journal articles
POTENTIAL ROLE OF MRI TO OPTIMIZE CLINICAL TRIAL DESIGN FOR PROGRESSIVE SUPRANUCLEAR PALSY AND CORTICOBASAL DEGENERATION
Jesús García-Castro, Lawren VandeVrede, Michael C. Donohue, Lídia Vaqué-Alcázar, Sara Rubio-Guerra, Judit Selma-González, Hilary W. Heuer, Alejandra O. Morcillo-Nieto, María Franquesa, Oriol Dols-Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona-Iragui, Carla Abdelnour, Isabel Barroeta, Miguel Santos-Santos, María Belen Sánchez Saudinós, Isabel Sala, Alberto Lleó, Maria Luisa Gorno-Tempini, Maria Luisa Mandelli, Rema Raman, Anne-Marie A Wills, Eden Barragan, Irene Litvan, Brad Boeve, Brad Dickerson, Murray Grossman, Edward D. Huey, David J. Irwin, Alex Pantelyat, Carmela Tartaglia, Julio C. Rojas, Adam L. Boxer, Ignacio Illán-Gala, on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators
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.
CITATION:
Jesús García-Castro ; Lawren VandeVrede ; Michael C. Donohue ; Lídia Vaqué-Alcázar ; Sara Rubio-Guerra ; Judit Selma-González ; Hilary W. Heuer ; Alejandra O. Morcillo-Nieto ; María Franquesa ; Oriol Dols-Icardo ; Alexandre Bejanin ; Olivia Belbin ; Juan Fortea ; Daniel Alcolea ; Maria Carmona-Iragui ; Carla Abdelnour ; Isabel Barroeta ; Miguel Santos-Santos ; María Belen Sánchez Saudinós ; Isabel Sala ; Alberto Lleó ; Maria Luisa Gorno-Tempini ; Maria Luisa Mandelli ; Rema Raman ; Anne-Marie A Wills ; Eden Barragan ; Irene Litvan ; Brad Boeve ; Brad Dickerson ; Murray Grossman ; Edward D. Huey ; David J. Irwin ; Alex Pantelyat ; Carmela Tartaglia ; Julio C. Rojas ; Adam L. Boxer ; Ignacio Illán-Gala ; on behalf of theFour Repeat Tau Neuroimaging Initiative (4RTNI) and the AL108-231 Investigators (2026): Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration. The Journal of Prevention of Alzheimer’s Disease (JPAD). https://doi.org/10.1016/j.tjpad.2026.100486