Automated Magnetic Resonance Volumetry to Measure Multiple System Atrophy Disease Progression in Clinical Trials

Background Recent studies have reported longitudinal brain atrophy in multiple system atrophy (MSA) in relatively small patient cohorts. Objective To compare longitudinal regional brain volume and clinical changes as endpoint measures for MSA clinical trials. Methods MSA patients with 1‐year longitudinal brain magnetic resonance imaging (MRI) were selected from the placebo arm of the M‐STAR Study (NCT03952806) and stratified into MSA‐cerebellar (MSA‐C) and MSA‐parkinsonism (MSA‐P) subtypes. A multisite healthy control (HC) cohort from international datasets was included for comparison. Baseline and longitudinal atrophy were assessed through automated MRI volumetry. Standardized longitudinal effect size values with 95% confidence intervals (CIs) and sample sizes required to detect treatment effect were estimated for 42 individual regional brain volumes, four combined volumetric indexes, nine clinical scales, and serum neurofilament light chain. Results The final study cohort included 129 MSA patients (76 MSA‐C, 53 MSA‐P) and 184 HC. The most atrophic structures at baseline were infratentorial regions in MSA‐C and putamen in MSA‐P. In both subtypes, infratentorial structures showed the largest longitudinal volume loss compared with HC. The annualized change of a cerebellum‐pons‐putamen volumetric index was the most powerful progression biomarker in MSA patients (effect size: −1.81 [95% CI: −2.14, −1.55]) and in both subtypes (MSA‐C: −2.04 [95% CI: −2.58, −1.68], MSA‐P: −1.55 [95% CI: −2.08, −1.22]), requiring the lowest sample size per arm (MSA, N = 55 to detect 30% treatment effect), and outperforming clinical measures (−59.6% patients required per arm). Conclusion These findings support longitudinal MRI‐derived regional atrophy rates as sensitive imaging endpoints to assess treatment efficacy in MSA clinical trials.