Cited by 596Cerebrospinal fluid and hydrocephalusIon Transport and Channel RegulationBarrier Structure and Function Studies

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The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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Abbott, N. Joan, Pizzo, Michelle E., Preston, Jane E., Janigro, Damir, Thorne, Robert G.·2018·Acta Neuropathologica

DOI 10.1007/s00401-018-1812-4

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Abstract

, 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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A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β
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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.
ORCID: Abbott, N. Joan
Pizzo, Michelle E.
Preston, Jane E.
Janigro, Damir
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2018-02-10
Volume: 135
Issue: 3
Pages: 387-407
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-018-1812-4
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
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
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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The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

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