Longitudinal Neuroimaging Reveals Divergent Clinical Associations of Glymphatic Dysfunction and Dopaminergic Degeneration in Parkinson's Disease

To investigate the association between glymphatic function and dopaminergic degeneration in PD assessed via diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) and dopamine transporter imaging striatal binding ratio (DAT-SBR), aiming to clarify their controversial relationship and distinct roles in disease progression. A total of 70 early-stage, drug-naïve patients with PD and 70 age- and sex-matched healthy controls (HCs) were selected from the Parkinson's Progression Markers Initiative database for cross-sectional analysis. Longitudinal data at 4-year follow-up were available for the PD group. Glymphatic function was evaluated using DTI-ALPS, and dopaminergic function using DAT-SBR derived from DAT-SPECT imaging. Clinical motor and non-motor assessments were performed at baseline and follow-up. Correlations between imaging index and clinical variables were analyzed using Spearman correlation and multivariate regression. At baseline, both DTI-ALPS and DAT-SBR index were significantly lower in PD patients compared to HCs. Notably, no significant correlation was observed between ALPS and SBR index. Clinically, the DTI-ALPS index showed negative correlations with body mass index, disease duration, Hoehn and Yahr stage, and UPDRS III scores, and its longitudinal decline correlated with white matter microstructural degeneration. The DAT-SBR index was negatively correlated with Epworth Sleepiness Scale, REM sleep behavior disorder score, and serum urate. Our findings suggest that glymphatic dysfunction and nigrostriatal denervation represent independent, parallel pathological trajectories in early PD. While the ALPS index may serve as a potential imaging marker of structural network integrity linked to motor execution. These indices offer distinct, complementary mechanistic insights into PD pathology.