Abstract
BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.