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Mild Cognitive Impairment as a Target for Drug Development

Mild Cognitive Impairment as a Target for Drug Development. Steven H. Ferris, Ph.D. Silberstein Aging and Dementia Research Center New York University School of Medicine. Aging, AAMI (ARCD), MCI, and AD. 1 SD. Elderly. Young. Frequency. A. B. AD. MCI. AAMI. Cognitive Performance.

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Mild Cognitive Impairment as a Target for Drug Development

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  1. Mild Cognitive Impairment as a Target for Drug Development Steven H. Ferris, Ph.D. Silberstein Aging and Dementia Research Center New York University School of Medicine

  2. Aging, AAMI (ARCD), MCI, and AD 1 SD Elderly Young Frequency A B AD MCI AAMI Cognitive Performance Adapted from Ferris and Kluger. Aging, Neuropsychology and Cognition, 1996.

  3. Longitudinal Course of MCI AAMI / ARCD MCI Cognitive Decline AD Age

  4. Syndrome of Mild Cognitive Impairment (MCI) • Mild cognitive decline that isworse than typical for age but less severe than in dementia (Flicker, et al, 1991) • Mild Impairment involves memory and generally other cognitive domains that are more impaired in dementia • Common activities of daily living (ADL) are intact, but there may be subtle impairment in very complex ADL • Often a very early stage of dementia(most eventually progress to dementia, 10 - 15% per year, 80% over 10 years) • When selected using “AD” inclusion/exclusion criteria, cases generally have prodromal AD (80% have hippocampal atrophy, 75% have AD neuropathology at autopsy)

  5. Decline To Dementia Among Nondemented Elderly (N=213)1 *** 1Adapted from Kluger, Ferris, Golomb et al, J. of Geriatric Psychiatry and Neurology, 1999

  6. Heterogeneous Syndrome vs. Specific Disease Normal MCI Dementia Aging Normal MCI of Alzheimer’s Aging AD Type Disease Syndrome Disease

  7. MCI is Prodromal Dementia Brain Aging Normal Cognition Mild Cognitive Impairment Stable Or Reversible Impairment Prodromal Dementia Reversible Other Dementias Alzheimer’s Disease Vascular Dementia Dementia Mixed Mixed

  8. Clinical Criteria for MCI of AD Type • Mild cognitive decline reported by subject or informant • Globally, GDS = 3 or CDR = 0.5 • Memory impairment confirmed objectively • Cognitive and ADL impairment is insufficient for diagnosis of dementia • Inclusion and exclusion criteria for AD, except for severity of cognitive and ADL impairment

  9. 1.1 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 0 5 10 15 20 25 Conversion to AD in MCI Normal Group Proportion Remaining Nondemented MCI Group Years Since Baseline Evaluation

  10. Neuropsychologic Prediction of Decline to Dementia* Negative Predictive Value Positive Predictive Value Study (Nondemented sample) N (% decline) Specificity Sensitivity • Masur et al, 1994 317 94.0% 50.0% 88.1% 68.1% • (Community-based) (20.2%) • Tierney et al, 1996 123† 94.0% 76.0% — — • (Memory-impaired) (23.6%) • Devanand et al, 1997 75 76.9% 81.0% 83.3% 73.9% • (Memory clinic-based) (41.3%) • Dal Forno et al, 1995 196 — — 91.0% 62.0% • (Community-based) (12.2%) • Kluger, et al, 1999 213 91.4% 78.4% 88.8% 82.9% • (Research clinic-based) (34.7%) • 179† 96.8% 89.3% 95.2% 92.6% • (31.3%) *N = >75. †Decline to AD.

  11. Logistic Regression Analyses: Predicting Decline to AD (N = 179)1 Predictive Value (%) Order of Entry into Logistic Regression† Specificity (%) Sensitivity (%) Overall Accuracy Negative Positive 1. Education*** 89.4 41.1 74.3 76.9 63.9 2. GDS grouping (1, 2, or 3)*** 89.4 73.2 84.4 88.0 75.9 3. Psychometric tests (set of four): 96.8 89.3 94.4 95.2 92.6 (Paragraph Delayed Recall**, Paired Associate Initial Recall*; Digit Symbol*; and Digit Span Forward*) *p<0.05; **p<0.001; ***p<0.0001. †Forcing in age, sex, and follow-up interval first in all three steps, next sequentially forcing in education and then GDS, and finally allowing for the possible stepwise entry of the psychometric variables. 1Kluger, Ferris, Golomb et al, J. of Geriatric Psychiatry and Neurology, 1999

  12. 100 80 60 40 20 0 Predicting Decline from MCI to AD with Delayed Paragraph Recall (N=71) Accuracy of prediction % Specificity Sensitivity Overall accuracy >12 >11 >10 >9 >8 >7 >6 >5 >4 >3 >2 >1 >0 Cut Scores

  13. Regression of Delayed Recall on Hippocampal Size1 Residualized Delayed Recall (rDR) r = 0.49 Residualized Hippocampal size (rHF) 1Adapted from Golomb et al. Learning and Memory, 1994.

  14. MCI Trials As a Bridge to Prevention • Primary prevention trials require very large samples and long treatment durations due to low annual rate of conversion to AD • StudyMCI rather than normal elderly, since conversion rates are high (study duration 2-3 years, N < 1000) • Disease progression study rather than primary prevention (most already have prodromal AD) • Outcome: Time to clinical diagnosis of AD or rate of cognitive decline • May be confounded by “symptomatic” effects • May be corroborated by effect on MRI atrophy

  15. Memory Screening in MCI Trials • Objective confirmation of mild memory impairment • Increase proportion of cases with prodromal AD • Enrich study population for conversion to AD

  16. Increasing MCI to AD Conversion Rate with Memory Impairment Criteria* 100 Memory above cutoff 90 80 70 ProportionFree ofDementia(AD) 60 50 40 Memory below cutoff 30 20 10 0 2.5 3.5 0.0 0.5 1.0 1.5 2.0 3.0 *Grundman-ADCS pooled data: Logical Memory II cutoff scores Follow-up Time (Years)

  17. MCI Screening / Enrichment Tests • Rey Auditory Verbal Learning Test • WMS Logical Memory II • NYU Paragraph Recall Test • Buschke Cued Recall Selective Reminding Test

  18. Outcome Measures for MCI Trials • Conversion to AD (survival design) • Traditional AD outcome domains • Cognitive function – Global status or change • Functioning (ADL) – Behavior • Quality of Life – Pharmacoeconomics • MRI atrophy • whole brain or hippocampal volume • currently best biomarker for supporting disease progression claim

  19. Special Requirements for MCI Outcome Measures • Cognitive battery must be sensitive to very mild impairments (ADAS-cog is not optimal) • Global and ADL instruments must be sensitive to subtle impairments in complex activities • Depression is the most relevant behavioral domain • Suitable instruments have been developed and are being used in current MCI trials

  20. Conclusions • MCI is a heterogeneous syndrome • Homogeneous groups representing prodromal AD or other subtypes can be identified • MCI trials can examine disease progression and provide a bridge to prevention • Suitable outcome measures for MCI trials are available • Labeling for specific prodromal dementias (e.g., MCI of the AD type) is appropriate

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