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

Abstract

Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , 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.

Spectral Diffusion Analysis of Intravoxel Incoherent Motion MRI in Cerebral Small Vessel Disease

“…Although it has previously been shown in the rat brain that diffusion MRI has the potential for the assessment of perivascular fluid motion in relation to the glymphatic system, whether the current clinical application of NNLS‐based IVIM can accurately detect glymphatic failure remains to be investigated. For this, future studies should combine these measures with assessments of cardiac pulsatility (eg, pulsatility of small perforating lenticulostriatal arteries) and aquaporin‐4 dependent fluid movement . Additionally, it would be interesting to compare the NNLS approach with methods that can separate diffusion properties of brain tissue from surrounding free water while mapping the free water volume …”

Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain

“…Historically, ISF is considered to be produced at the blood–brain barrier and to drain out of the brain towards the CSF [1, 14, 24, 53]. Pathways for a bulk flow of ISF from the brain parenchyma were found to be along peri-(or para-) vascular spaces (PVS) to reach the subarachnoid space (SAS) [13, 24, 53, 57] or along white matter fiber tracts to reach the ventricles [13, 46, 48].…”

“…Interestingly, this system was found to be more active during sleeping or anesthetized conditions compared to awake conditions [54]. However, at this time, these studies remain highly controversial and several groups have challenged various aspects of the concept [1, 3, 5, 19, 21, 25, 26, 50, 51]. …”

Central nervous system lymphatic unit, immunity, and epilepsy: Is there a link?

“…At spinal cord level, protein concentration in the CSF is higher and includes a component of white blood cells. The CSF has a pulsatile flow (along the antero-posterior axis), as systolic and diastolic pressure changes impact CSF flow velocity and direction 21 . The CSF is produced by the choroid plexus (up to 80%) filling the lateral, third, and fourth ventricles, while the remaining 20% may derive from the ependymal cells lining the ventricles and from the subarachnoid space.…”

“…19,21 A component of the CSF flows along the Virchow-Robin space and in the perivascular space (pia and the glia limitans). 21,22 The interchange and mixing between the CSF and ISF is difficult to estimate, as it may vary depending on brain region (eg, depth of the cortical layers or proximity to ventricles where the CSF can diffuse). The CSF has a pulsatile flow (along the antero-posterior axis), as systolic and diastolic pressure changes impact CSF flow velocity and direction 21 .…”