Veins and Neurodegeneration

Since the earliest years of research into MS, there has been suspicion that the venous system might be involved in its aetiology, with Dawson [12], Putnam [13, 14] and others [15-19] all implicating veins in the pathophysiology of the disease. MS plaques are often venocentric and frequently form in the periventricular white matter (WM) [6]. The formation of fingerlike plaques at the junction of the

C. Beggs, PhD

Buffalo Neuroimaging Analysis Center, Department of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo, 100 High St, Buffalo 14203, NY, USA

Institute for Sport, Physical Activity and Leisure, Carnegie Faculty, Leeds Beckett University,

Leeds LS1 3HE, UK

e-mail: This email address is being protected from spam bots, you need Javascript enabled to view it © Springer International Publishing AG 2017

A. Minagar, J.S. Alexander (eds.), Inflammatory Disorders of the Nervous System, Current Clinical Neurology, DOI 10.1007/978-3-319-51220-4_13

subependymal and medullary veins was first reported by Dawson [12] in the early twentieth century. Later, Putnam and Adler [14], commenting on the appearance of these ‘Dawson fingers’, observed that the medullary veins were enclosed in a sleeve of plaque and that, adjacent to these plaques, the veins were grossly distorted and distended. Others [19-22] have also shown that inflammatory lesions tend to form axially around veins in the WM, with Tallantyre et al. [23] finding 80% of MS lesions to be perivenous in nature. MS lesions in the grey matter have also been associated with veins, with Kidd et al. [21] finding the majority of cortical lesions arising within the territory of the principal vein, V5, whose course begins in the WM [24], and the remaining cortical lesions forming in the region drained by its branches or those of the superficial veins. Others have confirmed these observations, finding intracortical [25-27], leucocortical [25] and subcortical [20] lesions all to be perivenous in nature.

It is thought that the infiltration of leukocytes across the blood-brain barrier (BBB) into the central nervous system (CNS) is an essential step in the pathophysiology of MS. Chemokines on the endothelial lumen bind to receptors on the leukocytes, and it is thought that this initiates a cascade of events that culminates in breaching of the BBB [28]. The ease with which the leukocytes are able to enter the brain parenchyma depends on the chemokines present and the characteristics of the endothelia. While the BBB has traditionally been considered a uniform element, there is evidence of heterogeneity within the BBB [28], which varies depending on its location within the cerebral vascular bed. In particular, there is considerable heterogeneity in the tight junctions between the endothelial cells [29, 30], which appear weaker and more leaky in the cerebral collecting veins [31]. Furthermore, the expression of the chemokine CXCL12 (which regulates leukocyte access to the CNS parenchyma) at the abluminal endothelial membrane appears altered in the postcapillary venules in MS [28], something that correlates with the perivascular infiltration of T-cells [32, 33]. It has also been shown that the blood flow characteristics of the venules tend to promote margination [28, 34], with the result that the leukocytes are displaced to the periphery of the vessels [34], where they come into contact with the endothelial cells [35], something that may enhance intercellular interactions, leading to the attachment of leukocytes to the endothelial wall.

Perivenous WM changes have also been associated with ageing. In a series of related studies, Chung and co-workers [36-38] investigated jugular venous reflux (JVR) in elderly individuals. They found JVR to be associated with severe age- related WM changes, similar to those associated with leukoaraiosis [38]. Leukoaraiosis is characterised by WM morphological changes around the periventricular veins [39-42] that are thought to be associated with chronic cerebral ischemia [43]. In cases of ischemic injury, histological changes of the WM can range from coagulative necrosis and cavitation to non-specific tissue changes such as sponginess, patchy demyelination and astrocytic proliferation [43]. Such changes are consistent with the lesions seen in patients with leukoaraiosis [44], suggesting that the condition is linked with ischemia [43]. In particular, leukoaraiosis is characterised by noninflammatory collagenosis of the periventricular veins [39, 41], resulting in thickening of the vessel walls and narrowing, or even occlusion, of the lumen [39]. Moody et al. [39] found a strong association between the probability of severe leukoaraiosis and periventricular venous collagenosis.

A strong epidemiological link exists between leukoaraiosis and cerebrovascular disease [45-47]. Arterial hypertension and cardiac disease are also frequently associated with leukoaraiosis [43], and these are thought to induce arteriolosclerotic changes in the arteries and arterioles of the WM, replacing the smooth muscle cells by fibro-hyaline material, causing thickening of the vessel walls and narrowing of the vascular lumen [48]. Indeed, arteriolosclerosis is frequently found within areas of leukoaraiosis [49, 50]. Furthermore, the arterioles supplying the deep WM, which are some of the longest in the brain, frequently become tortuous with ageing [42, 51-53], with the result that there is a trend towards increased tortuosity in individuals with leukoaraiosis [42]. This tortuosity usually begins abruptly as the arteriole passes from the cortex into the WM [42] and greatly increases the length of the vessel. The combination of increased vessel length and reduced diameter means that the hydraulic resistance of the arterioles will greatly increase [53], inhibiting blood flow to the deep WM [42, 54-56]. It is therefore perhaps not surprising that the periventricular veins, being a ‘distal irrigation field’ [43], appear prone to ischemic damage under conditions of moderate deficit in blood flow.

Like leukoaraiosis, MS appears also to be associated with a reduction in cerebral blood flow (CBF) [57-60], raising questions about whether or not ischemia might be involved in the pathology of this disease. Wakefield et al. [61] found morphological changes in the venous endothelia, which progressed to occlusive vascular inflammation. They proposed that these changes were the precursor to lesion formation and suggested that demyelination may have an ischemic basis in MS. Similarities have been found between the tissue injury associated with inflammatory brain lesions and that found under hypoxic conditions in the CNS [62]. Ge et al. [63] identified subtle venous wall signal changes in small MS lesions, which they interpreted as early-stage vascular changes, thought to be the result of ischemic injury, marking the beginning of trans-endothelial migration of vascular inflammatory cells, before any apparent BBB breakdown. Werring et al. [64] found that the formation of lesions was preceded by subtle progressive alterations in tissue integrity, and Wuerfel et al. [65] found that changes of perfusion parameters, such as CBF, cerebral blood volume (CBV), and mean transit time (MTT) were detectable prior to the BBB breakdown. They concluded that in MS, inflammation is accompanied by altered local perfusion, which can be detected prior to permeability of the BBB. Lochhead et al. [66], using a rat model, demonstrated that hypoxia followed by reoxygenation altered the conformation of the occludin in the tight junctions between the endothelial cells, resulting in increased BBB permeability. In doing so, they confirmed the findings of earlier studies undertaken by the same team [67, 68].

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