Impaired glymphatic clearance independently contributes to poor outcomes in Parkinsons disease
Background: Impaired glymphatic clearance may contribute to pathological accumulations in Parkinsons (PD), but how it interacts with other processes causing dementia and poor outcomes remains unclear. Objectives: Clarify how glymphatic clearance impacts cognition in PD and its interaction with established imaging markers. Methods: We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) as an indirect marker of glymphatic clearance in 98 PD patients (31 PD-poor outcomes: dementia, mild cognitive impairment, frailty or death within 3-year follow-up; 67 PD-good outcomes) and 28 controls. We assessed DTI-ALPS relationship to cognition, white matter (fibre cross-section), cortical thickness, iron accumulation (quantitative susceptibility mapping (QSM)), and plasma markers (phosphorylated tau-181 (p-tau181 and neurofilament light (NFL)) cross-sectionally and longitudinally. Results: DTI-ALPS was lower in PD-poor outcomes compared to PD-good outcomes and controls (p=0.005) with further longitudinal reductions only in PD-poor outcomes (group*time interaction: beta=-0.013, p=0.021). Lower DTI-ALPS was associated with lower fibre cross-section in PD, at baseline and longitudinally but with different spatial distribution from white matter changes relating to PD cognition. There was no correlation between baseline DTI-ALPS and plasma ptau-181 (p=0.642), NFL (p=0.448) or baseline cortical thickness. Lower DTI-ALPS was associated with accelerated cortical thinning within left precentral gyrus and changes in brain iron distribution. Conclusions: PD patients who develop poor outcomes show impaired glymphatic clearance at baseline that worsened longitudinally. DTI-ALPS correlated with white matter integrity and brain iron accumulation. However, both showed different spatial distribution than that seen in PD dementia; suggesting impaired glymphatic clearance contributes to cognitive decline in a distinct manner.