Background: Spinocerebellar ataxia type 1 (SCA1) is a rare, neurodegenerative disease. Upcoming clinical disease-modifying trials require biomarkers sensitive to disease progression. This study aims to investigate diffusion MRI (dMRI) metrics as a possible outcome measure in such trials.

Methods: 46 participants (26 SCA1, 20 matched healthy controls (HC)) underwent 3 T MRI examination and clinical assessment of ataxia severity (SARA) at three timepoints over the duration of two years, including dMRI. Diffusion metrics (fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity) were examined using tract-based spatial statistics (TBSS) and ROI-based extraction. Results were evaluated for change over time and relation to disease severity.

Results: Cerebellar white matter, in particular all cerebellar peduncles, showed significant (p < 0.001) differences between SCA1 and HC groups at baseline in all diffusion metrics. After two years, dynamics were only observed in the inferior cerebellar peduncle (ICP). However, a sub-group of early-stage disease patients (SARA ≤ 11) showed significant change in the corticospinal tract (CST) and pontine crossing tract (PCT), indicating stage-dependent dynamics. Cortical regions did not show cross-sectional differences between groups, but did change significantly in both anterior and posterior regions in the SCA1 group (p < 0.001).

Conclusion: SCA1 patients showed significantly impaired white matter integrity in the cerebellar regions, when compared to HC. At the group level, diffusion metrics show dynamic effects in the ICP and in cortical regions. Patients in early disease stages furthermore show dynamic change in the CST and PCT. This indicates that white matter alterations follow a specific pattern throughout the disease and that measurements thereof are most useful in clinical trials targeting early disease stages.