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

Abstract

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 Examination 241; hippocampal volume 21; temporal horn volume 54.

Conclusion: The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

Figure 1. One year temporal horn enlargement

Coronal images obtained at base line (top panel) and 12.5 months later (from an 85 year old woman). The dramatic increase in size of the temporal horns in just over 12 months is visually apparent. The temporal horns increased in volume by 3416 mm³ (36.6%).

Figure 2. Annual change in ADAS-Cog vs. temporal horn

Scatter plot of the annualized percent change in ADAS-Cog score vs. annualized percent change in temporal horn volume.