Glymphatic dysfunction as a potential driver of cerebral iron deposition in Parkinson's disease

Abstract Cerebral iron deposition is a pathological hallmark of Parkinson's disease. Notably, Parkinson's disease patients exhibit the characteristic neuroimaging features of enlarged choroid plexus volume (CPV) and diminished glymphatic function. While previous research has focused on potential iron influx dysregulation in Parkinson's disease, the critical question of whether impaired iron clearance stemming from choroid plexus and glymphatic system dysfunction constitutes a key mechanism underlying pathological iron accumulation remains unexplored. Therefore, the aim of this study was to investigate the relationship between cerebral iron deposition and glymphatic dysfunction in Parkinson's disease, and explored its clinical relevance. We hypothesized that impaired glymphatic clearance contributes to pathological iron accumulation in Parkinson's disease. This cross-sectional study enrolled 65 patients with mild-to-moderate Parkinson's disease and 38 age- and sex-matched healthy controls. Multimodal MRI was used to assess the CPV, diffusion tensor imaging analysis along the perivascular space (ALPS) index (indirectly reflecting glymphatic function) and quantitative susceptibility mapping-derived iron levels. The clinical evaluations included motor, cognitive and psychiatric assessments. Statistical analyses compared group differences, correlations, mediation effects and diagnostic performance via receiver operating characteristic analysis. Compared to healthy controls, Parkinson's disease patients exhibited bilateral CPV enlargement (P < 0.01), reduced ALPS indices (P < 0.05) and elevated iron deposition in the substantia nigra, red nucleus and putamen (P < 0.05). CPV negatively correlated with ALPS index (left hemisphere: r = −0.305, P = 0.014; right hemisphere: r = −0.357, P = 0.004). Notably, the degree of glymphatic dysfunction, manifested by either choroid plexus enlargement or a reduced ALPS index, was significantly correlated with regional iron deposition patterns, especially between the CPV and substantia nigra iron deposition (left hemisphere: r = 0.236, P = 0.029; right hemisphere: r = 0.233, P = 0.031). Mediation analysis revealed that ALPS and putamen iron deposition-mediated CPV affected daily living impairments and psychiatric symptoms. A comprehensive diagnostic model integrating neuroimaging, cognitive and psychiatric variables achieved near-perfect discrimination for mild-to-moderate Parkinson's disease (area under the receiver operating characteristic curve = 0.972, sensitivity = 100%, specificity = 97.4%). In conclusion, our results suggest that CPV enlargement and reduced ALPS index are closely linked to pathological iron deposition in Parkinson's disease. These biomarkers correlate with motor deficits, cognitive decline and psychiatric symptoms, highlighting their roles in disease progression. The integrated diagnostic model demonstrated exceptional accuracy, advocating multimodal approaches for Parkinson's disease management. These findings suggest that glymphatic modulation and iron chelation are potential therapeutic targets that warrant further longitudinal validation.