Glymphatic Function in Prodromal Parkinson's Disease: Associations With Symptoms, Gray Matter Volume, and...

Glymphatic dysfunction occurs in Parkinson's disease (PD), but its status in prodromal PD (pPD) is unclear. Using the diffusion tensor imaging along perivascular spaces (DTI-ALPS) index as an indirect proxy, this study aims to evaluate glymphatic-related changes in a pPD cohort and to explore their relationship with symptoms, gray matter volume, and risk of phenoconversion.

We analyzed data from the Parkinson's Progression Marker Initiative, including 51 healthy controls (HC), 83 individuals with pPD, and 202 with de novo PD (dnPD). The pPD cohort underwent ≥ 4-year follow-up. Cross-sectional analyses compared the DTI-ALPS index across three groups and examined associations between the DTI-ALPS index and clinical features/gray matter volume in the pPD cohort. For longitudinal analysis, the relationship of DTI-ALPS index with the risk of phenoconversion was assessed via Kaplan-Meier and Cox regression.

DTI-ALPS index was significantly reduced in pPD and dnPD vs. HC (p < 0.001). In pPD, lower DTI-ALPS index correlated with: higher anxiety (STAI: r = -0.46, p = 0.02), elevated CSF p-tau (r = 0.52, p = 0.04) and t-tau (r = 0.42, p = 0.03), lower volumes of right temporal pole (p = 0.03), left thalamus (p = 0.01), right superior occipital gyrus (p = 0.04), and higher volume of left posterior central gyrus (p = 0.03). Among 83 pPD subjects, 10 phenoconverted to PD. Each standard deviation decrease in DTI-ALPS increased conversion risk by 13% (adjusted HR = 0.87, 95% CI 0.83-0.92; p = 0.018).

Reduced DTI-ALPS index in pPD-which may reflect altered glymphatic function-is associated with accelerated phenoconversion and correlates with clinical symptoms and cortico-thalamic structural changes.