MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD

作者：Clifford R. Jack, Mary Slomkowski, S. Gracon, Toni M. Hoover, Joel P. Felmlee, Keith Stewart, Yun Xu, Maria S. Shiung, Peter C. O’Brien, Ruitao Cha, David S. Knopman, Ronald Carl Petersen · 发表于：Neurology · 年份：2003 · DOI：10.1212/01.wnl.0000042480.86872.03 · 被引用次数：298 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Attention Deficit Hyperactivity Disorder、Neurotransmitter Receptor Influence on Behavior

OBJECTIVE: To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD. METHODS: A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans. RESULTS: The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status E...