Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration

J Prev Alzheimers Dis. 2026 Mar;13(3):100486. doi: 10.1016/j.tjpad.2026.100486. Epub 2026 Jan 24.

Abstract

Background: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4-repeat tauopathies (4RT) presenting with overlapping syndromes. Imperfect clinicopathological associations increase sample-size demands in clinical trials. We test whether MRI can enrich trials for PSP/CBD and provide sensitive MRI-based outcome measures.

Methods: Longitudinal cohort analysis including participants from the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) and phase 2/3 Davunetide trial (DAV). An MRI model trained on autopsy-confirmed cases predicted PSP (MRI-PSP) or CBD (MRI-CBD); corticobasal syndrome (CBS) with positive Alzheimer's biomarkers was reclassified. Clinical scales and MRI-derived thickness/volume were analyzed with linear mixed-effects models. We derived data-driven MRI-signatures (optimal regional combinations) to minimize required trial sample sizes.

Results: 206 participants from 4RTNI (n = 106 with Richardson's syndrome [RS], CBS, or nonfluent/agrammatic primary progressive aphasia [nfvPPA]) and DAV (n = 100 with RS). In 4RTNI, 49 participants were predicted MRI-PSP and 43 MRI-CBD. 76% of MRI-PSP had RS, 24% had CBS/nfvPPA; 66% of MRI-CBD had CBS. PSP and CBD signatures shared midbrain/pontine atrophy but differed in cortical involvement. PSP signature correlated strongly with 12-month change on the PSP Rating Scale (β = -0.59, p < 0.001). MRI-based signatures reduced the estimated sample sizes required to detect 30% reduction in progression over 12-months by 50% for MRI-PSP and 87% for MRI-CBD, compared with clinical outcomes. In DAV, feasibility was replicated.

Conclusion: MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT.

Keywords: Biomarkers; Corticobasal degeneration; Magnetic resonance imaging; Progressive supanuclear palsy; Tauopathy.

MeSH terms

  • Aged
  • Corticobasal Degeneration* / diagnostic imaging
  • Corticobasal Degeneration* / drug therapy
  • Corticobasal Degeneration* / pathology
  • Female
  • Humans
  • Longitudinal Studies
  • Magnetic Resonance Imaging* / methods
  • Male
  • Neuroimaging
  • Research Design*
  • Supranuclear Palsy, Progressive* / diagnostic imaging
  • Supranuclear Palsy, Progressive* / drug therapy
  • Supranuclear Palsy, Progressive* / pathology