The role of the brain-lymphatic axis in traumatic brain injury-associated cognitive impairment: from glymphatic system clearance dysfunction to peripheral lymphatic stasis

Traumatic brain injury (TBI) affects over 69 million people yearly, and post‑TBI cognitive impairment (CTTI) often persists for years. The brain‑lymphatic axis – the central glymphatic system and peripheral lymphatic vessels – plays a key role. Glymphatic dysfunction (loss of AQP4 polarization) causes metabolic waste accumulation and neuroinflammation, while peripheral lymphatic stasis worsens cognitive decline. Most studies investigate the two systems in isolation; longitudinal data, non‑invasive biomarkers, and combined therapies are lacking. This review synthesizes current evidence, identifies gaps, and proposes integrated axis‑targeted approaches.

Introduction
TBI is a major cause of disability. Secondary cognitive impairment severely affects quality of life. The brain‑lymphatic axis (glymphatic system + meningeal/ peripheral lymphatics) clears wastes (Aβ, tau) and regulates neuroinflammation. After TBI, glymphatic dysfunction and peripheral stasis drive a vicious cycle of waste accumulation, inflammation, and neuronal damage, leading to CTTI. Research gaps include isolated system studies, lack of longitudinal tracking, insufficient diagnostic tools, and few combined therapies.

Epidemiology and Clinical Features
Annual TBI incidence: 69 million. Severe TBI causes significant IQ reduction persisting into chronic phase. Older age and comorbidities (hypertension, diabetes) increase risk. Clinical features: short‑term memory loss, executive dysfunction, attention deficits, slowed processing speed.

Pathophysiology
Neuronal injury, axonal damage, sustained neuroinflammation (IL‑1β, TNF‑α), and oxidative stress drive CTTI.

Brain‑Lymphatic Axis: Physiology and Pathophysiology
Physiology: Glymphatic system – periarterial CSF inflow → AQP4‑mediated exchange → perivenous ISF outflow. Clears wastes, enhanced during sleep. Meningeal lymphatics drain glymphatic effluents to cervical nodes. Together they maintain BBB integrity and limit neuroinflammation.

After TBI:

• Glymphatic dysfunction: Mechanical damage to astrocytic endfeet disrupts AQP4 polarization, reduces waste clearance. BBB disruption worsens inflammation.

• Neuroinflammation loop: Microglial cytokines downregulate AQP4, further impairing clearance and creating positive feedback.

• Peripheral stasis: Trauma to cervical lymphatics blocks drainage, traps inflammatory mediators, and amplifies neuroinflammation via a compromised BBB. This vicious cycle drives CTTI.

Diagnosis

• Neuropsychological tests: Wechsler scales, Digit Symbol, Rey Auditory Verbal Learning Test, Trail Making Test.

• Imaging: Near‑infrared fluorescence (lymphatic contractility); contrast MRI/PET (CSF outflow); optical coherence tomography (meningeal lymphatics).

• Biomarkers: DTI‑ALPS index (lower = glymphatic dysfunction); CSF neurofilament light chain (injury severity).

Therapeutic Strategies

• Glymphatic enhancement: Regulate AQP4 (VEGF‑C); optimize sleep (lateral position, good quality).

• Peripheral drainage: Lymphatic massage; VEGF‑C therapy (promotes lymphangiogenesis).

• Multi‑target combinations: Anti‑inflammatory drugs + glymphatic enhancers.

• Surgery: Cisternostomy reduces intracranial pressure by facilitating CSF backflow.

Future Directions & Challenges

• Longitudinal multimodal imaging (PET‑MRI) to track axis changes across TBI stages.

• Individualized treatment using CSF biomarkers and AQP4 genetic variants.

• Translational challenges: animal models poorly mimic human TBI; need better trial endpoints (including quality of life).

Limitations
Limited clinical research; caution in generalizing to humans. Few studies on disease heterogeneity linked to brain‑lymphatic axis.

Conclusions
The brain‑lymphatic axis is central to post‑TBI cognitive impairment. Glymphatic dysfunction and peripheral stasis create a vicious cycle of waste accumulation and inflammation. Key gaps: isolated system studies, lack of longitudinal tracking, insufficient diagnostic tools, and few combined therapies. Addressing these will improve long‑term TBI outcomes.

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https://www.xiahepublishing.com/3067-6150/NSSS-2025-00025

The study was recently published in the Neurosurgical Subspecialties.

Neurosurgical Subspecialties (NSSS) is the official scientific journal of the Department of Neurosurgery at Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. NSSS aims to provide a forum for clinicians and scientists in the field, dedicated to publishing high-quality and peer-reviewed original research, reviews, opinions, commentaries, case reports, and letters across all neurosurgical subspecialties. These include but are not limited to traumatic brain injury, spinal and spinal cord neurosurgery, cerebrovascular disease, stereotactic radiosurgery, neuro-oncology, neurocritical care, neurosurgical nursing, neuroendoscopy, pediatric neurosurgery, peripheral neuropathy, and functional neurosurgery.

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