Glymphatic Dysfunction, Brain Damage, and Clinical Disability in Spinocerebellar Ataxia Type 3

BACKGROUND: The glymphatic system, a key fluid clearance pathway in the central nervous system, is emerging as a potential therapeutic target for synucleinopathies. Dysregulation of this system may contribute to spinocerebellar ataxia type 3 (SCA3) pathogenesis, in which the accumulation of misfolded proteins acts as a central driver. OBJECTIVES: The goal was to investigate glymphatic system function in SCA3 patients and evaluate its relationship with brain damage and clinical disability. METHODS: Ninety-two SCA3 patients (14 with premanifest SCA3 and 78 with manifest SCA3) and 98 healthy controls underwent clinical evaluation and magnetic resonance imaging (MRI) scans. MRI parameters, including the diffusion along the perivascular space (DTI-ALPS) index (a proxy for glymphatic function); cerebral, cerebellar, and subcortical gray matter volumes; and whole-brain microstructural properties of white matter, were calculated. RESULTS: Patients with premanifest and manifest SCA3 had lower ALPS indices compared with healthy controls, and patients with manifest SCA3 had a lower ALPS index compared with premanifest SCA3. In SCA3 patients, lower ALPS index was associated with more severe disability and longer disease duration. A negative correlation between ALPS and disease duration emerged after 3 years, with no significant association observed before the 3-year cutoff. Moreover, lower ALPS index was correlated with more pronounced cortical and subcortical gray matter atrophy, decreased fractional anisotropy, and elevated mean diffusivity in white matter. CONCLUSIONS: Our findings demonstrate that glymphatic function is impaired, particularly in the presymptomatic stage of SCA3, and this impairment is associated with disability, neurodegeneration, and demyelination. Therefore, glymphatic dysfunction may contribute to the pathogenesis of SCA3. © 2026 International Parkinson and Movement Disorder Society.