Impaired Glymphatic Clearance, Measured Using Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS), is Linked to Poor Cognitive Outcomes in Parkinson's Disease.

BACKGROUND Impaired glymphatic clearance may contribute to pathological accumulations in Parkinson's (PD), but how it interacts with other processes causing dementia remains unclear. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed as an indirect proxy for glymphatic clearance. OBJECTIVES To clarify DTI-ALPS' relationship with cognition in PD, and its relationship with established imaging markers. METHODS We assessed DTI-ALPS in 98 PD patients (31 PD poor outcomes: dementia, mild cognitive impairment, frailty, or death within a 3-year follow-up; 67 PD good outcomes) and 28 controls. We assessed DTI-ALPS' relationship to cognition, white matter (fiber 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 with PD good outcomes and controls (P = 0.005) with further longitudinal reductions only in PD poor outcomes (group × time interaction: β = -0.013, P = 0.021). Lower DTI-ALPS was associated with lower fiber 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 p-tau181 (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 lower DTI-ALPS, potentially reflecting impaired glymphatic clearance. DTI-ALPS correlated with white matter integrity and brain iron accumulation. However, both showed different spatial distribution than that seen in PD dementia, suggesting DTI-ALPS captures a distinct contribution to cognitive decline. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.