A systematic review and meta-analysis on glymphatic flow dysfunction in Parkinson's disease and Parkinsonism spectrum

This systematic review and meta-analysis synthesized evidence of glymphatic dysfunction in Parkinson's disease (PD) and related Parkinsonian syndromes using the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Following the PRISMA 2020 guidelines, 28 studies published up to May 12, 2025, were included. The primary meta-analysis of 21 studies (1678 patients with PD and 1088 HCs) demonstrated a significant reduction in the DTI-ALPS index in patients with PD (Cohen's d = -0.57; 95% CI: -0.67 to -0.47; p < 0.001), indicating moderate glymphatic dysfunction. This impairment was significantly associated with clinical progression, including longer disease duration (β = -0.08, p = 0.005) and higher Hoehn and Yahr (H-Y) stages (β = -0.18, p = 0.057). This association was particularly strong in patients with early-stage PD (H-Y < 2.5). Phenotypic analyses revealed a gradient of dysfunction, with the most severe impairment found in patients with PD with dementia (Glass's Δ = -1.04) and atypical Parkinsonian syndromes (Δ = -1.01). Technical subgroup analyses showed consistent findings, with region-of-interest size significantly moderating effect size (p = 0.04). The methodological quality of the included studies was high, with no evidence of publication bias. The methodological quality was high, with no evidence of publication bias (p ≥ 0.88). These findings underscore the progressive glymphatic decline with PD severity and duration, independent of age or cognition, and highlight distinct impairment patterns across different clinical phenotypes.