Mellow Subjective Debilitation as an Objective for Medication Improvement.


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. . . . . . . . . . . . . . . . . . . Maturing, AAMI (ARCD), MCI, and AD. Psychological Performance. Recurrence. Youthful. Adjusted from Ferris and Kluger. Maturing, Neuropsychology and Cognition, 1996.. Elderly. 1 SD. . A. . B. . Notice. MCI. AAMI. . . Longitudinal Course of MCI. . . . . . AAMI/ARCD. MCI. Advertisement. . . Age.
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Slide 1

Gentle 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

Slide 2

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

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

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Syndrome of Mild Cognitive Impairment (MCI) Mild subjective decay that is more regrettable than normal for age yet less serious than in dementia (Flicker, et al, 1991) Mild Impairment includes memory and by and large other psychological areas that are more debilitated in dementia Common exercises of day by day living (ADL) are in place, however there might be unobtrusive disability in extremely complex ADL Often an early phase of dementia (most in the end advance to dementia, 10 - 15% every year, 80% more than 10 years) When chosen utilizing "Advertisement" incorporation/prohibition criteria, cases by and large have prodromal AD (80% have hippocampal decay, 75% have AD neuropathology at dissection)

Slide 5

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

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Heterogeneous Syndrome versus Particular Disease Normal MCI Dementia Aging Normal MCI of Alzheimer\'s Aging AD Type Disease Syndrome Disease

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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 Mixed

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Clinical Criteria for MCI of AD Type Mild intellectual decay reported by subject or witness Globally, GDS = 3 or CDR = 0.5 Memory hindrance affirmed impartially Cognitive and ADL disability is deficient for determination of dementia Inclusion and prohibition criteria for AD, with the exception of seriousness of psychological and ADL impedance

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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

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Neuropsychologic Prediction of Decline to Dementia* Negative Predictive Value Positive Predictive Value Study (Nondemented test) N (% decrease) 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-hindered) (23.6%) Devanand et al, 1997 75 76.9% 81.0% 83.3% 73.9% (Memory center 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 facility based) (34.7%) 179 ��  96.8% 89.3% 95.2% 92.6% (31.3%) *N = >75. ��  Decline to AD.

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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 gathering (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 interim first in every one of the three stages, next consecutively compelling in training and afterward GDS, lastly considering the conceivable stepwise passage of the psychometric factors. 1 Kluger, Ferris, Golomb et al, J. of Geriatric Psychiatry and Neurology , 1999

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

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

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MCI Trials As a Bridge to Prevention Primary anticipation trials require expansive specimens and long treatment spans because of low yearly rate of transformation to AD Study MCI instead of typical elderly, since transformation rates are high (study length 2-3 years, N < 1000) Disease movement ponder as opposed to p rimary counteractive action (most as of now have prodromal AD) Outcome: Time to clinical determination of AD or rate of intellectual decrease May be frustrated by "symptomatic" impacts May be verified by impact on MRI decay

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Memory Screening in MCI Trials Objective affirmation of gentle memory weakness Increase extent of cases with prodromal AD Enrich think about populace for transformation to AD

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Increasing MCI to AD Conversion Rate with Memory Impairment Criteria* 100 Memory above cutoff 90 80 70 Proportion Free of Dementia (AD) 60 50 40 Memory beneath cutoff 30 20 10 0 2.5 3.5 0.0 0.5 1.0 1.5 2.0 3.0 *Grundman-ADCS pooled information: Logical Memory II cutoff scores Follow-up Time (Years)

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

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Outcome Measures for MCI Trials Conversion to AD (survival outline) Traditional AD result areas Cognitive function – Global status or change Functioning (ADL) – Behavior Quality of Life – Pharmacoeconomics MRI decay entire mind or hippocampal volume as of now best biomarker for supporting ailment movement guarantee

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Special Requirements for MCI Outcome Measures Cognitive battery must be touchy to exceptionally mellow impedances (ADAS-machine gear-piece is not ideal) Global and ADL instruments must be delicate to unobtrusive hindrances in complex exercises Depression is the most significant behavioral space Suitable instruments have been created and are being utilized as a part of ebb and flow MCI trials

Slide 20

Conclusions MCI is a heterogeneous disorder Homogeneous gatherings speaking to prodromal AD or different subtypes can be recognized MCI trials can look at ailment movement and give a scaffold to avoidance Suitable result measures for MCI trials are accessible Labeling for particular prodromal dementias (e.g., MCI of the AD sort) is fitting

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