The glymphatic system and Parkinson's disease: a narrative review

The glymphatic system, a glia-dependent perivascular fluid transport pathway, has provided new insights into brain homeostasis and neurodegeneration. Although Parkinson's disease (PD) is classically defined by dopaminergic neuronal loss and α-synuclein aggregation, impaired clearance of metabolic waste via glymphatic pathways may contribute to its pathophysiology. Advances in neuroimaging, particularly Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS), now enable in vivo assessment of glymphatic-related alterations.

This narrative review synthesizes current experimental, imaging, and clinical evidence on glymphatic dysfunction in PD. We focus on DTI-ALPS as a surrogate marker of glymphatic activity, examining its relationship with motor and non-motor features, and its potential as a biomarker. Methodological and conceptual limitations are also considered.

Reduced DTI‑ALPS indices are frequently reported in PD and correlate with greater motor severity and cognitive impairment, providing indirect, diffusion‑based evidence that perivascular fluid transport is altered in this disease. These findings support a role for glymphatic dysfunction in disease burden and progression. Mechanistically, impaired perivascular clearance may promote the accumulation of misfolded α-synuclein and other neurotoxic metabolites. However, the specificity of DTI-ALPS as a direct measure of glymphatic function remains debated, and its relationship with vascular pathology and structural brain changes requires further clarification.

Glymphatic dysfunction represents a promising but evolving framework in PD. Understanding its interaction with α-synuclein pathology and vascular integrity may facilitate the development of imaging biomarkers and disease-modifying strategies. Longitudinal and standardized studies are needed to establish clinical relevance.