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The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?
Open accessAbstract
, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.
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“Leveraging convective CSF flow along perivascular spaces could overcome diffusional limitations and provide a direct mechanism for transport to deep brain structures [13–15].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [13]
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Metadata
- Authors
- Abbott, N. J., Pizzo, M. E., Preston, J. E., Janigro, D., & Thorne, R. G.
- Affiliations
- King's College London (GB)
- University of Wisconsin–Madison (US)
- Case Western Reserve University (US)
- Corresponding author
- Abbott, N. Joan
- Thorne, Robert G.
- Venue
- Acta Neuropathologica
- Published
- 2018-02-10
- Volume
- 135
- Issue
- 3
- Pages
- 387-407
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2789376055
- Cited by
- 593
- References
- 202
- Citations by year
- 2026: 38 · 2025: 55 · 2024: 72 · 2023: 64 · 2022: 102 · 2021: 84 · 2020: 79 · 2019: 63 · 2018: 35
- FWCI
- 8.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Acta Neuropathologica (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- Michael J. Fox Foundation for Parkinson's Research (Therapeutic Pipeline Grant Award)
- NIH National Center for Advancing Translational Sciences (UL1TR000427, KL2TR00428)
- National Science Foundation Graduate Research Fellowship Program (DGE-1256259)
- Medical Research Council
- NIH Predoctoral Training Fellowship-Univ Wisconsin-Madison Clinical Engineering Program (NRSA T32 EBO11434)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, cerebrospinal fluid, interstitial fluid, brain extracellular space, aquaporin-4, perivascular spaces, brain waste clearance, astrocytes, hydraulic conductivity, extracellular matrix, neurovascular unit, cerebrospinal fluid drainage, brain drug delivery, neuropathology
- MeSH terms
- Animals, Blood-Brain Barrier, Cerebrospinal Fluid, Humans, Extracellular Fluid, Hydrodynamics
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