The glymphatic pathway in neurological disorders.
Open accessAbstract
Background The glymphatic (glial-lymphatic) pathway is a fluid-clearance pathway identified in the rodent brain in 2012. This pathway subserves the flow of CSF into the brain along arterial perivascular spaces and subsequently into the brain interstitium, facilitated by aquaporin 4 (AQP4) water channels. The pathway then directs flow towards the venous perivascular and perineuronal spaces, ultimately clearing solutes from the neuropil into meningeal and cervical lymphatic drainage vessels. In rodents, the glymphatic pathway is predominantly active during sleep, when the clearance of harmful metabolites such as amyloid β (Aβ) increases two-fold relative to the waking state. Glymphatic dysfunction, probably related to perturbed AQP4 expression, has been shown in animal models of traumatic brain injury, Alzheimer's disease, and stroke. The recent characterisations of the glymphatic and meningeal lymphatic systems in rodents and in humans call for revaluation of the anatomical routes for CSF-interstitial fluid flow and the physiological role that these pathways play in CNS health.Recent developments Several features of the glymphatic and meningeal lymphatic systems have been shown to be present in humans. MRI scans with intrathecally administered contrast agent show that CSF flows along pathways that closely resemble the glymphatic system outlined in rodents. Furthermore, PET studies have revealed that Aβ accumulates in the healthy brain after a single night of sleep deprivation, suggesting that the human glymphatic pathway might also be primarily active during sleep. Other PET studies have shown that CSF clearance of Aβ and tau tracers is reduced in patients with Alzheimer's disease compared with healthy controls. The observed reduction in CSF clearance was associated with increasing grey-matter concentrations of Aβ in the human brain, consistent with findings in mice showing that decreased glymphatic function leads to Aβ accumulation. Altered AQP4 expression is also evident in brain tissue from patients with Alzheimer's disease or normal pressure hydrocephalus; glymphatic MRI scans of patients with normal pressure hydrocephalus show reduced CSF tracer entry and clearance. WHERE NEXT?: Research is needed to confirm whether specific factors driving glymphatic flow in rodents also apply to humans. Longitudinal imaging studies evaluating human CSF dynamics will determine whether a causal link exists between reduced brain solute clearance and the development of neurodegenerative diseases. Assessment of glymphatic function after stroke or traumatic brain injury could identify whether this function correlates with neurological recovery. New insights into how behaviour and genetics modify glymphatic function, and how this function decompensates in disease, should lead to the development of new preventive and diagnostic tools and novel therapeutic targets.
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AQP4 alteration is associated with glymphatic dysfunction and increased Aβ burden.
“Considering that AQP4 is the gold‐standard marker for astrocyte endfeet, and its alteration has been associated with glymphatic dysfunction [103] and increased Aβ burden [104]”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [103]
The brain glymphatic and meningeal lymphatic systems work together to clear waste and macromolecules from the brain parenchyma in homeostasis and following injury.
“The brain glymphatic and meningeal lymphatic systems work together to clear waste and macromolecules from the brain parenchyma in homeostasis and following injury”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Rasmussen et al., 2018
Several lines of evidence implicate meningeal-located structures in the genesis and progression of Alzheimer's disease (AD).
“Several lines of evidence implicate meningeal-located structures in the genesis and progression of Alzheimer’s disease (AD)”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Rasmussen et al., 2018
The transport of interstitial fluids and macromolecules (including amyloid-β peptides) out of the brain occurs via a complex transport network that utilizes the perivascular glymphatic system of the brain and lymphatic vessels of the meninges.
“The transport of interstitial fluids and macromolecules (including amyloid-β peptides) out of the brain occurs via a complex transport network that utilizes the perivascular glymphatic system of the brain and lymphatic vessels of the meninges”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Rasmussen et al., 2018
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- Authors
- Rasmussen, M. K., Mestre, H., & Nedergaard, M.
- Affiliations
- University of Copenhagen (DK)
- University of Rochester Medicine (US)
- Corresponding author
- Nedergaard, Maiken
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 17
- Issue
- 11
- Pages
- 1016-1024
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC6261373
- OpenAlex
- W2895939677
- Cited by
- 1,560
- References
- 73
- Citations by year
- 2026: 249 · 2025: 291 · 2024: 206 · 2023: 174 · 2022: 251 · 2021: 176 · 2020: 138 · 2019: 73 · 2018: 1
- FWCI
- 12.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke
- Novo Nordisk Fonden
- Cure Alzheimer's Fund
- National Institutes of Health (R01NS100366, RF1AG057575)
- EU Joint Programme – Neurodegenerative Disease Research
- Fondation Leducq
- Lundbeckfonden
- National Institute on Aging
- Horizon 2020 (666881)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- meningeal lymphatic system, aquaporin-4, cerebrospinal fluid clearance, amyloid-beta, sleep, Alzheimer's disease, traumatic brain injury, stroke, normal pressure hydrocephalus, cerebrospinal fluid flow, glymphatic dysfunction, neurodegeneration, brain interstitial fluid, sleep deprivation
- MeSH terms
- Glymphatic System, Humans, Nervous System Diseases
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