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.

Figure 1

(A) Enlarged PVS are key pathological features of SVD as shown on MRI from patients with sporadic SVD (Top panel, insert: PVS detected on T2 MRI), and associate with WMH (bottom panel). (B) The cycle of events we believe are involved in SVD pathogenesis and PVS dysfunction, including altered blood flow, BBB dysfunction and disrupted brain fluid flow. (C) Some of the key outstanding questions in SVD research, which also outline the scientific goals of the Fondation Leducq TNE ‘Understanding the role of the PVS in cerebral SVD’.

Figure 2

Translation between preclinical and clinical findings will be facilitated by comparing and harmonising rodent and human imaging techniques, allowing the relationship between enlarged PVS on MRI (A and B) to fluid flow (C and D) to be determined. A. Clinical imaging. Top: FLAIR (L) and T2 (R) MRI shows WMH (L) form along the PVS (R, arrow). Below: T2 shows a PVS running inwards from cortex (arrow); T2* shows white matter venule (arrow) closely related to the PVS. (B) T2*-weighted MRI of a normotensive mouse (top panel) and hypertensive mouse showing cortical vessels associated with susceptibility contrast probably due to thickening of the vessel wall and/or altered PVSs (lower panel). (C) ‘Glymphatic’ transport pathways detected by T1 MRI and Optimal Mass Tomography analysis in a rodent brain following tracer infusion into the CSF. The timecourse of fluid flow from the cisterna magna throughout the brain can be revealed using this technique (D). Fluid transport in the PVS detected by macroscopic fluorescent optical imaging in the cortex following injection of fluorescent markers into the CSF and vasculature.