The pathological increase in brain catabolites after traumatic brain injury strongly correlates with a higher risk of neurodegenerative disease. This review examines the pathogenic role of glymphatic clearance dysfunction in that process. The glymphatic network enables cerebrospinal and interstitial fluid exchange and paracellular flow. These processes are mediated by astrocytic aquaporin-4. Glymphatic function is regulated by arterial pulsatility, sleep-wake cycles, and intramural periarterial drainage, with meningeal lymphatic vessels acting as the final drainage site. Mechanical trauma causes aquaporin-4 depolarization and mislocalization; it also triggers neuroinflammatory activation and blood-brain barrier disruption. These processes ultimately impair glymphatic function and neurotoxic proteins become more localized and overproduced. Previous studies have linked clearance defects to secondary neuron injury. Current evidence in humans has come mostly from pilot studies. Recent advances in neuroimaging provide new assessment tools. Dynamic contrast-enhanced magnetic resonance imaging (MRI) reveals delayed tracer clearance. Diffusion tensor imaging along perivascular spaces shows abnormalities in key parameters. These imaging findings preliminarily associate with fluctuations in cerebrospinal fluid catabolites. Therapeutic research suggests several reparative strategies. Physical exercise improves aquaporin-4 polarization integrity. Cannabidiol administration in experimental models increases meningeal lymphatic drainage and reduces tau pathology. Angiotensin II type 1 receptor antagonists may indirectly improve clearance by stabilizing the blood-brain barrier. Lymphatic pathways have been used as therapeutic targets for cannabidiol. Biological evidence also supports their role in traumatic brain injury progression. Further investigation is needed to validate whether these represent independent contributing processes. Multimodal imaging, novel biomarker assays, and chronobiological modulation strategies are improving visualization. Microfluidic modeling could clarify the glymphatic-biomarker relationship; it may also advance precision medicine approaches for traumatic brain injury.
Yang et al. (2026) studied this question.