Objective:

Background:

The glymphatic system facilitates clearance of neurotoxic proteins such as α-synuclein, and its dysfunction may contribute to PD pathogenesis. DTI metrics like APLS capture microstructural complexity and may serve as indirect markers of glymphatic efficiency. However, the magnitude and regional distribution of APLS alterations in PD remain unclear.

Design/Methods:

A systematic search of PubMed identified studies reporting APLS values in PD patients and HC. Data were extracted for whole brain, left-hemisphere, and right-hemisphere. Standardized Mean Difference (SMD) as summary measure, employing DerSimonian-Laird T2 and Hedges’ g bias-corrected estimate, were performed. Fixed and random-effects models with I2 were done. Egger’s regression and funnel plot inspection were used.

Results:

62 comparisons from 27 studies (2021–2025) were included. PD patients exhibited significantly lower APLS than HC (g fixed-effect –0.58 [95% CI: –0.63 to –0.53] and random-effect –0.66 [95% CI: –0.77 to –0.56]). Reductions were consistent across the whole brain (g –0.59 [95% CI: –0.67 to –0.51]), left hemisphere (g –0.60 [95% CI: –0.69 to –0.51]), and right hemisphere (g –0.55 [95% CI –0.66 to –0.43]), with no significant subgroup difference (p = 0.72). Egger’s test indicated small-study effects (p < 0.001). The adjusted effect estimate after accounting for ‘trim and fill’ analysis was g –0.50, indicating a notable change in the effect size by 25%.

Conclusions:

Lower APLS in PD suggests widespread microstructural disruption potentially linked to impaired glymphatic clearance of α-synuclein and other metabolites. These findings support APLS as a promising imaging biomarker for glymphatic dysfunction in PD. Standardized protocols and longitudinal studies are needed to validate its role in early detection and therapeutic monitoring.