Objective: The study investigated alterations of glymphatic system in both patients and mouse model of Parkinson’s disease (PD) with cognitive impairment (CI), and elucidated the underlying mechanisms.

Background: CI is a salient feature of PD, typically indicating an advanced disease stage and associated with the spread of α-synuclein across the striatum, hippocampus, amygdala and cortex. Glymphatic system has been found to play a crucial role in the clearance of α-synuclein from the brain. α-synuclein propagation can impair glymphatic system, while glymphatic dysfunction in turn accelerates the aggregation of toxic proteins. However, the precise relationship and underlying mechanisms linking glymphatic function to CI in PD remain unclear.

Method: We assessed glymphatic function of PD patients with different cognitive status using diffusion-tensor imaging along the perivascular space (DTI-ALPS). In the A53T mouse model with α-synuclein pre-formed fibril (PFF) injected to hippocampus, glymphatic system was further assessed by the clearance of fluorescent tracer (ovalbumin-647) from parenchyma, and aquaporin-4 (AQP4) polarization at astrocytic endfeet. Additionally, CSF proteomics analysis was performed in PD patients with longitudinal cognitive follow-ups to identify potential biomarkers associated with the risks of cognitive decline.

Results: Patients with PD dementia showed significantly lower DTI-ALPS than PD patients with normal cognition. In the A53T mouse with PFF injection, cognitive impairment was confirmed by novel object recognition and Y-maze tests. We also observed that mis-location of AQP4 in the model of A53T+PFF, which impaired the glymphatic clearance of ovalbumin-647 from hippocampus. Hippocampal astrocytes in the A53T+PFF group were pathologically activated, with upregulation of pathological markers (GFAP and S100β) and morphological alterations, including swelling soma and increased intersections. Furthermore, we identified that decreased APOE levels in CSF were correlated with reduced hippocampus volume and increased risks of cognitive decline in patients with PD.

Conclusion: Glymphatic dysfunction triggered pathological alterations of both astrocytes and neurons in hippocampus, ultimately contributing to cognitive impairment in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-influence-of-glymphatic-system-impairment-on-cognitive-decline-in-parkinsons-disease/