)
Data: Satoris, Inc.
Leptin (ng/ml)
In elderly, higher serum
leptin appears to protect
against cognitive decline
(5 yr prospective study,
2,871 elders, Holden et
al., 2009)
78
PROTEOMICS:
Expression patterns of Alzheimer disease (AD)
signature proteins discriminate between plasma
samples from patients with AD and controls.
Britshgi & Wyss-Coray, 2009
Correlation networks of Alzheimer disease (AD) signature proteins in plasma of controls without dementia and patients with AD.
CSF in Alzheimer’s Disease,
both MCI and Dementia patients:
Low Aβ and High Tau
AD Patients
Control Patients
Concentration (pg/mL)
700
600
500
400
300
200
100
0
Aβ
Sunderland T, et al. JAMA. 2003;289:2094-2103.
Tau
ADNI data, 2008
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
ADNI CSF Data – total tau
Number of participants that provided CSF at baseline
Ages +std of participants that provided CSF at baseline
APOE
genotype
Normal
MCI
Mild AD
APOE
genotype
Normal
MCI
Mild AD
33
67 (72%)
82 (44%)
29 (31%)
33
75.8 ± 5.0
75.4 ± 8.4
76.3 ± 8.6
34
24 (26%)
81 (44%)
42 (45%)
34
75.8 ± 6.0
73.9 ± 6.7
75.6 ± 6.6
44
2 (2%)
22 (12%)
22 (24%)
44
77.0 ± 1.4
72.2 ± 6.0
69.8 ± 7.0
CSF ABeta levels ± std
CSF tau levels ± std
APOE
genotype
Normal
MCI
Mild AD
APOE
genotype
Normal
MCI
Mild AD
33
212.4 ± 48.4
189.1 ± 59.8
168.8 ± 52.3
33
67.8 ± 26.9
83.6 ± 40.8
123.8 ± 68.6
34
156.0 ± 47.8
148.4 ± 42.4
139.0 ± 27.2
34
81.8 ± 42.6
122.4 ± 72.7
113.3 ± 42.0
44
126.0 ± 2.8
119.8 ± 23.5
116.2 ± 22.3
44
71.0 ± 2.8
110.6 ± 45.9
128.9 ± 53.1
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?