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The glymphatic system’s role in traumatic brain injury-related neurodegeneration

Molecular Psychiatry volume 28, pages 2707–2715 (2023)Cite this article

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Abstract

In at least some individuals who suffer a traumatic brain injury (TBI), there exists a risk of future neurodegenerative illness. This review focuses on the association between the brain-based paravascular drainage pathway known as the “glymphatic system” and TBI-related neurodegeneration. The glymphatic system is composed of cerebrospinal fluid (CSF) flowing into the brain parenchyma along paravascular spaces surrounding penetrating arterioles where it mixes with interstitial fluid (ISF) before being cleared along paravenous drainage pathways. Aquaporin-4 (AQP4) water channels on astrocytic end-feet appear essential for the functioning of this system. The current literature linking glymphatic system disruption and TBI-related neurodegeneration is largely based on murine models with existing human research focused on the need for biomarkers of glymphatic system function (e.g., neuroimaging modalities). Key findings from the existing literature include evidence of glymphatic system flow disruption following TBI, mechanisms of this decreased flow (i.e., AQP4 depolarization), and evidence of protein accumulation and deposition (e.g., amyloid β, tau). The same studies suggest that glymphatic dysfunction leads to subsequent neurodegeneration, cognitive decline, and/or behavioral change although replication in humans is needed. Identified emerging topics from the literature are as follows: link between TBI, sleep, and glymphatic system dysfunction; influence of glymphatic system disruption on TBI biomarkers; and development of novel treatments for glymphatic system disruption following TBI. Although a burgeoning field, more research is needed to elucidate the role of glymphatic system disruption in TBI-related neurodegeneration.

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Fig. 1: CSF Drainage Pathways from Subarachnoid Space.
Fig. 2: Glymphatic System.

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  1. Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Matthew E. Peters & Constantine G. Lyketsos

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MEP: conceptualization, methodology, writing—original draft preparation, writing—review and editing, visualization. CGL: conceptualization, writing—review and editing, visualization, supervision.

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Peters, M.E., Lyketsos, C.G. The glymphatic system’s role in traumatic brain injury-related neurodegeneration. Mol Psychiatry 28, 2707–2715 (2023). https://doi.org/10.1038/s41380-023-02070-7

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