Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration.
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García-Castro Jesús, VandeVrede Lawren, Donohue Michael C, Vaqué-Alcázar Lídia, Rubio-Guerra Sara, Selma-González Judit, Heuer Hilary W, Morcillo-Nieto Alejandra O, Franquesa María, Dols-Icardo Oriol, Bejanin Alexandre, Belbin Olivia, Fortea Juan, Alcolea Daniel, Carmona-Iragui Maria, Abdelnour Carla, Barroeta Isabel, Santos-Santos Miguel, Sánchez Saudinós María Belen, Sala Isabel, Lleó Alberto, Gorno-Tempini Maria Luisa, Mandelli Maria Luisa, Raman Rema, Wills Anne-Marie A, Barragan Eden, Litvan Irene, Boeve Brad, Dickerson Brad, Grossman Murray, Huey Edward D, Irwin David J, Pantelyat Alex, Tartaglia Carmela, Rojas Julio C, Boxer Adam L, Illán-Gala Ignacio, Four Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators
Аннотация
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.