International Conference on Alzheimer’s Disease SCREENING TOOLS FOR Mild Cognitive Impairment by SupremeLord

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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)
    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

                                      Not normal for age                    1/3 AD,
                                         Not demented
                                       Cognitive decline
                                                                            1/3 not,
                            Essentially normal functional activities        1/3 both.
                                              MCI

                  Yes                 Memory impaired?                 No

               Amnestic MCI                                Non-amnestic MCI

                                                          Single non-memory
                 Memory
      Yes                             No            Yes    cognitive domain      No
             impairment only?
                                                              impaired?


    Amnestic MCI             Amnestic MCI      Non-amnestic MCI        Non-amnestic MCI
    Single domain           Multiple domain     Single domain           Multiple domain
                                                                                 CP1265413-4
Petersen: J Int Med, 2004
                       What’s the Difference?
                  Normal Aging                                                   MCI
     Occasional loss of memory                                       Memory impairment
      for words and names.                                             beyond that expected for
     Slowed processing speed.                                         age, increasing over last
                                                                       six to 12 months.
     Difficulty sustaining
      attention when faced with                                       Other cognitive functions
      competing environmental                                          generally unimpaired.
      stimuli.                                                        Daily function not
     No functional impairment.                                        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            MCI                 AD




   0                    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)

             30
             25
MMSE score




             20
             15         The best model to fit the progression,
                        both mathematically and biologically,
             10         is the Gompertz survival curve
                        (99.7% fit to mean changes over time):
             5
                        S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
             0
                  -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
              /Functional Status


                                           Threshold
Progression




                                              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 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
         No Testing:
What happens without screening?

           Total Population
               Risk=P

             P’               P




   Do not have AD                 Have AD
                                  No effective intervention




                                                  Helena Kraemer, 2003
       Testing: What happens with testing?
                                                                            Helena Kraemer, 2003
                                   Total Population
Specificity = Sp              P’                 P                         Sensitivity = Se

                                                       AD
             No AD
                                                                      Se
                                                Se’
          Sp’            Sp


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
  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
                               Estimated Age-related Benefit
                               of Early Alzheimer Treatment

                       50000
delayed nursing home
 Dollar savings from




                       40000
     placement




                       30000

                       20000

                       10000

                          0
                               50    60     70         80   90   100
                                                 AGE
                                       Value of Diagnosis versus Time-Index
                                                                             Value across continuum
                                                                             Value at transition
                              100%                                           Value early
                              90%
Relative value of detection




                              80%
                              70%
                              60%
                              50%
                              40%
                              30%
                              20%
                              10%
                               0%
                                 -10   -8   -6    -4    -2    0     2    4      6     8     10
                                                 Estimated years into illness
                                                      (TimeIndex Scale)
   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,    2t = 8.2yrs
                    1.0000             Fem ales, 2t = 7.5 yrs
                                       dem entia incidence, 2t = 5 yrs
    Hazard / year




                                       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            Using the Gompertz equation
                 1000                              to model rate of dementia
                              APOE 4/4 (x7.5)
                                                   increase with age:
                  100         APOE 3/4 (x2)
                                                   U(t) = Ro * exp (alpha * t)
Hazard / year



                              APOE 3/3 (x0.6)
                   10
                              Early onset (x200)

                    1

                   0.1

                  0.01

                 0.001

                0.0001
                         50          60            70          80          90    100

                                                   Age (years)
                         MCI rate, assume Td = 5 yrs
                              mean rate
                 1000         APOE 4/4
                              APOE 3/4
                  100         APOE 3/3
Hazard / year



                              Early Onset
                   10

                    1

                   0.1

                  0.01

                 0.001

                0.0001
                         50      60         70      80    90   100

                                            Age (years)
                           Probability of Dementia Onset
                   0.06
                                     mean rate
                                     APOE 4/4
                   0.05
probability / yr



                                     APOE 3/4
                                     APOE 3/3
                   0.04

                   0.03    Using Gompertz equations
                           to model probability of
                           dementia with age:
                   0.02
                           D(t) = U(t) * S(t)
                   0.01

                     0
                          50         60           70         80   90   100

                                                       Age
                               Probability of MCI Onset
                   0.06
                                 mean rate
                                 APOE 4/4
                   0.05
probability / yr



                                 APOE 3/4
                                 APOE 3/3
                   0.04

                   0.03

                   0.02

                   0.01

                     0
                          50       60        70         80   90   100

                                                  Age
                                    Probability of Dementia Onset
                                         APOE 4/4-M
                             0.04
prob/ yr * live population

                                         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      100

                                         Age (single mortality correction)
                                         Probability of MCI Onset

                             0.04          APOE 4/4-M
prob/ yr * live population


                                           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      100

                                          Age (single mortality correction)
        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
                                          Probability Not Demented
                            1
Proportion of population


                           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
                           0.3        curve to model probability of
                           0.2        not having dementia with age:
                                      S(t) = exp(Ro/alpha *(1- exp (alpha * t)))
                           0.1
                            0
                                 50              60             70            80   90   100

                                                                     Age
                                          Probability Not MCI
                            1
Proportion of population


                           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   90   100

                                                       Age
                                  Cost-Worthy Test Evaluation
                              Benefit = $50,000 - 0; False Pos = $500

                      600
                      550                                               Se, Sp
                      500
Cost Justified for
Dementia Screen




                      450
                      400                                                .8, .8
                      350
                      300                                                .9, .9
                      250                                                .95, .95
                      200
                      150                                                1,1
                      100
                       50
                        0
                      -50
                     -100
                            50 55 60 65 70 75 80 85 90 95
                                            AGE
                          Cost-Worthy Test Evaluation
                         Sensitivity = 0.9, Specificity = 0.9
Cost Justified for
Dementia Screen




                     $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-Worthy Dementia Screening
                                   Se=0.9; Sp=0.9
                       Benefit = $25,000 - 0; False Pos = $500
Cost Justified for
Dementia Screen




                      600
                      500
                      400
                      300
                      200
                      100
                        0
                     -100
                                                            mean
                            50 55 60 65 70 75 80 85 90 95
                                                            ApoE 4/4
                                          AGE               ApoE 3/4
                                                            ApoE 3/3
                           FDG-PET

                           MRI hipp

  CSF-Aβ42
(protein decline)
                           Cognition

    Amyloid imaging        Function
       (ligand increase)

                           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.  Recent memory changes affecting daily life
      2.  Challenges in problem solving and planning
      3.  Difficulty performing familiar tasks
      4.  Disorientation to time and/or place
      5.  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
                                                                                     PENCIL
                      MMSE         AD all (easiest to hardest at p=.5)               APPL-REP
                                                                                     WATC
                      items           Mini-Mental State Exam items                   LOCATION
                                                                                     PENY-REP
                       1                                                             TABL-REP
                                                                                     CLOS-IS
                      0.9                                                            RIT-HAND
PROBABILITY CORRECT




                                                                                     CITY
                      0.8                                                            FOLD-HLF
                                                                                     SENTENCE
                      0.7                                                            COUNTY
                                                                                     NO-IFS
                      0.6                                                            FLOOR
                                                                                     SEASON
                      0.5                                                            YEAR
                                                                                     PUT-LAP
                      0.4                                                            MONTH
                                                                                     ADDRESS
                      0.3                                                            DRAW-PNT
                                                                                     DAY
                      0.2                                                            SPEL_ALL
                                                                                     DATE
                      0.1                                                            APPL-MEM
                                                                                     PENY-MEM
                       0                                                             TABL-MEM

                            -4 -3 -2 -1   0   1   2   3   4   5   6   7   8   9 10
                                   DISABILITY ("time-index" year units)
                                                                                             PENC
                                    AD all (easiest to hardest at p=.5)                      AP
                                                                                             WATC
                                                                                             LOCA
                                                                                             PE
                   0.16
                                                                                             TA
                                                                                             REDO
                   0.14                                                                      RIGH
                                                                                             CITY
                                                                                             FOLD
                   0.12
ITEM INFORMATION




                                                                                             SENT
                                                                                             COUN
                   0.10                                                                      PHRA
                                                                                             LEVE
                                                                                             SEAS
                   0.08                                                                      YEARA
                                                                                             LAP
                                                                                             MONT
                   0.06                                                                      ADDR
                                                                                             DRAW
                   0.04                                                                      DAYA
                                                                                             SPEL_1
                                                                                             DATE
                   0.02                                                                      APPL
                                                                                             PENN
                                                                                             TABL
                   0.00
                          -4   -3   -2    -1   0   1   2   3   4   5   6   7    8   9   10
                                         DISABILITY ("time-index" year units)
                                                    AD all

                   0.60
TEST INFORMATION




                   0.50

                   0.40

                   0.30

                   0.20

                   0.10

                   0.00
                          -4   -3 -2   -1   0   1    2   3   4   5   6   7   8   9   10
                                                DISABILITY SCALE
          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                                 Halstead, 1943
Rey Auditory Verbal Learning Test                         Rey, 1958
Abbreviated Mental Test                                   Hodkinson, 1972
Short Portable Mental Status Questionnaire (SPMSQ)        Pfeiffer, 1975
Clifton Assessment Procedures for the Elderly-Cognitive
                                                          Pattie, 1981
Assessment Scale (CAPE-CAS)
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

                     12
  percent of total




                     10

                      8

                      6

                      4

                      2

                      0
                          0         5         10             15            20   25
                                        number of animals named

                                          Normal Controls, n=386
                                          Mild Alzheimer Patients, n=380
JW Ashford, MD PhD, 2001
                            Anim als nam ed in 1 m in (m m s>19) - CERAD data set


                   12

                   10
percent of total




                   8

                   6

                   4

                   2

                   0
                        0               10                20               30       40
                                             num ber of anim als nam ed

                                             Normal Controls, CS = 1, n = 386
                                             Alzheimer patients, CS = 0, n = 380
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   23   24        25   26   27-39

JW Ashford, MD PhD, 2001
                                                     BAS Score
                                                              BRIEF ALZHEIMER SCREEN
                                                               (Normal vs Mild AD, MMS>19)


                                                                                               20
                                       100
                                                          27                              13
True Positive Rate (%) (Sensitivity)


                                        90                                      12
                                                  26           14
                                                 25                       11
                                        80
                                                                    10
                                        70
                                                               9
                                        60
                                        50                8              animals 1 m      AUC = 0.868

                                        40                               animals 30 s     AUC = 0.828
                                                 97
                                                                         MMSE             AUC = 0.965
                                        30
                                                 6
                                        20                               Date+3 Rec       AUC = 0.875

                                                                         BAS              AUC = 0.983
                                        10
                                         0
                                             0       10       20    30   40    50    60   70        80   90 100
                                                          False Positive Rate (%) (1-Specificity)
JW Ashford, MD PhD, 2003
          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


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., 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
2Trenkle 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
        Developing The Measurement Technology: Memory Patterns
    Raw CWL Data Matrix              Correspondence Analysis1
                                                                   • Logistic Regression        Classification algorithm &
       of Recalled and                (Multivariate Gaussian-
                                                                   • ROC Curve Analysis        Memory Performance Index
      Forgotten Words                Distributed Optimal Patient
                                                                   • Age-Specific Prevalence          (MPI) scaling
      (eg: 0010101101)                 & Word Score Vectors)

    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                       Item Responses Are Usually Scored As 0 or 1: All Items Have Equal Value
 Exposure Frequency
 Delay
 Being Recalled or Not
                                      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   & Stuart, The Advanced Theory of Statistics. 1961.
 2Shankle   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=250,000 4                          0.008-0.095%
                                         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.
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 Used 1
   N=121,481 Applicants for Long-Term Care Insurance: Ages 20-100

 Delayed, Immediate or Total Free Recall                            MPI Score
  R2 = 23.4-26.9% of variance explained                R2   = 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                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!!
 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
                        25                                        Probable Normal
Number False positive




                                                                  ? fronto-temporal
                        20
                                                                  dementia
                                                                  ? MCI
                        15
                                                                  ? dementia
                        10
                                                                  Random
                        5                                         Performance
                                                                  Regression
                        0
                             0     5     10     15      20   25
                                    Number False negative
                                       True Negative Performance

                 25
                 24                                                         y = -0.0352x + 25.564
                 23                                                                2
                                                                                 R = 0.039
Number Correct   22
                 21
                 20                                                         y = -0.0597x + 27.24
                 19                                                              R2 = 0.141
                 18
                 17                                                             Male true-
                 16                                                             Female true-
                 15
                 14                                                             Linear (Male true-)
                 13
                 12                                                             Linear (Female true-)

                  40.0   50.0   60.0       70.0       80.0   90.0   100.0
                                        Age (years)



                                       True Positive Performance

                 25                                                         y = -0.0438x + 27.029
                 24                                                                2
                 23                                                              R = 0.0617
                 22
Number Correct




                 21                                                         y = -0.0418x + 26.746
                 20                                                               2
                 19                                                              R = 0.0605
                 18
                 17                                                             Male true+
                 16
                 15                                                             Female true+
                 14                                                             Linear (Male true+)
                 13
                 12                                                             Linear (Female true+)
                  40.0   50.0   60.0       70.0       80.0   90.0   100.0
                                        Age (years)
     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
• Experimental tests at:    www.medafile.com
•   Social network tests at: www.memtrax.net
•   Clinical test at: www.memtrax.com
 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

   In elderly, higher serum
   leptin appears to protect                         Data: Satoris, Inc.
   against cognitive decline
   (5 yr prospective study,




                               Leptin (ng/ml)
                                                20                   AD
   2,871 elders, Holden et
   al., 2009)
                                                10
   Patients with AD have
   lower serum leptin levels
   compared to controls,
   independent of BMI




                                                                     Moderate
                                                     Normal




                                                                                Severe
                                                              MiId
   (Power et al., 2001)

                                                                                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
                        700
Concentration (pg/mL)




                        600
                        500
                        400

                        300
                        200
                        100
                         0
                                 Aβ                           Tau
Sunderland T, et al. JAMA. 2003;289:2094-2103.
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                                                     APOE
                Normal         MCI         Mild AD                      Normal         MCI         Mild AD
 genotype                                                 genotype

    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                                                      APOE
              Normal          MCI           Mild AD                     Normal         MCI           Mild AD
genotype                                                  genotype

   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?

								
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