Agenda 3:00 PMIntroduction to Workshop Barry Reisberg, M.D. 3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCP function

Agenda 3:00 PM Introduction to Workshop Barry Reisberg, M.D.

3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCPfunction influences the risk of cognitive decline

3:35 PM Current Knowledge of Methodologies for Barry Reisberg, M.D.Clinical Trials in Pre-MCI Persons with SubjectiveCognitive Impairment (SCI)

4:25 PM Discussion of Current Knowledge and Joel Sadavoy M.D., FRCPCMethodologies

4:35 PM Discussion of Clinical Instrumentation for Barry Reisberg, M.D.Subject Selection and Assessment

4:55 PM Subject Interview Workshop Faculty and Participants

5:25 PM Final Discussion Joel Sadavoy M.D., FRCPC

Current Knowledge

of

Methodologies

for

Clinical Trials

in

Pre-MCI Persons

with

Subjective Cognitive Impairment

(SCI)

Barry Reisberg, M. D.

Professor of Psychiatry

Director, Fisher Alzheimer's Disease Program

Clinical Director, Aging & Dementia Research Center

Director, Clinical Core, NYU Alzheimer's Disease Center

New York University School of Medicine

Barry Reisberg, M.D.

Adjunct ProfessorCenter for Studies in Aging, Faculty of MedicineMcGill University, Montreal, Canada(1993 – present)

MemberADI Medical & Scientific Advisory Panel (MSAP)(1997 – present)

Founder and ChairADI Prevention Work Group

Research Support(1978 to Present)

USDHHS

National Institute on Aging

AG 03051, AG 08051, AG 11505, AG 09127, AG 01344

National Institute on Mental Health

MH 43486, MH 38275, MH 29590, MH 42216, MH 35976, MH 40410, MH 32577, MH 29590

National Institute of Neurologic Diseases and StrokeNS 15638

Adminstration on AgingAR 2160, AM 2552

FOUNDATIONZachary and Elizabeth M. Fisher Medical FoundationWilliam and Sylvia Silberstein Bequest

Mr. Leonard LitwinThe Louis J. Kay and June E. Kay Foundation

Disclosures

I am the developer, and copyright holder

with respect to some of the instruments

and procedures

which I will be discussing.

Copyrights

These include the:

Global Deterioration Scale (GDS)

Functional Assessment Staging (FAST) Brief Cognitive Rating Scale (BCRS) Behavioral Pathology in Alzheimer’s Disease

Assessment (BEHAVE-AD)

I have coined the terms and, with my associates, developed the concepts behind:

Mild Cognitive Impairment


Disclosures

My measures have been made freely available to:

All researchers, academics and students

Governmental bodies e.g., US: Medicare (Center for Medicare and Medicaid Services [CMS])

US Veterans Administration 5 Canadian Provinces

Not for profit associations e.g., Alzheimer’s Association

American Psychiatric Association

> 90 % of currently used Alzheimer’s disease medications in the U.S.

have been approved by the FDA in pivotal trials employing methods (scales)

developed by myself and my colleagues

Collaborators

Primary – NYU Institute for Basic Research- Steven H. Ferris, Ph.D. Staten Island, N.Y. Mony J. de Leon, Ed.D. Jerzy Weigel, DVM

Other NYU Collaborators Henry Wisniewski, M.D., Ph.D.

Emile H. Franssen, M.D. Maciek Bobinski, M.D.

Liduin Souren, RN, MSN MAS Austria Sunnie Kenowsky, DVM Stefanie Auer, Ph.D.

Alan Kluger, Ph.D. Tohoku University, Sendai, Japan Carol Torossian, Psy.D. Masumi Shimada, O.T. Isabel Monteiro, M.D. Kenichi Meguro, M.D., Ph.D.

Industry Collaborators Ravi Anand, M.D. (Switzerland & US) Hans Jorg Mobius (Frankfurt, Germany) Albrecht Stoëffler (Frankfurt, Germany)

Risk Factors for AD.

Now Appear to Operate

Early in Life

For example:

ApoE – є4 allele

genotypic risk for AD

Reiman, et al., Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia., Proc Natl Acad Sci U S A., 2004 101(1):284-9.

http--www_kavlifoundation_org-uploads 1215817302_Moser_EntorhinalCortex_jpg.mht

• Development of neurofibrillary changes (n=2369)

Braak, H. & Braak, E., Aspects of cortical destruction in Alzheimer’s disease, in Hyman, B.T., Duykaerts, C., & Christen, Y. (Eds.), Connections Cognition and Alzheimer’s Disease, Springer-Verlag, Berlin Heidelberg, 1997.

GDS Stage 3 Mild Cognitive Impairment1,2

Earliest subtle deficits

Objective evidence of memory deficit obtained only with an intensive

interview

Decreased performance in demanding employment and social settings

1 Reisberg, et al., Drug Development Research, 1988; 15:101-114. 2 Flicker, C., Ferris, S.H., Reisberg, B. Mild Cognitive Impairment in the elderly:

prediction of dementia. Neurology, 1991, 41:1006-1009.

Psychometric/Mental Status/Behavior

SCI vs MCI

Significant differences on the:

MMSEBlessed Dementia ScaleBlessed et al., information test, memory test, and concentration

test, WAIS vocabulary scores

Paragraphs, initial and delayed recall testsPaired associates, initial and delayed recall Designs test Shopping list selective reminding testDigits backward recallDigit symbol substitution test Finger tapping speed (mean R & L)Comprehensive psychometric test

Reisberg, et al., Drug Dev Res, 1988; 15:101-114.

No Cognitive Subjective Cognitive Mild Cognitive

Impairment Impairment Impairment

(NCI) (SCI) (MCI)

Kluger et al., Journal of Geriatric Psychiatry and Neurology, 1999; 12: 168-179

This study verified our earlier estimatethat the MCI stage of eventual AD lasts approximately 7 years in otherwise healthy persons.

This estimate of duration is almost precisely in the midpoint of the timecourse observed for MCI in subsequent worldwide studies.

Selected Studies of Clinically Defined MCI (GDS stage 3) with Ddx from Normal Aging and/or Dementia, 1983-2001

Abbrev. Citation* Modality Finding

Reisberg, et al., 1983 Clinically assessed Ddx MCI vsPsychopharm. Bull. modalities e.g., SCI &

concentration, Mild ADReisberg & Ferris, 1988, calculation, etc. Psychopharm. Bull.

Reisberg, et al., 1992, Int. Psychoger.

Reisberg, et al., 1988, Mental status, Ddx MCI Drugs. Dev. Res. Psychometric tests vs SCI &

Mild AD


Reisberg, et al., 1985, Subjective complaints, Ddx MCI

in B. Stanley (ed.), American subject & spouse rated, vs SCI &

Psychiatric Press insight & denial Mild AD

Reisberg, et al., 1989 Nature of behavioral Ddx MCI Bull. Clin. Neurosci. disturbances vs. SCI and

and Mild AD

de Leon, et al., 1989, MRI hippocampal MCI atrophy Lancet. atrophy predicts ADde Leon, et al., 1993, Am. J. Neuroradiology

Franssen et al., 1991, Neurological reflexes ↑ DTRs, glabellar Arch. Neurology blink &

palmomental reflexes in

MCIvs NL aged


Prichep, et al., 1994, Neurobiol. QEEG ↑ theta activ. InAging MCI vs. SCI

Kluger, et al., 1997, Motor measures Ddx MCI vs. Journ. Gerontology SCI &

Mild AD

Franssen et al., 1999, Equilibrium and coordination Ddx MCI Joun. Am. Geriatr. Soc. measures vs NL aged

Reisberg, et al., 2001, ADLs, Ddx MCI Int. Psychogeriatrics 13 areas vs SCI and

Mild AD

*Complete citations in Reisberg, Ferris, Kluger, Franssen, Wegiel, and de Leon, Mild cognitive impairment (MCI): a historical perspective, International Psychogeriatrics, 20:1, 18-31, 2008.

MCIPeterson, et al., 20011

Memory complaint

Objective memory impairment

Normal general cognitive function

Intact activities of daily living

Not demented

1 Peterson, Stevens, Ganguli, et al., Neurology, 56:1133-1142.

MCI International Working Group

(IWG)

Criteria 2004

* Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med., 2004; 256: 240-6.

MCI

International Working Group

(IWG)

Criteria (2004)*

Do not require self report of decline

Instead suggest that MCI subjects have:

“self and/or informant report and

impairment on objective cognitive tests

and/or,

evidence of decline over time on objective cognitive tasks”

Global Deterioration Scale Stage Diagnosis and Nl Nl MCI Mild Mod Mod- Severity without with AD AD Severe SCI SCI AD

Questions referring to the subject’s status. Category 1: memory functioning: Query 1: What kinds of problems do you (does your spouse) have with memory?

Recommend a clinical, rather than a psychometric definition of MCI

Functioning

“A wide range of cognitive functions appear to decline … including memory, attention, language, visuospatial skill, perceptual speed and executive functioning.”

Entirely compatible with the original GDS Stage 3 MCI definition.

* Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med., 2004; 256: 240-6.

Adapted from Reisberg, Dementia, Adapted from Reisberg, Dementia, GeriatricsGeriatrics, 1986; 41(4): 30-46., 1986; 41(4): 30-46.

Subjective Cognitive ImpairmentClinical Diagnosis Normal Adult Subjective Cognitive Impairment Mild Cognitive Impairment Mild Mod Mod to Seve Severe

NL SCI MCI AD AD AD AD


Very common

Jonker, et al., 2000

Reviewed 3 community based studies

of persons ≥ 65 years of age

Prevalence = 25% to 56%


• Quite troubling

For the past 30 years,

~ 1/3 of the persons presenting

at the NYU School of Medicine,

Aging and Dementia Research Center

have SCI

These people frequently want help.


Persons with these symptoms need to be

differentiated from –

Healthy non-SCI persons

Persons with MCI

The Global Deterioration Scale (GDS)1 which we have been using for the past 30 years makes these distinctions.

Other elements of the GDS Staging System also make these distinctions.

Brief Cognitive Rating Scale (BCRS)Functional Assessment Staging (FAST)

1Reisberg, B., Ferris, S.H., de Leon, M.J., and Crook, T., The global deterioration scale for

assessment of primary degeneration dementia. American Journal of Psychiatry, 1982;

139:1136-1139.

GDS Stage 1

Healthy older persons

Free of subjective complaints of cognitive

impairment

Free of objective evidence of cognitive

impairment

GDS Stage 2

Subjective complaints of memory deficit.

e.g., forgetting names

one formerly knew well

Forgetting where one has placed familiar objects.

No objective evidence of memory deficit on clinical interview

No objective deficit in employment or social situations

GDS and FAST Stages of ADGDS and FAST Stages of AD GDSGDS

StageStageFASTFASTStageStage

FAST FAST Functional AssessmentFunctional Assessment

Subjective complaints only, e.g., forgetting names, forgetting location of objects

22. SCI

Duration of the SCI stageHypothesized duration = 15 years (Reisberg, 1986)Longitudinal Study of 44 GDS Stage 2 Subjects Followed for 8.9 ± 1.8 Years(Prichep, et al., 2006)

The hypothesized mean duration of the subjective cognitive impairment (SCI) stage, synonymous with Global Deterioration Scale (GDS) stage 2, was published in Reisberg, B. (1986). Dementia: a systematic approach to identifying reversible causes. Geriatrics, 41(4), 30-46. The observed results for the duration of the SCI stage, synonymous with GDS stage 2, are calculated from Prichep, L.S., et al. (1994). Quantitative EEG correlates of cognitive deterioration in the elderly. Neurobiology of Aging, 15, 85-90.

Result: For a stage with a 15 year duration, the observed result differed from the hypothesized result by 2 %.

Reisberg, B. and Gauthier, S., International Psychogeriatrics, 20:1, 1-16, 2008..

59.33% 61.36%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

Percentage of Subjects

Declining at Follow-Up

Hypothesized Observed

Cross Sectional Studies

are

Beginning to Show Differences

between

SCI Subject Groups

and

Healthy, Non-SCI

as well as MCI

Subjects Groups

Prichep, et al., Neurobiology of Aging, 1994, 15: 85-90.

Physiologic Differences between GDS Stage 2 SCI Subjects

and

GDS Stage 1 Subjects with No Cognitive Impairment (NCI)

Physiologic ChangesHormonal

NCI vs SCI

↑ 12 hour urinary cortisol levels in SCI subjects

Wolf, et al., Neurobiol Aging, 2005; 26:1357-1363.

Brain Changes: Function Neurometabolism

NCI vs SCI

↓ metabolism:

parahippocampal gyrus

(bilaterally 18% reduction)

middle temporal gyrus

inferior parietal lobe

inferior frontal gyrus

fusiform gyrus

thalamus

right putamen

Mosconi, et al., Biological Psychiatry, 63: 609-18, 2008.

P<0.05 FWE correctedMosconi e al, Biol Psych 2008: 63:609-18.

Subjective Cognitive Impairment Hypometabolism in SCI, Mosconi, et al. Biological Psychiatry, 2008

middle-age NL with SCI (n=13) vs NCI (n=15)

n=15n=13

Prevalence of CSF Markers of AD Pathology:* Percentage of Subjects with an AD Type CSF profilea

aThe CSF AD profile was defined as a score < 1 calculated with the formula:

Aβ42/(240+[1.18 x T-tau])

*Visser, Verhey, Knol, et al., Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA

study: a prospective cohort study, Lancet Neurology, 8, 619-627, 2009.

SCI vs NCIPrognostic Group Differences

Prediction of Dementia: Other Studies

St. John and Montgomery

International Journal of Geriatric Psychiatry, 2002.

After adjusting for age, gender, and depressive symptoms

→ SCI predicted dementia

15% developed dementia in 5 yrs.

After adjusting for mental status assessment scores,

→ SCI did not predict

dementia

SCI vs NCIPrognostic Group Differences

Prediction of Dementia: Negative Studies

Wang, et al., Journal of the American Geriatrics Society, 2000 3 yr study All persons ≥ 65 in a Chinese rural population

→ Subjective complaints subjects had ↓ cognitive performance at baseline

→ Subjective memory complaints did not predict faster cognitive decline or dementia

Subjects

Consecutive series

Healthy subjects, GDS stage 1 or 2

≥ 40 years of age

Presenting to the NYU ADRC

between 1-1-1984 and 12-31-1997

(14 year window)

Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

N = 260

NCI (GDS stage 1) n = 60

SCI (GDS stage 2) n = 200

Subjects were scheduled for F/U at ~ 2 yr intervals

Analysis cut off date: 12-31-2001

(18 years after the baseline)


Outcome:

Stable: if subject remained normal and had not declined to MCI or dementia over the

F/U observation period

Decline: if the subject declined to MCI or dementia; the first observation period of decline

was

used for time to decline Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

Results

Follow-up was completed in 213 subjects (81.9%)

Lost to follow-up:

NCI n = 13 SCI n = 34 N.S. stage, age or MMSE; Education, p = .02; Gender, more men lost to F/U, p = 0.05


Characteristics of Subjects Followed

NCI SCI (GDS Stage 1) (GDS Stage 2)

n = 47 n = 166

Age 64 68*MMSE 29.6 29.0***Hamilton 3.1 4.4*

* p < 0.05, *** p < 0.001Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

Characteristics of Subjects Followed

No significant difference at baseline in:

Gender: Majority > 60% female

Education: Mean: 16 years

Any psychometric test or PDS


NCI SCI

(GDS Stage 1) (GDS Stage 2)

Time in study: 6.7 yrs 6.8 yrs


Outcome

NCI SCI (GDS Stage 1) (GDS Stage 2) n=47 n=166

Progressed Stable % Progressed Stable % 7 40 15% 90 76

54%****

Differences between the groups in outcome were significant P < 0.0001 Fisher’s exact testReisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and

without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

Mean Time to Decline

NCI SCI (GDS Stage 1) (GDS Stage 2) 8.8 years 5.3 years

Savage two sample test for event time, p = 0.0003


Survival AnalysisWeibull Proportional Hazards Model

Controlling for: Age Gender Education Level Follow-up time

The hazard ratio of SCI subjects 4.5 times the risk of decline

as NCI subjects

(95% Confidence limits, 1.9 to 10.3)Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

Survival Analysis: Kaplan-Meier Method


Conclusion

SCI is a condition in which:

(1) Persons score in the normal range on tests, but complain of impairment

(2) SCI persons have a ~ 4.5 x greater risk of decline to MCI or dementia than same gender, similarly aged and educated, non-SCI persons


Conclusions Continued


(1) Persons declined more rapidly at 60% of the rate of NCI persons

(2) SCI persons declined sooner Mean decline time was 3.5 years longer for NCI


Accelerated Failure Time Model Analysis

Controlling for:

Baseline group

Age

Gender

Education level

Follow-up time


Baseline variables contributing significantly to the

time to decline:

MMSE p=0.05

BCRS (I-V) Total Score p<0.01

BCRS Axis 1

(Concentration &

Calculation) p<0.01

BCRS Axis 5

(Functioning) p<0.05



time to decline:

Hamilton - Item 8 p<0.05(Slowness of thought and speech

and/or impaired concentration &

decreased motor activity)

Hamilton - Item 11

Somatic Anxiety p<0.01



time to decline:

Psychometric Deterioration Score

(Composite of 9 tests) p<0.0001

Seven of 9 individual test variables p<0.05

Reisberg, Shulman, Torossian et al., Outcome over seven years of healthy adults with and without

subjective cognitive impairment, Alzheimer’s & Dementia, 6; 11-24, 2010.

SCI Subject Group

Baseline Variables Showing Significant Differences Between Stable and Decline Groups at Follow-up

Stable (n=76) Decline (n=90) P

Age 65.3 69.4 < 0.01

Education 16.2 15.1 < 0.01

MMSE 29.3 28.7 < 0.01

BCRS, Total score 8.5 9.3 < 0.01

BCRS Axis 1: Concentration and Calculation

2.0 2.4 < 0.001

BCRS Axis 5: Functioning

1.65 1.88 < 0.01


SCI Subject Group

Baseline Variables Showing Significant Difference Between Stable and Decline Groups at Follow-up

Behavior

Stable (n=76) Decline (n=90)

P

Hamilton – Item 10 (Tension, worry)

< 0.05


SCI Subject Group

Baseline Variables Showing Significant Difference Between Stable and Decline Groups at Follow-up

Behavior

Stable (n=76) Decline (n=90)

P

Hamilton – Item 10 (Tension, worry)

< 0.05


SCI Subject GroupBaseline Variables Showing Significant Differences Between

Stable and Decline Groups at Follow-up

Psychometric

Stable (n=76) Decline (n=90) PPsychometric Deterioration Score (PDS)

1.75 2.56 < 0.001

Paired Associates, Initial recall

5.22 4.17 < 0.01

Paired Associates, Delayed recall

5.66 4.47 < 0.01

Digit Span Forwards 7.26 6.58 < 0.001

Digit Span Reverse 5.86 5.12 0.001

DSST 54.6 48.8 < 0.01

WAIS Vocabulary 70.5 62.9 < 0.001


Conclusion


(1) Persons score in the normal range on tests, but complain of impairment

(2) SCI persons have a ~ 4.5 x greater risk of decline to MCI or dementia than same gender, similarly aged and educated, non-SCI persons

(3) Is accompanied by cognitive losses which are evident in aggregate but not in individual cases


Implications

for

AD Prevention

and

ADI Prevention Workgroup

We are now in a position to address

the prevention of AD

in persons with complaints

beginning >20 years

before dementia develops

Using some of the same measures

and kinds of measures

For example

MMSE,

BCRS, FAST

Psychometric measurements

as have been used in current medication approvals

for mild to severe AD

by worldwide regulatory agencies

78 y/o, MMSE = 26, 2009

JUNE 27, 2005

Agenda 3:00 PM Introduction to Workshop Barry Reisberg, M.D.

3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCPfunction influences the risk of cognitive decline

3:35 PM Current Knowledge of Methodologies for Barry Reisberg, M.D.Clinical Trials in Pre-MCI Persons with SubjectiveCognitive Impairment (SCI)

4:25 PM Discussion of Current Knowledge and Joel Sadavoy M.D., FRCPCMethodologies

4:35 PM Discussion of Clinical Instrumentation for Barry Reisberg, M.D.Subject Selection and Assessment

4:55 PM Subject Interview Workshop Faculty and Participants

5:25 PM Final Discussion Joel Sadavoy M.D., FRCPC

Documents

Agenda 3:00 PMIntroduction to Workshop Barry Reisberg, M.D. 3:05 PM Cognitive dynamics: how variability in brain Kenneth Rockwood M.D., FRCPC, FRCP function