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Coronavirus disease 2019 (COVID-19) has been a global pandemic affecting millions of people’s lives, which has led to ‘post-COVID-19 fatigue’. Alarmingly, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) not only infects the lungs but also influences the heart and brain. Endothelial cell dysfunction and hypercoagulation, which we know occur with this infection, lead to thrombo-inflammation that can manifest as many myriad cardio-cerebrovascular disorders, such as brain fog, fatigue, cognitive dysfunction, etc. Additionally, SARS-CoV-2 has been associated with oxidative stress, protein aggregation, cytokine storm, and mitochondrial dysfunction in neurodegenerative diseases. Accordingly, the identification of molecular targets involved in these actions could provide strategies for preventing and treating this disease. In particular, the very common enzyme dipeptidyl peptidase IV (DPPIV) has recently been identified as a candidate co-receptor for the cell entry of the SARS-CoV-2 virus with its involvement in infection. In addition, DPPIV has been reported as a co-receptor for some viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV). It mediates immunologic reactions and diseases such as type 2 diabetes mellitus, obesity, and hypertension, which have been considered the prime risk factors for stroke among other types of cardio-cerebrovascular diseases. Unlike angiotensin-converting enzyme 2 (ACE2), DPPIV has been implicated in aggravating the course of infection due to its disruptive effect on inflammatory signaling networks and the neuro–glia–vascular unit. Regarding the neurological, physiological, and molecular grounds governing post-COVID-19 fatigue, this review focuses on DPPIV as one of such reasons that progressively establishes cerebrovascular grievances following SARS-CoV infection.

A typical anatomical congregate and functionally distinct multicellular cerebrovascular dynamic confer diverse blood-brain barrier (BBB) and microstructural permeabilities to conserve the health of brain parenchymal and its microenvironment. This equanimity presupposes the glymphatic system that governs the flow and clearance of metabolic waste and interstitial fluids (ISF) through venous circulation. Following the introduction of glymphatic system concept, various studies have been carried out on cerebrospinal fluid (CSF) and ISF dynamics. These studies reported that the onset of multiple diseases can be attributed to impairment in the glymphatic system, which is newly referred as central nervous system (CNS) interstitial fluidopathy. One such condition includes cerebral small vessel disease (CSVD) with poorly understood pathomechanisms. CSVD is an umbrella term to describe a chronic progressive disorder affecting the brain microvasculature (or microcirculation) involving small penetrating vessels that supply cerebral white and deep gray matter. This review article proposes CSVD as a form of “CNS interstitial fluidopathy”. Linking CNS interstitial fluidopathy with CSVD will open a better insight pertaining to the perivascular space fluid dynamics in CSVD pathophysiology. This may lead to the development of treatment and therapeutic strategies to ameliorate the pathology and adverse effect of CSVD.

The human microbiota constitute a very complex ecosystem of microorganisms inhabiting both the inside and outside of our bodies, in which health maintenance and disease modification are the main regulatory features. The recent explosion of microbiome research has begun to detail its important role in neurological health, particularly concerning cerebral small vessel disease (CSVD), a disorder associated with cognitive decline and vascular dementia. This narrative review represents state-of-the-art knowledge of the intimate, complex interplay between microbiota and brain health through the gut–brain axis (GBA) and the emerging role of glymphatic system dysfunction (glymphopathy) and circulating cell-derived microparticles (MPs) as mediators of these interactions. We discuss how microbial dysbiosis promotes neuroinflammation, vascular dysfunction, and impaired waste clearance in the brain, which are critical factors in the pathogenesis of CSVD. Further, we discuss lifestyle factors that shape the composition and functionality of the microbiota, focusing on sleep as a modifiable risk factor in neurological disorders. This narrative review presents recent microbiome research from a neuroscientific and vascular perspective to establish future therapeutic avenues in targeting the microbiota to improve brain health and reduce the burden of CSVD.

Abstract 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.

Abstract 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), (r s = − .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.

This article provides a comprehensive review of deep learning-based blood vessel segmentation of the brain. Cerebrovascular disease develops when blood arteries in the brain are compromised, resulting in severe brain injuries such as ischemic stroke, brain hemorrhages, and many more. Early detection enables patients to obtain more effective treatment before becoming critically unwell. Due to the superior efficiency and accuracy compared to manual segmentation and other computer-assisted diagnosis procedures, deep learning algorithms have been extensively deployed in brain vascular segmentation. This study examined current articles on deep learning-based brain vascular segmentation, which examined the proposed methodologies, particularly the network architectures, and determined the model trend. We evaluated challenges and crucial factors associated with the application of deep learning to brain vascular segmentation, as well as future research prospects. This paper will assist researchers in developing more sophisticated and robust models in the future to develop deep learning solutions.

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)-1β 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.

Cerebral small vessel disease (CSVD) represents a spectrum of pathological processes of various etiologies affecting the brain microcirculation that can trigger neuroinflammation and the subsequent neurodegenerative cascade. Prevalent with aging, CSVD is a recognized risk factor for stroke, vascular dementia, Alzheimer disease, and Parkinson disease. Despite being the most common neurodegenerative condition with cerebrocardiovascular axis, understanding about it remains poor. Interestingly, modifiable risk factors such as unhealthy diet including high intake of processed food, high-fat foods, and animal by-products are known to influence the non-neural peripheral events, such as in the gastrointestinal tract and cardiovascular stress through cellular inflammation and oxidation. One key outcome from such events, among others, includes the cellular activations that lead to elevated levels of endogenous cellular-derived circulating microparticles (MPs). MPs can be produced from various cellular origins including leukocytes, platelets, endothelial cells, microbiota, and microglia. MPs could act as microthrombogenic procoagulant that served as a plausible culprit for the vulnerable end-artery microcirculation in the brain as the end-organ leading to CSVD manifestations. However, little attention has been paid on the potential role of MPs in the onset and progression of CSVD spectrum. Corroboratively, the formation of MPs is known to be influenced by diet-induced cellular stress. Thus, this review aims to appraise the body of evidence on the dietary-related impacts on circulating MPs from non-neural peripheral origins that could serve as a plausible microthrombosis in CSVD manifestation as a precursor of neurodegeneration. Here, we elaborate on the pathomechanical features of MPs in health and disease states; relevance of dietary patterns on MP release; preclinical studies pertaining to diet-based MPs contribution to disease; MP level as putative surrogates for early disease biomarkers; and lastly, the potential of MPs manipulation with diet-based approach as a novel preventive measure for CSVD in an aging society worldwide.

Schizophrenia is a complex psychiatric disorder associated with positive (delusion, hallucination, and disorganised speech) and negative (affective flatering, avolition and social withdrawal) symptoms. Agomelatine (AGO) has been used as an anti-depressant to improve the negative symptoms in schizophrenia patients with co-morbid major depressive disorder. Therefore, the present study aimed to investigate the anti-psychotic effect of AGO in ketamine (KET)-induced psychosis rat model. Four groups (n = 12/ group) of wistar rats were administered normal saline, KET (20 m/kg, i.p) and KET + AGO (20 and 40 mg/kg, i.p) for seven days. Behavioural tests were conducted on the seventh day after drug administration. Seven days administration of AGO at two different doses decreased the KET induced stereotypic and ataxic behaviour as compared with KET treated rats. In addition, AGO increased the social interaction time and decreased the horizontal and vertical locomotor behaviour in KET treated rats. Histologically, KET adminstration decreased hippocampal and increased basolateral amygdala (BLA) neuronal counts. AGO administration (at two different doses) significantly reversed the KET induced neuronal loss in the two brain areas. These findings suggest that AGO has a protective effect against KET-induced psychosis in this rat model. This study warrants further research to delineate the possible role of AGO in experimental model of psychosis particularly neurochemical and neuromolecular aspects.

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 β 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.

Cerebral small vessel disease (CSVD) refers to a spectrum of clinical and imaging findings resulting from pathological processes of various etiologies affecting cerebral arterioles, perforating arteries, capillaries, and venules. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural progression of the disease. CSVD might progress for many years during the early stage of the disease as it remains asymptomatic. Prevalent among elderly individuals, CSVD has been alarmingly reported as an important precursor of full-blown stroke and vascular dementia. Growing evidence has also shown a significant association between CSVD’s radiological manifestation with dementia and Alzheimer’s disease (AD) pathology. Although it remains contentious as to whether CSVD is a cause or sequelae of AD, it is not far-fetched to posit that effective therapeutic measures of CSVD would mitigate the overall burden of dementia. Nevertheless, the unifying theory on the pathomechanism of the disease remains elusive, hence the lack of effective therapeutic approaches. Thus, this chapter consolidates the contemporary insights from numerous experimental animal models of CSVD, to date: from the available experimental animal models of CSVD and its translational research value; the pathomechanical aspects of the disease; relevant aspects on systems biology; opportunities for early disease biomarkers; and finally, converging approaches for future therapeutic directions of CSVD.

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.

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

Asymptomatic (or “silent”) manifestations of cerebral small vessel disease (CSVD) are widely recognized through incidental findings of white matter hyperintensities (WMHs) as a result of magnetic resonance imaging (MRI). This study aims to examine the potential associations of surrogate markers for the evaluation of white matter integrity in CSVD among asymptomatic individuals through a battery of profiling involving QRISK2 cardiocerebrovascular risk prediction, neuroimaging, neurocognitive evaluation, and microparticles (MPs) titers. Sixty asymptomatic subjects (mean age: 39.83 ± 11.50 years) with low to moderate QRISK2 scores were recruited and underwent neurocognitive evaluation for memory and cognitive performance, peripheral venous blood collection for enumeration of selected MPs subpopulations, and 3T MRI brain scan with specific diffusion MRI (dMRI) sequences inclusive of diffusion tensor imaging (DTI). WMHs were detected in 20 subjects (33%). Older subjects (mean age: 46.00 ± 12.00 years) had higher WMHs prevalence, associated with higher QRISK2 score and reduced processing speed. They also had significantly higher mean percentage of platelet (CD62P)- and leukocyte (CD62L)-derived MPs. No association was found between reduced white matter integrity—especially at the left superior longitudinal fasciculus (LSLF)—with age and neurocognitive function; however, LSLF was associated with higher QRISK2 score, total MPs, and CD62L- and endothelial cell-derived MPs (CD146). Therefore, this study establishes these multimodal associations as potential surrogate markers for “silent” CSVD manifestations in the well-characterized cardiocerebrovascular demographic of relatively young, neurologically asymptomatic adults. Furthermore, to the best of our knowledge, this study is the first to exhibit elevated MP counts in asymptomatic CSVD (i.e., CD62P and CD62L), which warrants further delineation.