ROLE OF DIASTOLIC ARTERIAL PRESSURE IN MICROSTRUCTURAL CHANGES OF THE BRAIN IN PATIENTS WITH HYPERTENSION-RELATED CEREBRAL SMALL VESSEL DISEASE.

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.

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A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease

Cells ◽

10.3390/cells9061545 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1545

Author(s):

Narek Manukjan ◽

Zubair Ahmed ◽

Daniel Fulton ◽

W. Matthijs Blankesteijn ◽

Sébastien Foulquier

Keyword(s):

White Matter ◽

Small Vessel Disease ◽

Clinical Manifestations ◽

Cell Types ◽

Cerebral Small Vessel Disease ◽

White Matter Injury ◽

Small Vessel ◽

Limited Attention ◽

Vessel Disease

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.

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The role of small diffusion-weighted imaging lesions in cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000008364 ◽

2019 ◽

pp. 10.1212/WNL.0000000000008364 ◽

Cited By ~ 1

Author(s):

Kim Wiegertjes ◽

Annemieke ter Telgte ◽

Pedro B. Oliveira ◽

Esther M.C. van Leijsen ◽

Mayra I. Bergkamp ◽

...

Keyword(s):

Diffusion Weighted Imaging ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Small Diffusion ◽

Vessel Disease ◽

Diffusion Weighted

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Diets and Cellular-Derived Microparticles: Weighing a Plausible Link With Cerebral Small Vessel Disease

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.632131 ◽

2021 ◽

Vol 8 ◽

Author(s):

Che Mohd Nasril Che Mohd Nassir ◽

Mazira Mohamad Ghazali ◽

Sabarisah Hashim ◽

Nur Suhaila Idris ◽

Lee Si Yuen ◽

...

Keyword(s):

Small Vessel Disease ◽

Preventive Measure ◽

Cerebral Small Vessel Disease ◽

The Body ◽

Small Vessel ◽

Vessel Disease ◽

Disease States ◽

Circulating Microparticles ◽

Health And Disease ◽

The Brain

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.

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Abstract WP427: Examining the Role of Gut Dysbiosis in Cerebral Small Vessel Disease

Stroke ◽

10.1161/str.48.suppl_1.wp427 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

James W Nelson ◽

David Durgan ◽

Nadim Ajami ◽

Joseph Petrosino ◽

Robert Bryan

Keyword(s):

16S Rrna ◽

Small Vessel Disease ◽

Fold Increase ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Rrna Gene ◽

Gut Barrier ◽

Vessel Disease ◽

Gut Dysbiosis ◽

The Brain

The importance of a healthy gut microbiota on host physiology is becoming increasingly evident. Recent studies suggest that alterations to the microbiota can have adverse effects beyond the GI tract, and has been linked to hypertension and stroke. Thus we hypothesized that gut dysbiosis could contribute to the development of cerebral small vessel disease (CSVD). Giving merit to this hypothesis, we found that the microbiota of the spontaneously hypertensive stroke prone rat (SHRSP) is significantly different than that of WKY controls. Using 16s rRNA sequencing of bacterial DNA we found that SHRSP animals had decreases in measures of bacterial richness (p=.005) and diversity (p=.028), indicative of gut dysbiosis. Phenotypically, CSVD includes vessel remodeling, BBB breakdown and neuroinflammation. Gut dysbiosis is often associated with a leaky gut barrier that allows bacteria to enter the systemic circulation. We observed significantly greater permeability of the SHRSP colon barrier when compared to WKY (p=.026). We next sought to determine if impaired colon barrier function in SHRSP could lead to increased bacterial translocation to the periphery and ultimately to the brain. Brains were harvested from 24 week old SHRSP and WKY animals and qRT-PCR of the 16s rRNA gene was performed to detect the presence of bacteria in the brain. We discovered that SHRSP animals displayed a 50% increase in bacterial 16S rRNA load in the brain compared to WKY animals (p=.0063) confirming that bacteria are not only present in CSVD rats, but also in greater abundance than WKYs. Similarly, we found that SHRSP animals displayed a near 2-fold increase of the bacterial endotoxin LPS in the brain, as compared to WKY brain LPS levels (p=.01). Finally, to further confirm the presence of bacterial components in the brain we used immunofluorescence imaging to visualize peptidoglycan (PG), a molecule found solely in bacterial cell walls. We discovered that we could visualize the presence of PG in the brains of SHRSP animals, and note that PG was commonly observed inside microglia. We conclude from this study that SHRSP rats exhibit gut dysbiosis, gut barrier breakdown, and bacterial products in the brain. Further studies will examine how this bacterial presence contributes to the CSVD phenotypes.

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Rich-Club Analysis of the Structural Brain Network in Cases with Cerebral Small Vessel Disease and Depression Symptoms

Cerebrovascular Diseases ◽

10.1159/000517243 ◽

2021 ◽

pp. 1-10

Author(s):

Yanjing Lu ◽

Yifan Li ◽

Qian Feng ◽

Rong Shen ◽

Hao Zhu ◽

...

Keyword(s):

White Matter ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Depression Symptoms ◽

Rich Club ◽

Symptoms Of Depression ◽

Vessel Disease ◽

Severity Of Depression ◽

The Brain

Background: Altered white matter brain networks have been extensively studied in cerebral small vessel disease (SVD). However, there exists currently a deficiency of comprehending the performance of changes within the structural networks of the brain in cases with cerebral SVD and depression symptoms. The main aim of the present research is to study the network topology behaviors and features of rich-club organization in SVD patients using graph theory and diffusion tensor imaging (DTI) to characterize changes in the microstructure of the brain. Methods: DTI datasets were acquired from 26 SVD patients with symptoms of depression (SVD + D) and 26 SVD patients without symptoms of depression (SVD − D), and a series of neuropsychological assessments were completed. A structural network was created using a deterministic fiber tracking method. The analysis of rich-club was performed in company with analysis of the global network features of the network to characterize the topological properties of all subjects. Results: DTI data were obtained from SVD patients who manifested symptoms of depression (SVD + D) and from control SVD patients (SVD − D). In comparison with SVD − D patients, SVD + D cases demonstrated a diminished coefficient of clustering along with lower global efficiencies and longer path length characteristics. Rich-club analysis showed SVD + D patients had decreased feeder connectivity and local connectivity strengths compared to SVD − D patients. Our data also showed that the feeder connections in the brain correlated significantly with the severity of depression in SVD + D patients. Conclusions: Our study revealed that SVD patients with depressive symptoms have disrupted white matter networks that characteristically have reduced network efficiency compared to the networks in other SVD patients. Disrupted information interactions among the regions of nonrich-club and rich-club in SVD cases are related to the severity of depression. Our data suggest that DTI may be utilized as an appropriate biomarker for the diagnosis of depression in comorbid SVD patients.

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Oxidative stress in cerebral small vessel disease. Role of reactive species

Free Radical Research ◽

10.1080/10715762.2017.1402304 ◽

2017 ◽

Vol 52 (1) ◽

pp. 1-13 ◽

Cited By ~ 21

Author(s):

Cezary Grochowski ◽

Jakub Litak ◽

Piotr Kamieniak ◽

Ryszard Maciejewski

Keyword(s):

Oxidative Stress ◽

Small Vessel Disease ◽

Reactive Species ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease

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Cerebral Small Vessel Disease in subclinical and clinical stages, role of inflammation for risk prediction and potential treatment targets, and management strategies

Internal Medicine Review ◽

10.18103/imr.v2i11.265 ◽

2016 ◽

Vol 2 (11) ◽

Author(s):

C. Frances Fan ◽

José R Romero

Keyword(s):

Clinical Outcomes ◽

Small Vessel Disease ◽

Brain Mri ◽

Management Strategies ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Potential Treatment ◽

Treatment Targets ◽

Vessel Disease

Stroke and dementia are the most common neurological disorders worldwide. Cerebrovascular disease, particularly cerebral small vessel disease (CSVD) is implicated in both, and the two main types of CSVD (hypertensive vasculopathy and cerebral amyloid angiopathy) account for the majority of cerebrovascular contributions to stroke and dementia. Current knowledge of CSVD may influence treatment decisions and preventive efforts. Although the causes of CSVD are not entirely elucidated, ongoing research of the pathophysiology of CSVD, such as the role of inflammation, is helping identify potential treatment targets, evaluate prediction models and develop preventive strategies. Given the detectability of CSVD in preclinical stages using brain MRI, a long window of opportunity is presented to implement existent preventive measures. This review considers CSVD including its subclinical manifestations detected using brain MRI, clinical manifestations, use of markers of CSVD as predictors of clinical outcomes such as dementia and stroke, and presents potential management strategies when seeing patients with cerebral small vessel disease to reduce its disease burden and clinical consequences. Clinical trials have evaluated some aspects of CSVD treatment and are beginning to recognize CSVD as endpoint in subclinical stages. Future studies will clarify if this approach is able to delay onset of dementia and prevent stroke occurrence, meanwhile implementation of existent recommendations for the prevention and treatment of stroke and dementia may reduce disability and clinical outcomes related to CSVD.

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Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC – InTENse study

European Stroke Journal ◽

10.1177/2396987318776088 ◽

2018 ◽

Vol 3 (4) ◽

pp. 369-378 ◽

Cited By ~ 5

Author(s):

Annemieke ter Telgte ◽

Kim Wiegertjes ◽

Anil M Tuladhar ◽

Marlies P Noz ◽

José P Marques ◽

...

Keyword(s):

Temporal Dynamics ◽

Small Vessel Disease ◽

Clinical Importance ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Acute Ischaemia ◽

Origin And Evolution ◽

Vessel Disease ◽

And Function

Background Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods The RUN DMC – InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.

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