Associations between glymphatic dysfunction, white matter injury, and cognitive decline in Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms, with cognitive impairment significantly affecting patients' quality of life. This study aimed to investigate the relationships among glymphatic dysfunction, white matter (WM) injury and cognitive decline in PD patients. Seventy PD patients and 82 healthy controls (HCs) underwent clinical evaluations and magnetic resonance imaging (MRI) scans. Key metrics included the diffusion tensor imaging-along the perivascular space (DTI-ALPS) index, choroid plexus volume (CPV), white matter free water (WM-FW), and peak width of skeletonized mean diffusivity (PSMD). Statistical analyses included correlation analyses, mediation analysis and receiver operating characteristic (ROC) analyses. PD patients exhibited lower DTI-ALPS index (p < 0.001) and higher CPV (p < 0.001), WM-FW (p = 0.010), and PSMD (p < 0.001) compared to the HCs. The DTI-ALPS index was negatively correlated with WM-FW (r = -0.612, p < 0.001) and PSMD (r = -0.484, p < 0.001), whereas CPV was positively correlated with both (r = 0.613, p < 0.001; r = 0.540, p < 0.001). The DTI-ALPS index correlated positively with Montreal Cognitive Assessment (MoCA) score (ρ = 0.471, p < 0.001). CPV (ρ = -0.421, p = 0.002), WM-FW (ρ = -0.296, p = 0.029), and PSMD (ρ = -0.273, p = 0.044) correlated negatively with the MoCA score. Mediation analysis suggested that DTI-ALPS and CPV may be involved in the association between white matter injury and cognition, but the independent role of each individual indicator was not confirmed. Diagnostic performance evaluations indicated that the PSMD best predicted PD individually (AUC = 0.836), with the integrated four-biomarker model performing best (AUC = 0.855). These findings highlight the correlation between glymphatic function, WM integrity, and cognition in PD patients, supporting the use of these neuroimaging biomarkers for early diagnosis and monitoring of cognitive decline.