Mechanisms to explain the reverse perivascular transport of solutes out of the brain

Abstract

Experimental studies and observations in the human brain indicate that interstitial fluid and solutes, such as amyloid-$\beta$ $(\mathrm{A}\beta )$, are eliminated from grey matter of the brain along pericapillary and periarterial pathways. It is unclear, however, what constitutes the motive force for such transport within blood vessel walls, which is in the opposite direction to blood flow. In this paper the potential for global pressure differences to achieve such transport are considered. A mathematical model is constructed in order to test the hypothesis that perivascular drainage of interstitial fluid and solutes out of brain tissue is driven by pulsations of the blood vessel walls. Here it is assumed that drainage occurs through a thin layer between astrocytes and endothelial cells or between smooth muscle cells. The model suggests that, during each pulse cycle, there are periods when fluid and solutes are driven along perivascular spaces in the reverse direction to the flow of blood. It is shown that successful drainage may depend upon some attachment of solutes to the lining of the perivascular space, in order to produce a valve-like effect, although an alternative without this requirement is also postulated. Reduction in pulse amplitude, as in ageing cerebral vessels, would prolong the attachment time, encourage precipitation of $\mathrm{A}\beta$ peptides in vessel walls, and impair elimination of $\mathrm{A}\beta$ from the brain. These factors may play a role in the pathogenesis of cerebral amyloid angiopathy and in the accumulation of $\mathrm{A}\beta$ in the brain in Alzheimer's disease.

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, $\beta$-Amyloid $(\mathrm{A}\beta )$, 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 $\mathrm{A}\beta$ deposition in blood vessel walls is seen in transgenic mouse models of AD (Van Dorpe et al., 2000). Entrapment of $\mathrm{A}\beta$ 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 $\mathrm{A}\beta$ from the brain may be a significant factor in the accumulation of $\mathrm{A}\beta$ in brain tissue as one of the major features of AD.

If there is to be further development of therapies for the elimination of $\mathrm{A}\beta$ in the treatment or prevention of AD, it is essential that the driving forces for the elimination of $\mathrm{A}\beta$ from the brain along PVS are understood, and also why such forces fail with age.

The pattern of deposition of $\mathrm{A}\beta$ 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 $\mathrm{A}\beta$ 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 $\mathrm{A}\beta$ (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 $\mathrm{A}\beta$ 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 $\mathrm{A}\beta$ 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 $\mathrm{A}\beta$ 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.