Objective: The aim of this study is to investigate the contribution of the glymphatic system to the pathophysiology of Parkinson’s disease (PD).

Background: Neurotoxicity of pathological α-synuclein (α-syn) accumulations and dopaminergic cell loss play a key role in the pathophysiology of PD. The importance of the glymphatic system has recently been better understood as an important pathway in the clearance of macromolecules from the brain.

Method: Glymphatic system dysfunction was created by ligating lymphatic vessels of deep cervical lymph  nodes (dcLN) in a PD rat model induced by injection of α-syn preformed fibrils (PFF) into the striatum. Then, at 6th week, contrast enhanced MRI was performed three times intermittently following intrathecal paramagnetic contrast agent injection by lumbar puncture, and glymphatic system function was evaluated. Behavioral tests were performed at week 7, afterwards animal brains were perfused at week 8 and immunhistochemical staining was applied.This study (THD-2022-19910) was supported by Hacettepe University Scientific Research Projects Coordination Unit.

Results: The transition of contrast agent from subarachnoid space to the brain parenchyma was decreased extensively in the α-syn PFF injected with dcLN ligation group compared to the α-syn PFF group without ligation at 30^th and 60^th minutes. In the α-syn PFF injected without dcLN ligation group, decrease in contrast transition was prominent especially in the ventral brainstem at 30^th minute post-injection compared to the naive controls. However, this difference disappeared at 60^th minute. In the open field and apomorphine-induced locomotor activity tests performed at week 7, there was no significant difference between the groups (p>0.05). In the cylinder test, although there was a trend towards a decrease in the use of contralateral limb in both PFF injection groups compared to naive controls, no statistical significant difference was detected (p>0.05). Immunohistochemical staining showed α-syn expression and aggregate-like formations both in the striatum and substantia nigra.

Conclusion: In conclusion, glymphatic system dysfunction is detected in the α-sin PFF model of PD, especially in the brain regions where α-sin pathology was more intense, and dcLN ligation aggravate the dysfunction making it longer in duration and widespread throughout the brain.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-the-glymphatic-system-on-the-severity-and-distribution-of-alpha-synuclein-pathology-in-alpha-synuclein-fibril-induced-rat-model-of-parkinsons-disease/