Altered Glymphatic Network in Spinocerebellar Ataxia: a Multimodal MRI Study Within a Structure-Environment-Function...

This study characterizes in vivo glymphatic system alterations in spinocerebellar ataxia (SCA) using a structure-environment-function multimodal MRI framework and explores subtype-specific signatures and longitudinal progression. Twenty genetically confirmed SCA patients (SCA1 = 1, SCA2 = 11, SCA3 = 6, SCA7 = 2) and 23 matched healthy controls underwent MRI across two scanners. The framework included structural (perivascular space volume fraction, pPVS; choroid plexus volume, CPV), environmental (free water, FW), functional (DTI-ALPS index), and microstructural (fractional anisotropy, FA) metrics. Data were harmonized across sites. Cross-sectional, subtype, and longitudinal analyses were performed. SCA patients demonstrated significantly enlarged subcortical pPVS, elevated FW, and reduced FA compared to controls (all surviving FDR correction, q = 0.05), while CPV/rCPV showed non-significant trends and the ALPS index showed no group difference. Subtype analyses revealed higher white matter and total pPVS in SCA3 versus SCA2 (surviving FDR correction), but FW differences did not survive correction. Longitudinally, the SCA2 subset exhibited significant FA decline over time (p < 0.001), with robust group effects on FW and WM pPVS. Within a structure-environment-function framework, SCA exhibits prominent glymphatic-related abnormalities in perivascular and interstitial compartments, with preserved ALPS index. Distinct imaging signatures of SCA2 and SCA3 suggest divergent pathophysiologies. FW and FA emerge as promising complementary biomarkers for monitoring disease burden and progression in future trials.