Journal
NATURE MEDICINE
Volume 27, Issue 3, Pages 411-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-020-01198-1
Keywords
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Funding
- National Natural Science Foundation of China [81671267]
- Natural Science Foundation of Henan Province for Excellent Young Scholars [202300410357]
- National Key Plan for Scientific Research and Development of China [2016YFC1306000]
- Swedish Research Council [2019-01551]
- Swedish Research Council [2019-01551] Funding Source: Swedish Research Council
- Vinnova [2019-01551] Funding Source: Vinnova
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Animal studies have suggested a link between meningeal lymphatic dysfunction and neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. This study found that patients with idiopathic Parkinson's disease had reduced meningeal lymphatic flow and delayed cervical lymph node perfusion compared to patients with atypical Parkinsonian disorders. In mouse models, impaired meningeal lymphatic drainage was associated with worsened alpha-syn pathology and PD progression.
Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role(1-5). In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with alpha-synuclein (alpha-syn) preformed fibrils, we showed that the emergence of alpha-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with alpha-syn preformed fibrils increased alpha-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates alpha-syn pathology and contributes to the progression of PD.
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