Mechanisms to explain the reverse perivascular transport of solutes out of the brain
Introduction
Extracellular fluid of the brain consists of cerebrospinal fluid (CSF) in the ventricles and subarachnoid space (SAS) and interstitial fluid (ISF) within the brain parenchyma (Cserr and Knopf, 1992, Weller, 1998). CSF is produced by the choroid plexuses in the cerebral ventricles and drains from the subarachnoid spaces into the blood via arachnoid granulations and villi in humans (Davson et al., 1987) and largely into cervical lymph nodes via nasal lymphatics in rodents and other non-primates (Zakharov et al., 2003). ISF is mainly derived from the blood and drains from the grey matter of the brain by diffusion through the extracellular spaces and by bulk flow along perivascular spaces (PVS) (Cserr and Patlak, 1992, Zhang et al., 1992, Kida et al., 1993, Nicholson et al., 2000) that are, in effect the lymphatic drainage pathways of the brain.
There is evidence from tracer studies in experimental animals and from pathology of the human brain that the PVS carry solutes from the brain (Weller and Nicoll, 2003). Probably the best example is seen in the elderly and in Alzheimer's disease (AD) in which the soluble peptide, -Amyloid , is deposited in the PVS in an insoluble form resulting in cerebral amyloid angiopathy (CAA) (Weller et al., 1998, Preston et al., 2003). A similar pattern of deposition in blood vessel walls is seen in transgenic mouse models of AD (Van Dorpe et al., 2000). Entrapment of in blood vessel walls has implications for the pathogenesis of Alzheimer's disease as the blockage of ISF drainage pathways would result in alteration of the composition of ISF in the brain. Furthermore, failure of elimination of from the brain may be a significant factor in the accumulation of in brain tissue as one of the major features of AD.
If there is to be further development of therapies for the elimination of in the treatment or prevention of AD, it is essential that the driving forces for the elimination of from the brain along PVS are understood, and also why such forces fail with age.
The pattern of deposition of in CAA suggests that PVS are routes for the drainage of solutes and ISF drainage from the brain. Ultrastructural and immunocytochemical studies have shown that is deposited in the basement membranes that surround capillaries and the smooth muscle cells in artery walls (Yamaguchi et al., 1992, Wisniewski and Wegiel, 1994, Weller et al., 1998, Preston et al., 2003). These observations suggest that the vascular basement membranes are the conduit for the perivascular drainage of (Weller and Nicoll, 2003). Furthermore, as the extracellular spaces of the brain are only in direct contact with the basement membrane around capillaries, it seems likely that enters the drainage pathway at the level of the capillary and then drains along the walls of arteries out of the brain (Preston et al., 2003). In artery walls, there are multiple layers of basement membrane between the smooth muscle cells of the media but none is in direct contact with the extracellular space of the surrounding brain. Furthermore, cortical arteries are surrounded by a layer of pia mater and the glia limitans that separate the artery wall from the extracellular spaces of the brain (Zhang et al., 1990, Preston et al., 2003); see Fig. 1.
The PVS in the walls of cerebral capillaries consists of one layer, the basement membrane, some 150 nm in thickness; and cerebral arteries have multiple layers of basement membrane between smooth muscle cells of the media. From the patterns of deposition of tracers in experimental animal arteries (Carare-Nnadi et al., 2005) and of in human arteries (Preston et al., 2003, Wisniewski et al., 1997) it appears that the basement membrane could be a major conduit for the drainage of ISF and from the brain. The aim of this paper is to examine the mechanisms that might facilitate the transport of ISF and solutes within the PVS of capillaries and arteries in the brain. Firstly, fluid transport within the PVS is considered, as determined by local pressure differences and fluid flow inside the arterial system. Secondly, conditions under which solutes may be transported along the PVS as a result of global pressure differences are reviewed. Thirdly, a model of pulse driven flow of ISF and solutes along the PVS is proposed. The results for a number of different possibilities are presented and their implications for the pathogenesis, treatment and prevention of AD are considered in the discussion.
Section snippets
Pulse independent solute transport
In a fluid filled compartment, any pressure difference will result in fluid flow down the pressure gradient. This will continue until a pressure equilibrium has been attained; this may never occur if the upstream pressure is maintained by the production of fluid and the downstream pressure remains lower through the drainage of fluid.
In the normal brain, pressure of the ISF is higher than CSF pressure; this, favours flow of ISF from the interstitial spaces (ISS) of the cerebral cortex to CSF on
Pulse driven solute transport
In this section conditions under which fluid in the PVS may flow in the opposite direction to that of the blood in the artery lumen are considered, assuming that the only potential driving force is the pulsatile flow in the artery itself.
It appears that there are no previous models that consider the dynamics of the PVS. There has been extensive interest in the mathematical modelling of peristaltic pump mechanisms (see Section 3.2) which are applicable to this problem. Most peristaltic systems
Modelling results
Further assumptions to the general model developed above are required, both to make it amenable to analysis but more importantly for results to be directly relevant to arterial PVS. Therefore, a number of special cases are considered, to indicate which factor or factors are most significant—or, conversely, appear not to play a role—in determining the potential of pulsatile flow to drive reverse drainage.
Since it is unclear exactly how much radial fluid exchange occurs between the PVS and the
Discussion
In this paper, conditions have been outlined by which it is possible for pulsatile flow in arteries to generate reverse transport of interstitial fluid, and thus solutes, out of the brain along perivascular spaces (PVS). There are limitations to current experiments so that a theoretical approach has been necessary to investigate this transport system. Such limitations also apply to any practical test of results at the present time. It is suggested, however, that all modelling assumptions—which
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