MILD COGNITIVE IMPAIRMENT UNRESOLVED ISSUES Ronald C. Petersen Mayo Clinic Rochester, MN

MILD COGNITIVE IMPAIRMENT CONCEPTUAL OVERVIEW CLINICAL CRITERIA OUTCOME PREDICTORS OF PROGRESSION UNRESOLVED ISSUES

Cognitive Continuum Normal Mild Cognitive Impairment Dementia CP926864- 9

Function Age Mild cognitive impairment Probable AD Definite AD CP926864- 1

CAN MCI BE DEFINED IN A CLINICAL SETTING? FDA QUESTIONS 1 and 2 CAN MCI BE DEFINED IN A CLINICAL SETTING? ARE THERE VALID CRITERIA FOR THE DIAGNOSIS OF MCI?

MILD COGNITIVE IMPAIRMENT CRITERIA Memory complaint Normal general cognitive function Normal activities of daily living Memory impaired for age Not demented

Visual Reproductions II MMSE Full Scale IQ 10 20 30 75 80 85 90 95 100 105 110 Logical Memory II Visual Reproductions II 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16 18 Controls MCI AD AD CDR 0 0.5 0.5 1 Controls MCI AD AD CDR 0 0.5 0.5 1 CP926864- 3

FDA QUESTION 4 WHAT OUTCOME MEASURES ARE APPROPRIATE TO USE IN CLINICAL DRUGS TRIALS OF MCI?

Mild Cognitive Impairment (MCI) MCI ® AD 12%/yr Control ® AD 1-2%/yr 50 60 70 80 90 100 50 60 70 80 90 100 Initial 12 24 36 48 Initial 12 24 36 48 exam exam Months Months MCI AD Controls AD Petersen RC et al: Arch Neurol 56:303-308, 1999 CP926864- 12

Mild Cognitive Impairment Stable (%) Years CP926864- 7

FDA QUESTION 5 SHOULD CLINICAL DRUG TRIALS IN MCI INCORPORATE ANY SPECIAL FEATURES IN THEIR DESIGN?

PREDICTORS OF CONVERSION Clinical features Memory performance Apolipoprotein E Neuroimaging

MCI: Conversion to Dementia APOE 4 noncarrier % APOE 4 carrier Years CP926864- 13

NEUROIMAGING Structural MRI Functional Imaging Hippocampus Entorhinal cortex Functional Imaging MRS fMRI PET/SPECT

W £ -2.5 -2.5 < W < 0 W ³ 0 Stable (%) Years CP926864- 15

 MI  NAA  MI Control MCI AD Proposed Sequence of Biochemical Progression in the Posterior cingulate VOI Control MCI AD  MI  MI  NAA -Because MCI represents a transitional clinical state between cognitively normal elderly and AD patients, these results suggest that the increase in MI /Cr ratio precedes the decrease in NAA /Cr ratio

UNRESOLVED ISSUES CLINICAL CRITERIA-RATING SCALES REFERENCE GROUPS SOURCE OF SUBJECTS CLINICAL HETEROGENEITY SEMANTIC ISSUES

Mild Cognitive Impairment CDR and GDS Normal MCI AD CDR 0.5 GDS 2 3 CP926864- 5

CDR and GDS (means) CDR (SOBox) Norm 0.01 MCI 1.07 AD (.5) 2.71 GDS

REFERENCE GROUPS YOUNG NORMALS CHANGE IN PERFORMANCE AGE-APPROPRIATE NORMALS CONTAMINATION

SOURCE OF SUBJECTS REFERRAL CLINICS ADVERTISING GENERAL PRACTICE CLINICS

CLINICAL HETEROGENEITY

FDA QUESTION 3 CAN MCI BE DISTINGUISHED FROM ALZHEIMER’S DISEASE AND OTHER FORMS OF DEMENTIA?

Mild cognitive impairment Mild cognitive impairment Mild cognitive Amnestic Alzheimer’s disease Mild cognitive impairment Multiple domains slightly impaired Alzheimer’s disease ? normal aging Frontotemporal dementia Lewy body dementia Primary progressive aphasia Parkinson’s disease Alzheimer’s disease Mild cognitive impairment Single non- memory domain CP938653 - 24

SEMANTIC ISSUES NORMAL AGING THIS IS ALZHEIMER’S DISEASE IS THIS A CONTINUUM? WILL NEUROPATHOLOGY ANSWER THE QUESTION?

MCI CONCLUSIONS CLINICALLY RELEVANT CONCEPT CURRENTLY NOT CODIFIED RELIABLE CRITERIA EXIST OUTCOME MEASURES KNOWN NOT NORMAL NOT DEMENTED THERAPEUTIC TARGET

Cognitive Continuum Normal Mild Cognitive Impairment Dementia CP926864- 9

MAYO ALZHEIMER’S DISEASE RESEARCH CENTER ROCHESTER Emre Kokmen Brad Boeve Eric Tangalos Joe Parisi Cliff Jack Walter Rocca Bob Ivnik Glenn Smith Steve Edland Peter O’Brien JACKSONVILLE Steve Younkin John Hardy Dennis Dickson Neill Graff-Radford Shu-Hui Yen Todd Golde Mike Hutton John Lucas Tanis Ferman