Seeing with new eyes: finding a path to early intervention trials in Alzheimer's disease

Abstract

The clinical course of Alzheimer's Disease (AD) and other degenerative disorders affecting cognition can be visualized as a progression from normal cognition through the syndrome of Mild Cognitive Impairment (MCI) to dementia. The use of biomarker data can supplement clinical characterization and identification of MCI and dementia pathologies. Clinical staging algorithms that use both clinical and biomarker information can assist in the early identification of AD patients. A comprehensive outcome measure such as the Clinical Dementia Rating Sum of Boxes (CDR-SB), which has components that assess both cognitive and functional domains in parallel deserves consideration as a primary outcome measure for early AD clinical trials.

Figure 1

The one-year mean change from baseline for ADAS-Cog and CDR-SOB (1A), ADAS-Cog and FAQ (1B), and FAQ and. CDR-SOB (1C) in enriched vs. non-enriched MCI populations. Clinical and CSF biomarker data for MCI subjects in the ADNI database (accessed August 18, 2009) was used to identify 2 populations of subjects: an “enriched” (red dots) and “non-enriched” (blue dots). 2500 trial simulations were then run to compare outcomes on standard clinical measures in the two groups. Each simulation generates two plotted values on each graph; one red dot representing mean changes from baseline for two tests in the “enriched” group, and one blue dot representing the corresponding mean change pair for the “non-enriched group”.. The enrichment criteria used produced populations of patients that differed greatly in their progression rates, as demonstrated by the near complete segregation of blue and red dots.