Understanding the role of the perivascular space in cerebral small vessel disease

Abstract

Small vessel diseases (SVDs) are a group of disorders that result from pathological alteration of the small blood vessels in the brain, including the small arteries, capillaries and veins. Of the 35-36 million people that are estimated to suffer from dementia worldwide, up to 65% have an SVD component. Furthermore, SVD causes 20-25% of strokes, worsens outcome after stroke and is a leading cause of disability, cognitive impairment and poor mobility. Yet the underlying cause(s) of SVD are not fully understood. Magnetic resonance imaging has confirmed enlarged perivascular spaces (PVS) as a hallmark feature of SVD. In healthy tissue, these spaces are proposed to form part of a complex brain fluid drainage system which supports interstitial fluid exchange and may also facilitate clearance of waste products from the brain. The pathophysiological signature of PVS and what this infers about their function and interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development in the brain has not been established. Here we discuss the potential of enlarged PVS to be a unique biomarker for SVD and related brain disorders with a vascular component. We propose that widening of PVS suggests presence of peri-vascular cell debris and other waste products that form part of a vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, perivascular inflammation and ultimately impaired clearance of waste proteins from the interstitial fluid space, leading to accumulation of toxins, hypoxia, and tissue damage. Here, we outline current knowledge, questions and hypotheses regarding understanding the brain fluid dynamics underpinning dementia and stroke through the common denominator of SVD.

Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes

“…CSF is generated in the choroid plexus, transported via the subarachnoid space in the meninges, and drained via specialized connections to veins and lymphatic vessels present in the dura mater [55]. The subarachnoid space is continuous with the brain's perivascular spaces (PVS), thin cavities that surround and follow the penetrating (parenchymal) arteries and veins [56,57] ( Fig 1D). The PVS are important for water, solute, and waste product exchange between the CSF and ISF.…”

“…It may be that the enlargement causes impaired paravascular flow, leading to reduced clearance, or conversely that accumulation of Ab and other aggregates leads to the observed expansion of the PVS (for review see ref. [57]). Alternatively, PVS enlargement may be caused by inflammation, for example, in multiple sclerosis [158], and in line with this idea, inflammatory cells are indeed observed in the PVS [57].…”

“…[57]). Alternatively, PVS enlargement may be caused by inflammation, for example, in multiple sclerosis [158], and in line with this idea, inflammatory cells are indeed observed in the PVS [57]. Recent data reveal a genetic component for PVS enlargement, at least in certain regions of the brain (the basal ganglia) [159], and this genetic link could be a starting point for a search for genes implicated in PVS organization and function.…”

Glymphatic Optimal Mass Transport with Lagrangian Workflow Reveals Advective and Diffusion Driven Solute Transport

“…We therefore applied the rOMT framework to dissect modes of solute transport changes in an animal model of cerebral small vessel disease (cSVD). cSVD is the major pathology in vascular dementia, and GS dysfunction has recently been highlighted as a novel pathogenetic factor in cSVD 5 . The hypothesized link between GS dysfunction and cSVD is based on the observation of abnormally enlarged PVS in clinical cases of cSVD 56 .…”

Vascular contributions to cognitive impairment and dementia: Research consortia that focus on etiology and treatable targets to lessen the burden of dementia worldwide

“…A novel trans‐Atlantic VCID consortium funded by the Fondation Leducq is called Understanding the Role of the Perivascular Space in Cerebral Small Vessel Disease. This consortium is using parallel studies in humans who had stroke stroke or cognitive presentations of small vessel diseases, and a corresponding range of representative laboratory models, with harmonized protocols for human and rodent MRI to pursue the hypothesis that small‐vessel VCID–associated brain injury is related to structural changes in and dysfunction of the perivascular space and that a better understanding of the perivascular space and small vessel VCID interactions, including pathology, will result in the identification of novel therapeutic targets [25].…”