Defining Mild Cognitive Impairment

Steven T.DeKosky, M.D.Director, Alzheimer’s Disease Research

CenterUniversity of Pittsburgh

Pittsburgh, PA

MCI Issues

• Mild Cognitive Impairment is a bad term• It is very non-specific and encourages

generalization to a variety of late life cognitive disturbances

• MCI can be a useful concept if carefully defined

• MCI is a risk staterisk state for the development of dementia of the Alzheimer type

Mild Cognitive Impairment:The University of Pittsburgh ADRC

Experience• Two definitions of MCI

– “MCI-amnestic”: Isolated amnestic disorder (CDR 0.5); “Morris/Petersen definition”

– “MCI-other”: deficits in two or more areas of cognition > 1.5 standard deviations below the mean,controlling for age and education

• What is the outcome for these cases in a specialty clinic population?

Time to dementia in MCI patients

A B

A=MCI-amnesticB=MCI-multiple cognitive domains

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ive

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0

.2

.4

.6

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0 12 24 36 48 60 72 84 96 108 120 132 144Time in Months

How early does the cholinergic enzyme loss occur in AD?

• Early studies (1970’s, 1980’s) revealed severe loss of ChAT enzyme activity

• Davis (1999): no loss of ChAT activity in cortical regions in MCI (CDR = 0.5) and ‘mild AD’ as determined by postmortem CDR

• Tiraboschi et al. (2000) similar findings, studied frontal lobe only

• Levey and colleagues: little or no loss of basal forebrain cholinergic neurons in MCI

• DeKosky (2001) preservation of cortical and hippocampal ChAT in MCI and mild AD

• So early symptoms of AD might not be caused by cholinergic enzyme deficits, though cholinergic dysfunction is present

Pathological Confirmation

• Davis (retrospective study) approximately 60% of MCI (CDR 0.5) had evidence of AD at autopsy

• DeKosky et al. (prospective study) approximately 60% of MCI cases (defined by Z scores for the population) had evidence of AD at autopsy

• Other studies (Petersen, Morris) 60% or higher

MCI Issues

• Can MCI be defined clearly in a clinical setting?– Yes, but it requires careful examination and

neuropsychological testing and/or a reliable informant

• Are there valid criteria for the diagnosis of MCI?– Yes, at least amnestic MCI, in a specialty clinic, has

predictive validity. Still some uncertainty about the underlying pathology

– Hippocampal atrophy is the best structural predictor

MCI Issues

• Can MCI be distinguished from AD and other causes of dementia?– Neuropsychological definitions requiring 2

impaired areas of cognition allow separation– The difference may be quantitative rather

than qualitative– Amnestic MCI cannot be distinguished from

hippocampal sclerosis (low frequency, but can present exactly like amnestic MCI)

MCI Issues

• Should clinical drug trials in MCI incorporate any special features in their design?– Comparison of amnestic MCI to generalized MCI– Must find a way to diagnose in the absence of

an observant informant– Confirmation of hippocampal atrophy, other

diffuse atrophy– Search for other biomarkers (APOE4, serum

beta amyloid, etc.)– Disorder unlikely to be diagnosed quickly in a

primary care setting with current techniques

MCI Issues

• What outcome measures are appropriate to use in MCI trials?– Improvement in memory function– Improvement in global cognitive

function (if MCI-other is definition)– Delayed entry to a diagnosis of AD

(decline in cognitive function in a second domain)

– Differential loss of iADLs (functional measure)

MCI Studies: Conversion to AD Class I Studies

Rochester, MN 4 years, E4, Memory,MRI (Petersen) 12%/year volume of hippocampus

Toronto 29/107 in 2 years memory, E4 only with

(Tierney) 13.5%/year memory

New York 75 Ss, 2.5 years delayed recall,

(Devanand) 16.5%/year other neuropsychological measures