Thalamic free water elevation and its association with glymphatic dysfunction in Parkinson’s disease: A cross-sectional and longitudinal study

Free Water (FW) is considered an indicator of neuroinflammation, while the Index of Diffusivity along the Perivascular Space (ALPS) is a recently introduced measure of glymphatic function. However, no study has yet investigated the specific relationships between these factors simultaneously. This study aimed to examine changes in FW in the thalamic midline and lateral nuclei in Parkinson's disease (PD), with a particular focus on the potential influence of glymphatic system dysfunction. MRI data and clinical information were obtained from 32 healthy controls (HC), 32 participants with prodromal PD (pPD), and 90 participants with PD, sourced from the Parkinson's Progression Markers Initiative (PPMI) database. The ALPS index and Free Water fractional volume (FWF) were calculated based on diffusion tensor images. Intergroup comparisons of and correlations among MRI measures and clinical assessments were analyzed. FWF was elevated in the bilateral thalamic midline and right lateral nuclei of PD and in right midline nuclei of pPD compared to HC. In the PD group, the right ALPS index was significantly and negatively associated with FWF in the bilateral thalamic lateral nuclei, and mean ALPS index was negatively correlated to FWF in right lateral nuclei. Moreover, FWF in the right lateral thalamic nuclei of PD was correlated with follow-up Montreal Cognitive Assessment (MoCA) scores and its 2-years decrease rate. We provided indirect evidence to support that thalamic FW was significantly increased in PD participants, potentially exacerbated by glymphatic system dysfunction.