Reginaldo Capati

Background: The meninges have lymphatic vessels that exit the skull along the retroglenoid vein, sigmoid sinus, and meningeal portions of the pterygopalatine artery, draining to the deep cervical lymph nodes followed by the superficial cervical lymph nodes.¹ The function of meningeal lymphatic vessels is to drain cerebrospinal fluid (CSF), macromolecules, and immune cells from the central nervous system (CNS).² Evidence of meningeal lymphatic involvement in homeostasis and pathology is emerging.³ Lymphatic dysfunction is associated with and can worsen multiple neurologic conditions including post-operative cognitive dysfunction (POCD), Alzheimer’s Disease, and traumatic brain injury (TBI) .^4-6

Objective: In this narrative review we investigated the mechanisms behind meningeal lymphatic dysfunction, as well as potential therapeutic targets and strategies to improve meningeal lymphatic function, reduce neuroinflammation, and protect cognition.

Search Methods: PubMed search was conducted based on the keywords: “meningeal lymphatics”, “neuroinflammation”, “cognitive dysfunction”, and “CSF drainage”. Results were filtered by publication date range, only showing articles from 2018 to present.

 Results: Immune modulation and lymphangiogenic signaling are both being researched as therapeutic strategies targeting meningeal lymphatics.^4,7 CD4 and CD8 T cells accumulate in the meninges with age, influencing CNS function through secretion of cytokines.⁷ Increased IFNγ signaling in the endothelial meningeal lymphatic cells of older mice is seen with reduced meningeal lymphatic drainage.⁷ Young mice injected with IFNγ (AAV9-IFNγ) had decreased meningeal lymphatic drainage, and neutralization of elevated IFNγ with anti-IFNγ antibodies restored meningeal lymphatic function.⁷ VEGF-C (AAV-VEGF-C) enhanced meningeal lymphatic drainage following anesthesia and surgery in mice by promoting lymphangiogenesis and improving existing vessel function.⁴ VEGF-C also reduced microglial activation, decreased neuroinflammation, improved memory performance, and increased learning speed.⁴ Meningeal lymphatic drainage pathways have now been visualized in humans with magnetic resonance imaging (MRI).⁸

 Conclusions: Immune modulating and lymphangiogenic therapies for meningeal lymphatic dysfunction have shown promising results. These therapies have decreased POCD and improved efficacy of Alzheimer’s Disease treatment in mice by increasing meningeal lymphatic function and reducing neuroinflammation.^4,5 With meningeal lymphatics now visualized in humans, it is possible to further investigate these mechanisms and therapeutic avenues within the human population. This could improve outcomes for multiple neurocognitive conditions and potentially be used as a mitigating or preventative treatment across multiple disease states.

Works Cited:

1. Da Mesquita S, Fu Z, Kipnis J. The Meningeal Lymphatic System: A New Player in Neurophysiology. Neuron. 2018;100(2):375-388. doi:10.1016/j.neuron.2018.09.022
2. Chen J, Pan Y, Liu Q, et al. The Interplay between Meningeal Lymphatic Vessels and Neuroinflammation in Neurodegenerative Diseases. Curr Neuropharmacol. 2024;22(6):1016-1032. doi:10.2174/1570159X21666221115150253
3. Zhang Q, Niu Y, Li Y, et al. Meningeal lymphatic drainage: novel insights into central nervous system disease. Signal Transduct Target Ther. 2025;10(1):142. Published 2025 May 5. doi:10.1038/s41392-025-02177-z
4. Yu Y, Liu X, Zang Z, et al. Enhanced meningeal lymphatic drainage alleviates cognitive dysfunction induced by anesthesia and surgery in aged mice. Neuropharmacology. 2025;280:110674. doi:10.1016/j.neuropharm.2025.110674
5. Da Mesquita S, Papadopoulos Z, Dykstra T, et al. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature. 2021;593(7858):255-260. doi:10.1038/s41586-021-03489-0
6. Bolte AC, Dutta AB, Hurt ME, et al. Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis. Nat Commun. 2020;11(1):4524. doi:10.1038/s41467-020-18113-4
7. Rustenhoven J, Pavlou G, Storck SE, et al. Age-related alterations in meningeal immunity drive impaired CNS lymphatic drainage. J Exp Med. 2023;220(7):e20221929. doi:10.1084/jem.20221929
8. Zhou Y, Ran W, Luo Z, et al. Impaired peri-olfactory cerebrospinal fluid clearance is associated with ageing, cognitive decline and dyssomnia. EBioMedicine. 2022;86:104381. doi:10.1016/j.ebiom.2022.104381