Glymphatic dysfunction in Parkinson's disease: Aging-associated impairments, imaging biomarkers, and therapeutic strategies

Abstract

The accumulation of α-synuclein (α-syn) is a key pathophysiological feature of Parkinson’s disease (PD), and one contributing factor to this aggregation is impaired clearance mechanisms. Recent research has identified the glymphatic system as the brain’s intrinsic waste clearance pathway. This review examines glymphatic dysfunction in PD, with a focus on its impact on α-syn clearance and neurodegeneration. We summarize current evidence showing that disrupted aquaporin-4 (AQP4) polarization, reduced meningeal lymphatic drainage, and sleep disturbances collectively impair glymphatic flow, thereby promoting α-syn aggregation and dopaminergic neuronal loss. We also review emerging neuroimaging approaches, including the Diffusion Tensor Imaging Analysis Along the Perivascular Space (DTI-ALPS) index, enlarged perivascular spaces (EPVSs) and choroid plexus volume (CPV), which increasingly enable in vivo evaluation of glymphatic dysfunction and show correlations with motor severity and cognitive decline. In addition, we discuss potential therapeutic approaches aimed at restoring glymphatic function, including photobiomodulation, pharmacological AQP4 modulation, sleep based interventions, and surgical interventions like deep cervical lymphaticovenular anastomosis (dcLVA). Although these strategies show promise in preclinical studies, their clinical translation remains limited. By integrating insights from glymphatic biology, neuroimaging, and therapeutic development, this review highlights new avenues for PD management and underscores the glymphatic system as a promising therapeutic target for modifying disease progression.