Shubir Dutt1, Richard J Binney1, Hilary W Heuer1, Phi Luong1, Suneth Attygalle1, Priyanka Bhatt1, Gabe A Marx1, Jonathan Elofson1, Maria C Tartaglia1, Irene Litvan1, Scott M McGinnis1, Bradford C Dickerson1, John Kornak1, Dana Waltzman1, Lisa Voltarelli1, Norbert Schuff1, Gil D Rabinovici1, Joel H Kramer1, Clifford R Jack1, Bruce L Miller1, Howard J Rosen1, Adam L Boxer2. 1. Department of Neurology (S.D., R.J.B., H.W.H., P.L., S.A., P.B., G.A.M., J.E., D.W., L.V., G.D.R., J.H.K., B.L.M., H.J.R., A.L.B.), University of California, San Francisco, Memory and Aging Center; Department of Communication Sciences & Disorders (R.J.B.), Saffran Center for Cognitive Neuroscience, Temple University, Philadelphia, PA; Tanz Centre for Research in Neurodegenerative Disease (M.C.T.), University of Toronto, Canada; Department of Neurosciences (I.L.), University of California, San Diego, La Jolla, CA; Gerontology Research Unit (S.M.M., B.C.D.), Massachusetts General Hospital, Harvard Medical School, Charlestown, MA; Departments of Epidemiology & Biostatistics (J.K.) and Radiology (N.S.), University of California, San Francisco; Department of Psychiatry and Behavioral Sciences (D.W.), Stanford University, CA; Department of Radiology (C.R.J.), Mayo Clinic, Rochester, MN. 2. Department of Neurology (S.D., R.J.B., H.W.H., P.L., S.A., P.B., G.A.M., J.E., D.W., L.V., G.D.R., J.H.K., B.L.M., H.J.R., A.L.B.), University of California, San Francisco, Memory and Aging Center; Department of Communication Sciences & Disorders (R.J.B.), Saffran Center for Cognitive Neuroscience, Temple University, Philadelphia, PA; Tanz Centre for Research in Neurodegenerative Disease (M.C.T.), University of Toronto, Canada; Department of Neurosciences (I.L.), University of California, San Diego, La Jolla, CA; Gerontology Research Unit (S.M.M., B.C.D.), Massachusetts General Hospital, Harvard Medical School, Charlestown, MA; Departments of Epidemiology & Biostatistics (J.K.) and Radiology (N.S.), University of California, San Francisco; Department of Psychiatry and Behavioral Sciences (D.W.), Stanford University, CA; Department of Radiology (C.R.J.), Mayo Clinic, Rochester, MN. adam.boxer@ucsf.edu.
Abstract
OBJECTIVE: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. METHODS: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. RESULTS: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. CONCLUSIONS: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.
OBJECTIVE: To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. METHODS: Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. RESULTS: Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. CONCLUSIONS: Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.
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