The association of glymphatic system function with cognitive decline in PD-FOG: multimodal MRI evidence from cross-sectional and longitudinal studies.

This study aims to investigate glymphatic system dysfunction in idiopathic Parkinson's disease (PD) using a dual-cohort design, focusing on its associations with freezing of gait (FOG) and cognitive decline. A cross-sectional analysis was conducted on 43 PD patients with FOG, 106 without FOG, and 46 healthy controls. A longitudinal study followed 146 early-stage PD patients from the Parkinson's Progression Markers Initiative database over five years, with 65 developing FOG. Covariate analysis was performed, controlling for variables like gender, age, and education. Survival analysis compared cognitive decline between FOG and stable groups. Random forest analysis identified key predictors of FOG development. The cross-sectional study demonstrated significantly enlarged normalized choroid plexus volume in PD patients with FOG compared to healthy controls. Both FOG and non-FOG groups showed increased perivascular space enlargement in the basal ganglia and centrum semiovale, as well as reduced average analysis along the perivascular space index compared to healthy controls. PD patients with FOG exhibited more pronounced disease progression and cognitive decline than those without FOG. Glymphatic markers were associated with age, cognitive scores, and gait performance. The longitudinal study showed slightly more severe motor symptoms and accelerated cognitive decline in the FOG group during follow-up. Random forest analysis identified age, cognitive scales, and glymphatic function metrics as robust predictors of FOG development. These findings highlight the potential significance of brain glymphatic system function in the development of freezing of gait and cognitive decline in PD patients, offering novel neuroimaging biomarkers for early detection. These authors have contributed equally to this work and share first authorship.