Diffusion along perivascular spaces as a marker for Glymphatic system impairment in spinocerebellar Ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by the accumulation of polyglutamylated ATXN3 protein within neurons, which can potentially compromise the integrity of the brain's glymphatic system. Our objective is to investigate whether glymphatic function is impaired in patients with SCA3 and its clinical relevance. This study recruited 129 SCA3 subjects, including 98 symptomatic (ataxic SCA3) and 31 presymptomatic (preataxic SCA3) individuals, along with 67 healthy controls (HCs). We calculated the index for diffusion tensor image analysis along the perivascular space (DTI-ALPS) across groups and examined its correlation with SCA3 clinical features. Except for the left cerebral hemisphere DTI-ALPS index showing no statistically significant difference between HC and preataxic SCA3, statistically significant differences in ALPS index were observed among the remaining three groups. The DTI-ALPS index decreased in the order HC group > preataxic SCA3 group > ataxic SCA3 group. The Ataxic SCA3 group exhibited a significantly lower DTI-ALPS index than the HC group. The mean DTI-ALPS index showed negative correlations with the Scale for the Assessment and Rating of Ataxia (SARA) scores and International Cooperative Ataxia Rating Scale (ICARS) scores. In this study, we demonstrate that glymphatic waste clearance is impaired in SCA3 and that the magnitude of ALPS-detected dysfunction parallels clinical burden. DTI-ALPS may serve as a potential indicator for evaluating glymphatic system alterations and disease.