Progression of brain atrophy in PSP and CBS over 6 months and 1 year

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 voxelbased 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. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are rare neurodegenerative disorders associated with the accumulation of insoluble deposits of predominantly 4 microtubule binding domain repeat (4R) tau protein in specific brain regions, mainly in the absence of other pathogenic proteins including b-amyloid.1 Accordingly, PSP and CBD are classified as primary 4R tauopathies. There are currently no effective therapies for either disorder, but the development of new therapeutic agents that target the tau protein has led to increased interest in pursuing clinical trials in CBD and PSP, either individually or for a combined 4R tauopathy indication.

Abnormal Resting-State Functional Connectivity in Progressive Supranuclear Palsy and Corticobasal Syndrome

“…This finding is consistent with previous studies showing an increased involvement of cortical areas in CBS (5, 38). Accordingly, we observed increased within-network rsFC in the executive-control and insula RSNs.…”

Longitudinal magnetic resonance imaging in progressive supranuclear palsy: A new combined score for clinical trials

“…The smaller numbers reported by Whitwell et al 31 may result from the fact that they only included patients with a clinical diagnosis of probable PSP (NINDS-SPSP criteria), whereas the other studies 6,30 and our study also included patients with possible PSP or modified diagnostic criteria, which may affect the variability in disease progression markers. Finally, a most recent study 8 used SPM12-based longitudinal morphometric analysis and found that the annual change in midbrain volume as outcome measure requires only 56% of patients as the PSPRS. This rate compares well with the 63% observed in our study, which also used SPM12.…”

“…placebo and verum) patients from the davunetide trial and concluded that midbrain volumetry as outcome measure in a 1-year parallel-group trial would require comparable numbers of patients 6 as the best performing clinical scale, the PSP-rating scale (PSPRS). 5,7 Another study 8 proposed that annual midbrain volume change measured with SPM12 would require 44% less patients than the PSPRS.…”

Tracking brain damage in progressive supranuclear palsy: a longitudinal MRI study

“…Differences in MRI methodology and statistical testing might explain discrepancies among studies. The previous studies used voxel-based morphometry7 or measured ROI volumes using automated approaches 8 9. It is noteworthy that GM volume changes can result from alterations in two cortical components, cortical thickness and cortical surface area.…”

“…Extensive WM volume loss after 1 year in frontal and parietal lobes, brainstem, and cerebellum was observed in patients with PSP-RS using structural MRI 7. To our knowledge, only one longitudinal DT MRI study reported microstructural WM changes over 6 months in SCPs and left inferior frontal WM in patients with PSP-RS 19.…”