Glymphatic dysfunction in cerebellar neurodegeneration: mechanistic insights and emerging clinical implications

The glymphatic system is a glial-dependent perivascular clearance pathway that maintains central nervous system homeostasis through cerebrospinal fluid and interstitial fluid exchange. Emerging evidence suggests that glymphatic dysfunction contributes to the pathophysiology of neurodegenerative disorders involving cerebellar networks. This review summarizes current evidence linking glymphatic dysfunction to cerebellar neurodegeneration, with a particular focus on spinocerebellar ataxia type 3, multiple system atrophy, progressive supranuclear palsy, and essential tremor.

Mechanistic pathways involving aquaporin-4 mispolarization across astrocytic perivascular and Bergmann glial pial endfeet, neuroinflammation, vascular alterations, and sleep-dependent fluid dynamics are evaluated. Advanced neuroimaging approaches, including diffusion tensor image analysis along the perivascular space (DTI-ALPS), blood oxygen level-dependent-cerebrospinal fluid coupling, and structural perivascular space imaging, are reviewed as complementary surrogate markers of alterations in glymphatic-related fluid dynamics. Recent clinical studies indicate that these glymphatic-related imaging abnormalities correlate with clinical severity and, in specific disorders, may precede overt symptom onset.

Collectively, current evidence supports glymphatic dysfunction as a contributor to cerebellar neurodegeneration and related movement disorders. A deeper understanding of glymphatic clearance dynamics may facilitate the development of novel imaging biomarkers and targeted therapeutic strategies addressing impaired protein clearance, reactive astrogliosis, vascular dysfunction, and sleep disturbances.