Brain Atrophy Does Not Predict Clinical Progression in Progressive Supranuclear Palsy

Abstract

Background: Clinical progression rate is the typical primary endpoint measure in progressive supranuclear palsy (PSP) clinical trials.

Objectives: This longitudinal multicohort study investigated whether baseline clinical severity and regional brain atrophy could predict clinical progression in PSP-Richardson's syndrome (PSP-RS).

Methods: PSP-RS patients (n = 309) from the placebo arms of clinical trials (NCT03068468, NCT01110720, NCT02985879, NCT01049399) and DescribePSP cohort were included. We investigated associations of baseline clinical and volumetric magnetic resonance imaging (MRI) data with 1-year longitudinal PSP rating scale (PSPRS) change. Machine learning (ML) models were tested to predict individual clinical trajectories.

Results: PSP-RS patients showed a mean PSPRS score increase of 10.3 points/yr. The frontal lobe volume showed the strongest association with subsequent clinical progression (β: -0.34, P < 0.001). However, ML models did not accurately predict individual progression rates (R² <0.15).

Conclusions: Baseline clinical severity and brain atrophy could not predict individual clinical progression, suggesting no need for MRI-based stratification of patients in future PSP trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: atlas‐based volumetry; clinical trials; outcome; progression; progressive supranuclear palsy.

FIG. 1

The figure shows baseline regional volumes of cortical and subcortical structures associated with future 1‐year clinical progression rate as measured by the annualized absolute change in the PSP rating scale total score. All associations are shown on the left (A), whereas only significant associations with false discovery rate (FDR)‐adjusted P‐value <0.05 are shown on the right (B). The color scale represents the association strength as measured by the linear regression‐derived β value, with shades of red for negative associations (lower volume associated with faster progression) and shades of blue for positive associations (larger volume associated with faster progression). All models also included age and sex as follows: (annualized absolute change in the PSP rating scale ~ regional volume + age + sex). Please note that some structures (ie, cerebellar peduncles) are not shown in the figure; full data are shown in the tables. [Color figure can be viewed at wileyonlinelibrary.com]