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MILD COGNITIVE IMPAIRMENT UNRESOLVED ISSUES
Ronald C. Petersen Mayo Clinic Rochester, MN
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MILD COGNITIVE IMPAIRMENT
CONCEPTUAL OVERVIEW CLINICAL CRITERIA OUTCOME PREDICTORS OF PROGRESSION UNRESOLVED ISSUES
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Cognitive Continuum Normal Mild Cognitive Impairment Dementia
CP
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Function Age Mild cognitive impairment Probable AD Definite AD
CP
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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?
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MILD COGNITIVE IMPAIRMENT CRITERIA
Memory complaint Normal general cognitive function Normal activities of daily living Memory impaired for age Not demented
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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 Controls MCI AD AD CDR CP
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FDA QUESTION 4 WHAT OUTCOME MEASURES ARE APPROPRIATE TO USE IN CLINICAL DRUGS TRIALS OF MCI?
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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: , 1999 CP
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Mild Cognitive Impairment Stable (%) Years CP
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FDA QUESTION 5 SHOULD CLINICAL DRUG TRIALS IN MCI INCORPORATE ANY SPECIAL FEATURES IN THEIR DESIGN?
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PREDICTORS OF CONVERSION
Clinical features Memory performance Apolipoprotein E Neuroimaging
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MCI: Conversion to Dementia
APOE 4 noncarrier % APOE 4 carrier Years CP
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NEUROIMAGING Structural MRI Functional Imaging Hippocampus
Entorhinal cortex Functional Imaging MRS fMRI PET/SPECT
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W £ -2.5 -2.5 < W < 0 W ³ 0 Stable (%) Years CP
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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
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UNRESOLVED ISSUES CLINICAL CRITERIA-RATING SCALES REFERENCE GROUPS
SOURCE OF SUBJECTS CLINICAL HETEROGENEITY SEMANTIC ISSUES
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Mild Cognitive Impairment CDR and GDS
Normal MCI AD CDR 0.5 GDS 2 3 CP
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CDR and GDS (means) CDR (SOBox) Norm 0.01 MCI 1.07 AD (.5) 2.71 GDS
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REFERENCE GROUPS YOUNG NORMALS CHANGE IN PERFORMANCE
AGE-APPROPRIATE NORMALS CONTAMINATION
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SOURCE OF SUBJECTS REFERRAL CLINICS ADVERTISING
GENERAL PRACTICE CLINICS
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CLINICAL HETEROGENEITY
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FDA QUESTION 3 CAN MCI BE DISTINGUISHED FROM ALZHEIMER’S DISEASE AND OTHER FORMS OF DEMENTIA?
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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 CP
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SEMANTIC ISSUES NORMAL AGING THIS IS ALZHEIMER’S DISEASE
IS THIS A CONTINUUM? WILL NEUROPATHOLOGY ANSWER THE QUESTION?
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MCI CONCLUSIONS CLINICALLY RELEVANT CONCEPT CURRENTLY NOT CODIFIED
RELIABLE CRITERIA EXIST OUTCOME MEASURES KNOWN NOT NORMAL NOT DEMENTED THERAPEUTIC TARGET
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Cognitive Continuum Normal Mild Cognitive Impairment Dementia
CP
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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
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