Perivascular spaces and brain waste clearance systems: relevance for neurodegenerative and cerebrovascular pathology

Abstract

Perivascular spaces (PVS) of the brain, often called Virchow-Robin spaces, comprise fluid, cells and connective tissue, and are externally limited by astrocytic endfeet. PVS are involved in clearing brain waste and belong to the "glymphatic" system and/or the "intramural periarterial drainage" pathway through the basement membranes of the arteries. Related brain waste clearance systems include the blood-brain barrier, scavenger cells, cerebrospinal fluid, perineural lymphatic drainage pathways and the newly characterised meningeal lymphatic vessels. Any functional abnormality of PVS or related clearance systems might lead to accumulation of brain waste. It has been postulated that PVS enlargement can be secondary to accumulation of β-amyloid. Lack of integrity of the vascular wall, microbleeds, cerebral amyloid angiopathy (CAA) and enlarged PVS often occur in the preclinical stages of Alzheimer's disease, preceding substantial brain atrophy. PVS enlargement in the form of état criblé at the basal ganglia has also been considered to reflect focal atrophy, most probably secondary to ischaemic injury, based upon both pathological and imaging arguments. In addition, distinct topographic patterns of enlarged PVS are related to different types of microangiopathy: CAA is linked to enlarged juxtacortical PVS, whereas subjects with vascular risk factors tend to have enlarged PVS in the basal ganglia. Therefore, enlarged PVS are progressively being regarded as a marker of neurodegenerative and cerebrovascular pathology. The present review addresses the evolving concept of PVS and brain waste clearance systems, the potential relevance of their dysfunction to neurodegenerative and cerebrovascular pathology, and potential therapeutic approaches of interest.

Keywords: Brain; Cognitive impairment; Lymphatic; Perivascular spaces; Virchow-Robin spaces; “Glymphatic”.

Fig. 1

Schematic representation of a perivascular space (PVS) according to Weed et al. (1923). The PVS is represented as communicating borderless with the subarachnoid space, in keeping with the assumption that perivascular spaces were mere expansions of the subarachnoid space into the brain. Reproduced from Weed LH. The absorption of cerebrospinal fluid into the venous system. American Journal of Anatomy. 1923; 31(3):191–221 [11]

Fig. 2

Schematic representation of perivascular spaces (PVS) indirectly communicating with the subarachnoid space (SAS), according to Zhang et al. (1990); the SAS is represented between the arachnoid (A) and pia mater (Pia mater). Please note the existence of a reflected sheath of pia mater onto the surface of the brain at the site of the arterial entry and the venous exit, as well as the existence of leptomeningeal perforations (PF). These perforations increase in size as the vessel wall thickness diminishes, which leads to almost no identifiable pia mater cells at the level of capillaries (CAPS). Reproduced with permission from the Publisher (Wiley) and the authors: Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. Journal of Anatomy. 1990 Jun; 170:111–23 [13]

Fig. 3

Schematic representation of perivascular spaces (PVS) according to current notions at the level of an artery and an arteriole, and at the capillary level. The arrowheads at each side of the black lines point to the internal (endothelial basement membrane [BM]) and external (“Astrocytic endfeet”) boundaries of the PVS at each level. In general, PVS contain cell populations other than those depicted in the illustration; some are not represented (e.g. scavenger cells other than a “Pericyte”). The artery is surrounded by PVS externally covered by leptomeningeal cells (dashed lines). Fenestrations between leptomeningeal cells covering perforating arteries and arterioles gradually increase in size as the small arteries progressively enter the brain (dashed-dotted lines). At the capillary level, there is no longer an identifiable leptomeningeal covering. The current notion of PVS takes into account any compartment, within or outside the vascular wall, externally limited by the “Astrocytic endfeet” (i.e. glia limitans) represented in brown. Any substance entering (or exiting) the PVS from (or to) the brain inevitably crosses the “Astrocytic endfeet”. Likewise, any substance entering (or exiting) the PVS from (or to) the blood inevitably crosses the blood–brain barrier (not specifically represented in the illustration, but corresponding to the vascular endothelial cells, their tight junctions, and the underlying BM)

Fig. 4

État criblé, lacunar infarct, and white matter hyperintensities. A 77-year-old man with vascular risk factors and cognitive impairment (clinically expressed as lack of executive functioning and apathy) underwent magnetic resonance imaging (MRI). T2-weighted MRI (left column) shows multiple enlarged perivascular spaces (PVS) in the form of état criblé at the basal ganglia. Both arrows indicate the concomitance of a small right putaminal lacunar infarct. Please note the irregularly shaped peripheral rim of gliosis hyperintense on T2-weighted fluid-attenuated inversion recovery (FLAIR) image (right arrow) helping to differentiate the lacunar infarct from adjacent PVS. In addition, please note the associated white matter hyperintensities (e.g. asterisk on the bottom right T2-weighted FLAIR image)

Fig. 5

Enlarged juxtacortical perivascular spaces (PVS). Post-mortem T2-weighted magnetic resonance image acquired at 7 T (top) showing sharply demarcated juxtacortical hyperintensities corresponding to “many severely enlarged PVS” (arrow) in a patient with pathologically confirmed cerebral amyloid angiopathy (bottom). Please note the absence of PVS at the cortical level. Modified and reproduced with permission from the Publisher (SAGE) and the authors: van Veluw SJ, Biessels GJ, Bouvy WH, Spliet WG, Zwanenburg JJ, Luijten PR, Macklin EA, Rozemuller AJ, Gurol ME, Greenberg SM, Viswanathan A, Martinez-Ramirez S. Cerebral amyloid angiopathy severity is linked to dilation of juxtacortical perivascular spaces. Journal of Cerebral Blood Flow and Metabolism. 2016; 36(3):576–580 [91]