Fiber-specific micro- and macroscopic white matter alterations in progressive supranuclear palsy and corticobasal syndrome

Abstract

Abstract Progressive supranuclear palsy (PSP) and corticobasal degeneration, which frequently present as a corticobasal syndrome (CBS), are characterized by progressive white matter (WM) alterations associated with the prion-like spreading of four-repeat tau. Considering the interplay of tau pathologies with clinical symptoms, capturing the disease-specific patterns of WM alterations might provide valuable clinical information; however, the mechanisms of loss of WM integrity and its involvement in the clinical deficits in tauopathies remain unknown, likely due to the difficulties in estimating complex WM structure. Here, a novel fibre-specific fiber density and fiber cross-section, and their combined measure estimated using fixel-based analysis (FBA), were cross-sectionally and longitudinally assessed in PSP (n = 20) and CBS (n = 17), and healthy controls (n = 20). Cross-sectional and longitudinal FBA indicated disease-specific progression patterns of fiber density loss and subsequent bundle atrophy consistent with the tau propagation patterns suggested in previous histopathological findings. Furthermore, longitudinal changes in fixel-wise metrics in WM tracts which control motor and cognitive functions exhibited strong correlations with changes in clinical dysfunction in both diseases. Our findings suggest that the FBA can be useful in determining the mechanisms of clinical deficits related to sequential WM alterations in PSP and CBS.