A COMBINED MEASURE OF COGNITION AND FUNCTION FOR CLINICAL TRIALS: THE INTEGRATED ALZHEIMER’S DISEASE RATING SCALE (IADRS)

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer’s disease (AD) are needed. The integrated Alzheimer’s Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS – mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents

An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-beta concentrations collected by lumbar puncture and indwelling lumbar catheter

Contains fulltext : 154021.pdf (publisher's version ) (Open Access)INTRODUCTION: Amyloid-beta (Abeta) has been investigated as a diagnostic biomarker and therapeutic drug target. Recent studies found that cerebrospinal fluid (CSF) Abeta fluctuates over time, including as a diurnal pattern, and increases in absolute concentration with serial collection. It is currently unknown what effect differences in CSF collection methodology have on Abeta variability. In this study, we sought to determine the effect of different collection methodologies on the stability of CSF Abeta concentrations over time. METHODS: Grouped analysis of CSF Abeta levels from multiple industry and academic groups collected by either lumbar puncture (n=83) or indwelling lumbar catheter (n=178). Participants were either placebo or untreated subjects from clinical drug trials or observational studies. Participants had CSF collected by lumbar puncture or lumbar catheter for quantitation of Abeta concentration by enzyme linked immunosorbent assay. Data from all sponsors was converted to percent of the mean for Abeta40 and Abeta42 for comparison. Repeated measures analysis of variance was performed to assess for factors affecting the linear rise of Abeta concentrations over time. RESULTS: Analysis of studies collecting CSF via lumbar catheter revealed tremendous inter-subject variability of Abeta40 and Abeta42 as well as an Abeta diurnal pattern in all of the sponsors' studies. In contrast, Abeta concentrations from CSF samples collected at two time points by lumbar puncture showed no significant differences. Repeated measures analysis of variance found that only time and draw frequency were significantly associated with the slope of linear rise in Abeta40 and Abeta42 concentrations during the first 6 hours of collection. CONCLUSIONS: Based on our findings, we recommend minimizing the frequency of CSF draws in studies measuring Abeta levels and keeping the frequency standardized between experimental groups. The Abeta diurnal pattern was noted in all sponsors' studies and was not an artifact of study design. Averaging Abeta concentrations at each time point is recommended to minimize the effect of individual variability. Indwelling lumbar catheters are an invaluable research tool for following changes in CSF Abeta over 24-48 hours, but factors affecting Abeta concentration such as linear rise and diurnal variation need to be accounted for in planning study designs