Regional Glymphatic Dysfunction in Patients with Spinocerebellar Ataxia Type 3

Abnormal accumulation of polyglutamine proteins is considered a core pathogenic factor in spinocerebellar ataxia type 3 (SCA3). The glymphatic system, a lymphatic-like fluid transport system, plays a crucial role in maintaining the balance between protein production and clearance in the brain. However, it remains unclear whether SCA3 is associated with impairments in glymphatic function. Using multimodal imaging data, 34 SCA3 patients and 36 age-, sex- and educational matched healthy controls (HCs) were compared using multiple glymphatic measurements, including choroid plexus (CP) volume, cerebrospinal fluid (CSF) volume, diffusion tensor imaging along the perivascular (DTI-ALPS) index, and coupling relationship between blood-oxygen-level-dependent signals and CSF flow (BOLD-CSF coupling). Then, we evaluated regional glymphatic function by dividing DTI-ALPS and BOLD-CSF coupling into anterior, middle, posterior, and cerebellum regions, thereby identifying the spatial variation of glymphatic function in the two groups. We demonstrated that compared with HCs, larger CP and CSF volumes were found in SCA3 patients. More importantly, for DTI-ALPS index and BOLD-CSF coupling, these surrogate markers for glymphatic clearance were weaker in SCA3 patients. Furthermore, altered regional glymphatic functions were most prominent in midbrain, cerebellum and middle cortical regions. Crucially, the altered midbrain, cerebellum, middle and global glymphatic functions were accompanied by the severity of ataxia and other SCA3 symptoms. Similar to other neurodegenerative disorders, the associations between multiple glymphatic markers and SCA3 symptoms suggest that waste clearance is disrupted in SCA3 patients, shedding light on the pathogenesis of the disease from a glymphatic perspective. Our findings highlighted the dysregulated glymphatic function as a novel biomarker for SCA3 and provide insights for exploring effective treatment strategies.