Defining Mild Cognitive Impairment

1. Defining Mild Cognitive Impairment Steven T.DeKosky, M.D. Director, Alzheimer’s Disease Research Center University of Pittsburgh Pittsburgh, PA

2. 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 state for the development of dementia of the Alzheimer type

3. 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?

4. Time to dementia in MCI patients 1.2 1.0 A=MCI-amnestic B=MCI-multiple cognitive domains .8 Cumulative Survival .6 .4 B A .2 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Time in Months

5. 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

6. 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

7. 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

8. 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)

9. 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

10. 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)

12. MCI Studies: Conversion to AD Class I Studies Rochester, MN 4 years, E4, Memory,MRI (Petersen) 12%/yearvolume ofhippocampus 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