The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework

Abstract

Whether glymphatic dysfunction drives or merely follows brain injury and neurodegeneration remains unresolved. The glymphatic system mediates the transport, exchange, and clearance of solutes between cerebrospinal fluid (CSF) and interstitial fluid (ISF) through paravascular CSF influx, polarized aquaporin-4 (AQP4) at astrocytic endfeet, and meningeal lymphatic drainage. This narrative review synthesizes evidence on glymphatic regulation and its role in traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), and neurodegeneration, and appraises imaging, biomarker, and therapeutic approaches. PubMed/MEDLINE and Google Scholar were searched from inception to August 2026, and 128 sources were analyzed. In TBI, mechanical shear and NLR family pyrin domain-containing 3 (NLRP3)-dependent inflammation may alter AQP4 distribution and impair tau and amyloid-beta (Aβ) clearance; however, glymphatic failure has not been established as the causal mediator of later neurodegeneration, which is likely multifactorial. After SAH, blood and fibrin may obstruct perivascular pathways, and hemoglobin, heme, and iron toxicity may further disrupt CSF–ISF exchange; these changes are associated with delayed cerebral ischemia, cortical spreading depolarizations, and post-hemorrhagic hydrocephalus. Impaired clearance of Aβ, phosphorylated tau, and α-synuclein may link glymphatic dysfunction to Alzheimer’s and Parkinson’s diseases, although causality is unproven. Current imaging tools, including diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), and biomarkers do not yet provide a validated measure of glymphatic function. Sleep optimization is a low-risk strategy, and controlled lumbar drainage has the strongest clinical evidence among CSF-dynamics approaches. Translation requires appropriate animal models and prospective TBI/SAH studies combining serial DTI-ALPS with cognitive follow-up.