MILD COGNITIVE IMPAIRMENT UNRESOLVED ISSUES

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MILD COGNITIVE IMPAIRMENTUNRESOLVED 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
CP926864- 9
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Function
Age
CP926864- 1
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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 IMPAIRMENTCRITERIA

• Memory complaint
• Normal general cognitive function
• Normal activities of daily living
• Memory impaired for age
• Not demented

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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
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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
Initial
12
24
36
48
Initial
12
24
36
48
exam
exam
Months
Months
Petersen RC et al Arch Neurol 56303-308, 1999
CP926864- 12
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Mild Cognitive Impairment
Stable ()
Years
CP926864- 7
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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
CP926864- 13
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NEUROIMAGING

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

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Stable ()
Years
CP926864- 15
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Proposed Sequence of Biochemical Progression in
the Posterior cingulate VOI
Control
MCI
AD
?? MI ? NAA
? MI
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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 ImpairmentCDR and GDS
CP926864- 5
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CDR and GDS (means)

• CDR (SOBox)
• Norm 0.01
• MCI 1.07
• AD (.5) 2.71

• GDS
• Norm 1.12
• MCI 2.69
• AD (.5) 3.37

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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 ALZHEIMERS DISEASE
  AND OTHER FORMS OF DEMENTIA?

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Mild cognitive impairment Amnestic
Mild cognitive impairment Multiple
domains slightly impaired
Mild cognitive impairment Single non- memory
domain
CP938653 - 24
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SEMANTIC ISSUES

• NORMAL AGING
• THIS IS ALZHEIMERS 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
CP926864- 9
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MAYO ALZHEIMERS DISEASE RESEARCH CENTER

• ROCHESTER
• Emre Kokmen
• Brad Boeve
• Eric Tangalos
• Joe Parisi
• Cliff Jack
• Walter Rocca
• Bob Ivnik
• Glenn Smith
• Steve Edland
• Peter OBrien

• JACKSONVILLE
• Steve Younkin
• John Hardy
• Dennis Dickson
• Neill Graff-Radford
• Shu-Hui Yen
• Todd Golde
• Mike Hutton
• John Lucas
• Tanis Ferman