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.

Association Between Large Numbers of Enlarged Perivascular Spaces in Basal Ganglia and Motor Performance in Elderly Individuals: A Cross-Sectional Study

“…The glymphatic aberration results in the accumulation of toxic metabolic products that are harmful to the brain microenvironment. 35 Therefore, we speculate that large numbers of BG-EPVSs might disrupt the functioning of the BG, brain network, and brain microenvironment, then lead to poor motor performance. This hypothesis should be tested and verified by multimodal MRI (eg, functional MRI and diffusion-tensor imaging) in the future.…”

Enlarged Perivascular Spaces in the Basal Ganglia Independently Related to Gait Disturbances in Older People With Cerebral Small Vessel Diseases

“…Recent findings showed that EPVS leads to white matter microstructural damage by causing a glymphatic dysfunction that results in the accumulation of toxic metabolic products. These metabolic products were harmful to the brain microenvironment ( Che Mohd Nassir et al, 2021 ). Therefore, we speculated that large numbers of BG-EPVS may disrupt the functioning of the basal ganglia, brain network, and brain microenvironment and subsequently lead to gait disturbances and poor balance.…”

Association of enlarged perivascular spaces with upper extremities and gait impairment: An observational, prospective cohort study

“…EPVSs are thought to be caused by perivascular blockages that disrupt PVS normal functions. EPVS lead to the accumulation of toxic metabolic products that damage the microenvironment of the brain, disrupt fibers, and disrupt brain networks, eventually causing movement dysfunction ( 41 ). Studies have found that the BG–thalamocortical circuit, brain-network efficiency, and loss of WM-microstructure integrity are involved in gait impairment in subjects with CSVD ( 9 , 42 ).…”