MILD COGNITIVE IMPAIRMENT UNRESOLVED ISSUES

1. MILD COGNITIVE IMPAIRMENTUNRESOLVED ISSUES Ronald C. Petersen Mayo Clinic Rochester, MN

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

3. Normal Mild Cognitive Impairment Dementia Cognitive Continuum CP926864- 9

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

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

6. MILD COGNITIVE IMPAIRMENTCRITERIA • Memory complaint • Normal general cognitive function • Normal activities of daily living • Memory impaired for age • Not demented

7. 30 110 105 100 20 95 90 10 85 80 0 75 16 18 16 14 14 12 12 10 10 8 8 6 6 4 4 2 2 0 0 MMSE Full Scale IQ Logical Memory II Visual Reproductions II Controls MCI AD AD CDR 0 0.5 0.5 1 Controls MCI AD AD CDR 0 0.5 0.5 1 CP926864- 3

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

9. 100 100 90 90 80 80 70 70 60 60 50 50 MCI AD Controls AD Mild Cognitive Impairment (MCI) MCI ® AD 12%/yr Control ® AD 1-2%/yr Initial 12 24 36 48 Initial 12 24 36 48 exam exam Months Months Petersen RC et al: Arch Neurol 56:303-308, 1999 CP926864- 12

10. Mild Cognitive Impairment Stable (%) Years CP926864- 7

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

12. PREDICTORS OF CONVERSION • Clinical features • Memory performance • Apolipoprotein E • Neuroimaging

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

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

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

16. Proposed Sequence of Biochemical Progression in the Posterior cingulate VOI Control MCI AD  MI  NAA  MI

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

18. Normal MCI AD CDR 0.5 2 3 GDS Mild Cognitive ImpairmentCDR and GDS CP926864- 5

19. CDR (SOBox) Norm 0.01 MCI 1.07 AD (.5) 2.71 GDS Norm 1.12 MCI 2.69 AD (.5) 3.37 CDR and GDS (means)

20. REFERENCE GROUPS • YOUNG NORMALS • CHANGE IN PERFORMANCE • AGE-APPROPRIATE NORMALS • CONTAMINATION

21. SOURCE OF SUBJECTS • REFERRAL CLINICS • ADVERTISING • GENERAL PRACTICE CLINICS

22. CLINICAL HETEROGENEITY

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

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

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

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

27. Normal Mild Cognitive Impairment Dementia Cognitive Continuum CP926864- 9

28. 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 MAYO ALZHEIMER’S DISEASE RESEARCH CENTER