Aberrant Neurogliovascular Unit Dynamics in Cerebral Small Vessel Disease: A Rheological Clue to Vascular Parkinsonism

Abstract

The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood-brain barrier permeabilities to preserve the integrity of cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU-a crossroad of the immune-vascular-nervous system-which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.

Keywords: cerebral small vessel disease; glymphatic system; homeostasis; neurogliovascular unit; vascular parkinsonism.

Figure 1

Component of the neurogliovascular unit (NGVU) and glymphatic system. The NGVU includes the neuronal cells, glial cells, and the vasculature (arteries and veins), including the smooth muscle cells (SMCs) and the pericytes (not shown in the figure) surrounding the vascular endothelial cells (ECs). Whereby, the glymphatic system consists mainly of astrocytes and astrocytic end-feet sheathing the vasculature. The transport of waste product through cerebrospinal fluid (CSF) from arteries passing through astrocytic aquaporin pore-4 (AQP4) into the interstitial fluid (ISF), hence, mixing of CSF and ISF. The waste solutes and/or by-products flow (indicated as yellow dots in the figure) following the glymphatic pathway to be absorbed for further waste clearance system.

Figure 2

Vascular blood (Penetrating Arterial) supply to the brain, vasculo-pathological process (i.e., atheroma) of cerebral small vessel disease (CSVD), and neuroimaging manifestation and characterization of CSVD based on STandards for Reporting Vascular changes on nEuroimaging (STRIVE). (A) Diffusion-weighted imaging (DWI) showing recent small subcortical infarct (red arrow). Usual diameter is around 3–15 mm, with hyperintense rim surrounding ovoid cavity. It can also be seen as increased signal intensities in fluid-attenuated inverse recovery (FLAIR), T2-weighted, and DWI and decreased T1-weighted signal with isointense in T2*-weighted gradient-recoiled echo (GRE) signal and susceptibility-weighted imaging (SWI). It is best identified through DWI with usual infarct diameter of ≤20 mm. (B) FLAIR showing lacunar infracts (red arrow). Lacunar infarcts appeared as increased hyperintensity in T2-weighted signal, decreased T1-weighted, and FLAIR signal and isointense in DWI. Usual diameter is around 3–15 mm, with hyperintense rim surrounding ovoid cavity. (C) FLAIR showing white matter hyperintensities (WMHs) of presumed vascular origin (red arrow). WMHs seen as increased intensity or hyperintensity on T2-weighted imaging, T2*-weighted GRE and FLAIR (best identified), isointense on DWI, and hypointense (decreased intensity) on T1-weighted imaging. (D) T1-weighted imaging showing enlarged perivascular spaces (ePVS) (red arrow) with usual diameter of ≤2 mm. ePVS is seen as decreased FLAIR and T1-weighted signal intensity, with increased T2-weighted signal. Meanwhile, T2*-weighted GRE and DWI appeared isointense, and they also appeared in similar signal intensity with cerebrospinal fluid (CSF). (E) T2*-GRE showing cerebral microbleeds (CMBs) (red arrow). CMBs are small, rounded areas of signal void with blooming, whereby they were visualized as isointense T1- and T2-weighted signal, FLAIR, and DWI. They are best identified under T2*-weighted GRE or SWI as reduced signal intensities. Usual diameter is around ≤10 mm (mostly 2–5 mm). (F) T1-weighted (hypointense) of 3T MRI showing cortical microinfarcts (red arrow). Images (A–E), reproduced from [105], Frontiers, 2019, image F was adapted from [106], Mayo Clinic, 2019. ACA, anterior cerebral arteries; ICA, internal carotid artery; MCA, middle cerebral arteries.

Figure 3

Proposition—cardiocerebrovascular risk factors may induce the aberration of neurogliovascular unit (NGVU) and glymphatic system dynamics (such as reduced astrocytic aquaporin 4 (AQP4) polarization, perivascular space (PVS) loss, and subsequent increase in blood–brain barrier (BBB) permeability (yellow arrow in left schematic diagram)—influence the transmigration of unwanted waste products—yellow dots in left schematic diagram) in cerebral small vessel disease (CSVD): a rheological clue to vascular parkinsonism (VaP). CSVD and VaP share similar neuroimaging manifestation seen as increased findings of white matter hyperintensities (WMHs), enlarged perivascular spaces (ePVS), and multiple lacunar or brain infarcts especially in subcortical regions (i.e., basal ganglia). These will eventually lead to clinical manifestation such as motor and non-motor lower body parkinsonism.