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Acta Neuropathol. 2018 Mar;135(3):387-407. doi: 10.1007/s00401-018-1812-4. Epub 2018 Feb 10.

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

Abbott NJ1, Pizzo ME2,3, Preston JE4, Janigro D5,6, Thorne RG7,8,9,10,11,12.

Author information

1
Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building 3.82, 150 Stamford St, London, SE1 9NH, UK. joan.abbott@kcl.ac.uk.
2
Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA.
3
Clinical Neuroengineering Training Program, University of Wisconsin-Madison, Madison, WI, USA.
4
Faculty of Life Sciences and Medicine, Institute of Pharmaceutical Science, King's College London, Franklin Wilkins Building 3.82, 150 Stamford St, London, SE1 9NH, UK.
5
Flocel Inc., Cleveland, OH, USA.
6
Department of Physiology, Case Western Reserve University, Cleveland, OH, USA.
7
Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA. robert.thorne@wisc.edu.
8
Clinical Neuroengineering Training Program, University of Wisconsin-Madison, Madison, WI, USA. robert.thorne@wisc.edu.
9
Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI, USA. robert.thorne@wisc.edu.
10
Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin-Madison, Madison, WI, USA. robert.thorne@wisc.edu.
11
Institute for Clinical and Translational Research, University of Wisconsin-Madison, Madison, WI, USA. robert.thorne@wisc.edu.
12
, 5113 Rennebohm Hall, 777 Highland Avenue, Madison, WI, 53705, USA. robert.thorne@wisc.edu.

Abstract

Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K+, Ca2+, 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.

KEYWORDS:

Blood–brain barrier; Cerebrospinal fluid; Extracellular space; Glymphatic; Interstitial fluid; Perivascular space

PMID:
29428972
DOI:
10.1007/s00401-018-1812-4

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