The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework
6 affiliations
- 1Department of Neurosurgery, Mardan Medical Complex, Mardan 23200, Pakistan
- 2Bacha Khan Medical College, , Mardan 23200, Pakistan; (S.U.I.); (Z.B.); (S.S.)
- 3Khyber Girls Medical College, , Peshawar 25100, Pakistan; (S.R.); (S.R.I.)
- 4Khyber Medical College, , Peshawar 25120, Pakistan; (N.-u.-E.H.); (S.M.)
- 5Department of Pharmacy, Islamabad, Islamabad 45320, Pakistan;
- 6Department of Neurosurgery, , Tucson, AZ 85721, USA
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.
Related
- Noninvasive ultrashort wave neuromodulation enhances glymphatic clearance to alleviate traumatic brain edema and Alzheimer’s pathology
- Identification and In Vitro Validation of Metabolic Reprogramming-Related Hub Genes for the Diagnosis of Subarachnoid Hemorrhage
- Cerebrospinal fluid outflow pathways in neurodegeneration: nasopharyngeal lymphatics and the ocular glymphatic-like axis
- Linoleic Acid-Lyso PG Axis promoting lipid droplet-mitochondria tethering by stabilizing Noncanonically Mitochondrial PPAR β/δ to Ameliorate Microglial Dysfunction in subarachnoid hemorrhage
- Dietary Modulation of Neurobiological Mechanisms Underlying Executive Function and Decision-Making: A Systematic Review
BibTeX
@article{haq2026glymphatic,
title = {{The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework}},
author = {Naeem Ul Haq and Sardar Umer Irshad and Zainab Bibi and Sawera Rehman and Sumra Sohail and Sardar Remsha Irshad and Noor-ul-Eman Haider and Shah Mir and Asad Shareef and Brandon Lucke-Wold},
journal = {Biomedicines},
year = {2026},
month = oct,
doi = {10.3390/biomedicines14102314},
url = {https://europepmc.org/article/PMC/PMC13701540},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework
AU - Naeem Ul Haq
AU - Sardar Umer Irshad
AU - Zainab Bibi
AU - Sawera Rehman
AU - Sumra Sohail
AU - Sardar Remsha Irshad
AU - Noor-ul-Eman Haider
AU - Shah Mir
AU - Asad Shareef
AU - Brandon Lucke-Wold
PY - 2026
DA - 2026/10/01
JO - Biomedicines
DO - 10.3390/biomedicines14102314
UR - https://europepmc.org/article/PMC/PMC13701540
AB - 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.
SN - 2227-9059
ER -