Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials

Background
Several MRI measures and staging systems have been proposed as biomarkers of disease progression in progressive supranuclear palsy (PSP).

Objective
To compare structural MRI measures and staging systems for tracking brain atrophy progression in PSP and to estimate sample sizes needed for their use as clinical trial endpoints.

Methods
Patients with progressive supranuclear palsy–Richardson’s syndrome (PSP-RS) and one-year longitudinal MRI were selected from placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort comprised patients from NCT03068468, while other sources formed the validation cohort. Age-matched healthy controls (HC) from multiple sites were included. MRI measures included automated atlas-based volumetry of 44 regions, automated planimetric brainstem measures, and four previously described staging systems applied to volumetric data.

Results
A total of 508 participants were analyzed, including 226 PSP patients (discovery: n = 121; validation: n = 105) and 251 HC. In PSP patients, the annualized percentage change in brainstem and midbrain volumes, as well as a combined index incorporating midbrain, frontal lobe, and third ventricle volume changes, showed the largest effect sizes in both cohorts (discovery >1.6; validation >1.3). These measures required the smallest sample sizes (n < 100) to detect a 30% reduction in atrophy progression, outperforming other volumetric, planimetric, and staging-based measures.

Conclusions
Automated atlas-based volumetric MRI measures may be optimal imaging endpoints for PSP clinical trials, allowing detection of treatment effects on brain atrophy with smaller sample sizes than staging systems or planimetric approaches.

Rights

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