Cerebrospinal fluid outflow pathways in neurodegeneration: nasopharyngeal lymphatics and the ocular glymphatic-like axis
- 1Department of Neurosurgery, Affiliated Hospital of Zunyi Medical University , , ,
- 2Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University , , ,
Abstract
The glymphatic system supports cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange and has been implicated, to different extents, in the transport or clearance of amyloid-β (Aβ), tau, lactate and other solutes. Although most studies have focused on CSF influx, astrocytic aquaporin 4 (AQP4) expression, perivascular localisation and polarisation, AQP4-mediated transmembrane water transport, and perivascular exchange, brain clearance also depends on efficient extracranial drainage of waste-containing fluid. In this narrative Review, we examine this ‘outflow end’, including meningeal lymphatic vessels, the cribriform plate-olfactory-nasal mucosal route, cranial perineural spaces, the nasopharyngeal lymphatic plexus, cervical lymphatic vessels and deep cervical lymph nodes. We highlight the skull base and nasopharyngeal lymphatic plexus as potential interfaces between intracranial CSF and extracranial lymphatic drainage and evaluate the route- and cargo-specific evidence for bulk-fluid and generic-tracer transport, soluble-protein clearance, aggregated-protein handling and immune-antigen drainage. We also consider experimental strategies targeting lymphatic contractility, VEGF-C–VEGFR3 signalling, mechanical stimulation, pressure gradients, AQP4-mediated transmembrane water transport and experimentally observed light-induced pupillary modulation. Throughout, we emphasise that evidence for individual cargoes, including Aβ, tau and α-synuclein, is uneven across anatomical routes and remains predominantly preclinical or indirect. Future studies integrating high-resolution lymphatic imaging, functional biomarkers and longitudinal or interventional designs are needed to determine whether altered CSF outflow is a consequence of neurodegeneration, a contributor to disease progression or a potentially modifiable process in neurodegenerative disease.
Related
- The Glymphatic System in Traumatic Brain Injury, Subarachnoid Hemorrhage, and Neurodegeneration: A Unifying Neurobiological Framework
- Glaucoma neurodegeneration: targeted modulation of intraocular immune pathways – a review of novel therapeutic advances
- Noninvasive ultrashort wave neuromodulation enhances glymphatic clearance to alleviate traumatic brain edema and Alzheimer’s pathology
- Glymphatic system impairment in neurological disorders: potential mechanisms and therapeutic targets
- Modifiable glymphatic-related brain clearance physiology in humans: a critical narrative review of interventional evidence
BibTeX
@article{liu2026cerebrospinal,
title = {{Cerebrospinal fluid outflow pathways in neurodegeneration: nasopharyngeal lymphatics and the ocular glymphatic-like axis}},
author = {Jiaqi Liu and Junzhe Chen and Shaoxiang Yuan and Yuezhong Chen and Ziyi Luo and Mingguo Xie},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1929822},
url = {https://europepmc.org/article/PMC/PMC13669845},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cerebrospinal fluid outflow pathways in neurodegeneration: nasopharyngeal lymphatics and the ocular glymphatic-like axis
AU - Jiaqi Liu
AU - Junzhe Chen
AU - Shaoxiang Yuan
AU - Yuezhong Chen
AU - Ziyi Luo
AU - Mingguo Xie
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1929822
UR - https://europepmc.org/article/PMC/PMC13669845
AB - The glymphatic system supports cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange and has been implicated, to different extents, in the transport or clearance of amyloid-β (Aβ), tau, lactate and other solutes. Although most studies have focused on CSF influx, astrocytic aquaporin 4 (AQP4) expression, perivascular localisation and polarisation, AQP4-mediated transmembrane water transport, and perivascular exchange, brain clearance also depends on efficient extracranial drainage of waste-containing fluid. In this narrative Review, we examine this ‘outflow end’, including meningeal lymphatic vessels, the cribriform plate-olfactory-nasal mucosal route, cranial perineural spaces, the nasopharyngeal lymphatic plexus, cervical lymphatic vessels and deep cervical lymph nodes. We highlight the skull base and nasopharyngeal lymphatic plexus as potential interfaces between intracranial CSF and extracranial lymphatic drainage and evaluate the route- and cargo-specific evidence for bulk-fluid and generic-tracer transport, soluble-protein clearance, aggregated-protein handling and immune-antigen drainage. We also consider experimental strategies targeting lymphatic contractility, VEGF-C–VEGFR3 signalling, mechanical stimulation, pressure gradients, AQP4-mediated transmembrane water transport and experimentally observed light-induced pupillary modulation. Throughout, we emphasise that evidence for individual cargoes, including Aβ, tau and α-synuclein, is uneven across anatomical routes and remains predominantly preclinical or indirect. Future studies integrating high-resolution lymphatic imaging, functional biomarkers and longitudinal or interventional designs are needed to determine whether altered CSF outflow is a consequence of neurodegeneration, a contributor to disease progression or a potentially modifiable process in neurodegenerative disease.
SN - 1664-3224
ER -