The NLRP3 Inflammasome in Age-Related Cerebral Small Vessel Disease Manifestations: Untying the Innate Immune Response Connection.

In this narrative review, we present the evidence on nucleotide-binding and oligomerization (NOD) domain-like receptor (NLR) family pyrin domain (PYD)-containing 3 (NLRP3) inflammasome activation for its putative roles in the elusive pathomechanism of aging-related cerebral small vessel disease (CSVD). Although NLRP3 inflammasome-interleukin (IL)-1ß has been implicated in the pathophysiology of coronary artery disease, its roles in cerebral arteriothrombotic micro-circulation disease such as CSVD remains unexplored. Here, we elaborate on the current manifestations of CSVD and its' complex pathogenesis and relate the array of activators and aberrant activation involving NLRP3 inflammasome with this condition. These neuroinflammatory insights would expand on our current understanding of CSVD clinical (and subclinical) heterogenous manifestations whilst highlighting plausible NLRP3-linked therapeutic targets.

Regional cerebral blood perfusion changes in chronic stroke survivors as potential brain correlates of the functional outcome following gamified home-based rehabilitation (IntelliRehab)-a pilot study.

BACKGROUND: Hospital-based stroke rehabilitation for stroke survivors in developing countries may be limited by staffing ratios and length of stay that could hamper recovery potential. Thus, a home-based, gamified rehabilitation system (i.e., IntelliRehab) was tested for its ability to increase cerebral blood flow (CBF), and the secondary impact of changes on the upper limb motor function and functional outcomes. OBJECTIVE: To explore the effect of IntelliRehab on CBF in chronic stroke patients and its correlation with the upper limb motor function. METHODS: Two-dimensional pulsed Arterial Spin Labelling (2D-pASL) was used to obtain CBF images of stable, chronic stroke subjects (n = 8) over 3-months intervention period. CBF alterations were mapped, and the detected differences were marked as regions of interest. Motor functions represented by Fugl-Meyer Upper Extremity Assessment (FMA) and Stroke Impact Scale (SIS) were used to assess the primary and secondary outcomes, respectively. RESULTS: Regional CBF were significantly increased in right inferior temporal gyrus and left superior temporal white matter after 1-month (p = 0.044) and 3-months (p = 0.01) of rehabilitation, respectively. However, regional CBF in left middle fronto-orbital gyrus significantly declined after 1-month of rehabilitation (p = 0.012). Moreover, SIS-Q7 and FMA scores significantly increased after 1-month and 3-months of rehabilitation. There were no significant correlations, however, between CBF changes and upper limb motor function. CONCLUSIONS: Participants demonstrated improved motor functions, supporting the benefit of using IntelliRehab as a tool for home-based rehabilitation. However, within-participant improvements may have limited potential that suggests the need for a timely administration of IntelliRehab to get the maximum capacity of improvement.

Reduced cerebral vascular fractal dimension among asymptomatic individuals as a potential biomarker for cerebral small vessel disease.

Cerebral small vessel disease is a neurological disease frequently found in the elderly and detected on neuroimaging, often as an incidental finding. White matter hyperintensity is one of the most commonly reported neuroimaging markers of CSVD and is linked with an increased risk of future stroke and vascular dementia. Recent attention has focused on the search of CSVD biomarkers. The objective of this study is to explore the potential of fractal dimension as a vascular neuroimaging marker in asymptomatic CSVD with low WMH burden. Df is an index that measures the complexity of a self-similar and irregular structure such as circle of Willis and its tributaries. This exploratory cross-sectional study involved 22 neurologically asymptomatic adult subjects (42 ± 12 years old; 68% female) with low to moderate 10-year cardiovascular disease risk prediction score (QRISK2 score) who underwent magnetic resonance imaging/angiography (MRI/MRA) brain scan. Based on the MRI findings, subjects were divided into two groups: subjects with low WMH burden and no WMH burden, (WMH+; n = 8) and (WMH-; n = 14) respectively. Maximum intensity projection image was constructed from the 3D time-of-flight (TOF) MRA. The complexity of the CoW and its tributaries observed in the MIP image was characterised using Df. The Df of the CoW and its tributaries, i.e., Df (w) was significantly lower in the WMH+ group (1.5172 ± 0.0248) as compared to WMH- (1.5653 ± 0.0304, p = 0.001). There was a significant inverse relationship between the QRISK2 risk score and Df (w), (rs = - .656, p = 0.001). Df (w) is a promising, non-invasive vascular neuroimaging marker for asymptomatic CSVD with WMH. Further study with multi-centre and long-term follow-up is warranted to explore its potential as a biomarker in CSVD and correlation with clinical sequalae of CSVD.

Presence of enlarged perivascular spaces is associated with reduced processing speed in asymptomatic, working-aged adults.

BACKGROUND: Enlarged perivascular spaces (ePVS) and white matter hyperintensities (WMHs) are recognised neuroimaging lesions for symptomatic and/or occult cerebral small vessel disease (CSVD) that are linked with the predisposition to cardiocerebrovascular risk and neurocognitive impairment. This study aimed to determine the interrelation between the WMHs and ePVS, neurocognition, and cardiocerebrovascular risk profiles in asymptomatic working-aged adults at a single-center population-based cohort. METHODS: Fifty-four asymptomatic subjects (mean age: 39.6 ± 11.6 years) with low-to-moderate cardiocerebrovascular risk measured by QRISK3 prediction score were recruited and underwent neurocognitive evaluation and 3T MRI brain scan. Contour plot with multiple logistic and linear regression were utilized to study the interrelation between the variables. RESULTS: The presence of WMHs and ePVS was associated with hypertension, systolic blood pressure, QRISK3 score, and age, whereby asymptomatic older subjects had higher prevalence for WHMs and ePVS (mean age: WMHs [46.6 ± 12.2 years]; ePVS [43.12 ± 12.2 years]). Higher ePVS load and reduced hippocampal volume among ePVS subjects was associated with reduced processing speed (odd ratio, 1.06; 95% confidence interval: 1.00 to 1.13) and reduced working memory performance (standardized ß coefficients, -0.46 [95% CI: 0.46 to 12.1], p < 0.05), respectively. CONCLUSIONS: Albeit from a single center in the suburban east coast peninsular Malaysia, this study is to first from the region to highlight the subtle impacts of occult CSVD manifestations (WMHs and ePVS) on some aspects of neurocognition in an otherwise asymptomatic, relatively young working-aged adults with low-to-moderate cardiocerebrovascular risk scores.

Neuroinflammation and COVID-19 Ischemic Stroke Recovery-Evolving Evidence for the Mediating Roles of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis and NLRP3 Inflammasome.

Cerebrovascular events, notably acute ischemic strokes (AIS), have been reported in the setting of novel coronavirus disease (COVID-19) infection. Commonly regarded as cryptogenic, to date, the etiology is thought to be multifactorial and remains obscure; it is linked either to a direct viral invasion or to an indirect virus-induced prothrombotic state, with or without the presence of conventional cerebrovascular risk factors. In addition, patients are at a greater risk of developing long-term negative sequelae, i.e., long-COVID-related neurological problems, when compared to non-COVID-19 stroke patients. Central to the underlying neurobiology of stroke recovery in the context of COVID-19 infection is reduced angiotensin-converting enzyme 2 (ACE2) expression, which is known to lead to thrombo-inflammation and ACE2/angiotensin-(1-7)/mitochondrial assembly receptor (MasR) (ACE2/Ang-(1-7)/MasR) axis inhibition. Moreover, after AIS, the activated nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome may heighten the production of numerous proinflammatory cytokines, mediating neuro-glial cell dysfunction, ultimately leading to nerve-cell death. Therefore, potential neuroprotective therapies targeting the molecular mechanisms of the aforementioned mediators may help to inform rehabilitation strategies to improve brain reorganization (i.e., neuro-gliogenesis and synaptogenesis) and secondary prevention among AIS patients with or without COVID-19. Therefore, this narrative review aims to evaluate the mediating role of the ACE2/Ang- (1-7)/MasR axis and NLRP3 inflammasome in COVID-19-mediated AIS, as well as the prospects of these neuroinflammation mediators for brain repair and in secondary prevention strategies against AIS in stroke rehabilitation.

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

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.

COVID-19 Infection and Circulating Microparticles-Reviewing Evidence as Microthrombogenic Risk Factor for Cerebral Small Vessel Disease.

Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) due to novel coronavirus disease 2019 (COVID-19) has affected the global society in numerous unprecedented ways, with considerable morbidity and mortality. Both direct and indirect consequences from COVID-19 infection are recognized to give rise to cardio- and cerebrovascular complications. Despite current limited knowledge on COVID-19 pathogenesis, inflammation, endothelial dysfunction, and coagulopathy appear to play critical roles in COVID-19-associated cerebrovascular disease (CVD). One of the major subtypes of CVD is cerebral small vessel disease (CSVD) which represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger subsequent neuroinflammation and neurodegeneration. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, and Alzheimer's disease. In the background of COVID-19 infection, the heightened cellular activations from inflammations and oxidative stress may result in elevated levels of microthrombogenic extracellular-derived circulating microparticles (MPs). Consequently, MPs could act as pro-coagulant risk factor that may serve as microthrombi for the vulnerable microcirculation in the brain leading to CSVD manifestations. This review aims to appraise the accumulating body of evidence on the plausible impact of COVID-19 infection on the formation of microthrombogenic MPs that could lead to microthrombosis in CSVD manifestations, including occult CSVD which may last well beyond the pandemic era.