Glymphatic Dysfunction in Parkinson's Disease: A Systematic Review and Meta-Analysis of Neuroimaging Studies.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder marked by motor and non-motor symptoms. Impaired glymphatic clearance, which eliminates neurotoxic proteins, may contribute to PD pathogenesis. MRI techniques including Diffusion Tensor Imaging-Along the Perivascular Space (DTI-ALPS) and assessment of Enlarged Perivascular Spaces (EPVS) are used to evaluate glymphatic function.

OBJECTIVES: Assessment of glymphatic function in PD and its potential as an imaging biomarker.

METHODS: A systematic search of Web of Science, Scopus, and PubMed was conducted on October 27, 2024, for observational MRI studies evaluating glymphatic function in PD. Meta-analyses compared glymphatic indices between people with PD (PwPD) and healthy controls (HCs). Associations with clinical outcomes and participant characteristics were examined using effect-direction plots and meta-correlations.

RESULTS: Thirty-five studies involving 4224 PwPD and 1287 HCs were included. PwPD had lower DTI-ALPS (SMD = -0.97; 95% CI: -1.42, -0.52; p < 0.01; I2 = 91%; k = 15), higher EPVS numbers (SMD = 1.05; 95% CI: 0.37, 1.73; I2 = 94%; k = 9), and higher EPVS volumes (SMD = 1.08; 95% CI: 0.67, 1.50; I2 = 64%; k = 4) compared to HCs. Glymphatic dysfunction correlated with motor symptom severity (DTI-ALPS: Z-correlation = -0.29; EPVS number: Z-correlation = 0.39). It was not associated with psychiatric symptoms and sex, while associations with global cognition and sleep disturbances were conflicting.

CONCLUSIONS: Glymphatic dysfunction is a prominent feature of PD and correlates with motor symptom severity, supporting its potential as a biomarker or potential therapeutic target. Variability in measurement techniques and inconsistent findings on non-motor symptoms highlight the need for further research.