Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review

The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes.

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Total Cerebral Small Vessel Disease Score and Anthropometric Indices: A Population-Based Study in Older Adults of Amerindian Ancestry

European Neurology ◽

10.1159/000517915 ◽

2021 ◽

pp. 1-4

Author(s):

Oscar H. Del Brutto ◽

Robertino M. Mera

Keyword(s):

Older Adults ◽

Small Vessel Disease ◽

Brain Magnetic Resonance Imaging ◽

Population Based ◽

Cerebral Small Vessel Disease ◽

The Body ◽

Small Vessel ◽

Population Based Study ◽

Vessel Disease ◽

Ordinal Logistic Regression Model

A total of 590 older adults of Amerindian ancestry living in rural Ecuador received anthropometric measurements and a brain magnetic resonance imaging to estimate the total cerebral small vessel disease (cSVD) score. A fully adjusted ordinal logistic regression model, with categories of the total cSVD score as the dependent variable, disclosed significant associations between the waist circumference, the waist-to-hip, and the waist-to-height ratios – but not the body mass index (BMI) – and the cSVD burden. Indices of abdominal obesity may better correlate with severity of cSVD than the BMI in Amerindians. Phenotypic characteristics of this population may account for these results.

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Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Biomolecules ◽

10.3390/biom11070994 ◽

2021 ◽

Vol 11 (7) ◽

pp. 994

Author(s):

Natasha Ting Lee ◽

Lin Kooi Ong ◽

Prajwal Gyawali ◽

Che Mohd Nasril Che Mohd Nassir ◽

Muzaimi Mustapha ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Inflammatory Response ◽

Small Vessel Disease ◽

Ischemia Reperfusion ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Purinergic Signalling ◽

Vessel Disease ◽

The Brain

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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Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain

Neurology ◽

10.1212/wnl.0000000000013077 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013077

Author(s):

Corey W Bown ◽

Roxana O Carare ◽

Matthew S Schrag ◽

Angela L Jefferson

Keyword(s):

Fluid Transport ◽

Small Vessel Disease ◽

Treatment Strategies ◽

Small Vessel ◽

Aging Brain ◽

Perivascular Spaces ◽

Vessel Disease ◽

Clinical Consequences ◽

The Brain

Perivascular spaces (PVS) are fluid filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on magnetic resonance imaging. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as two possible mechanisms that drive ePVS formation. In this review, we describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the two most prominent theoretical views and review ePVS associations with other common small vessel disease markers. As ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer’s disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

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Abstract P332: Cerebral Small Vessel Disease Score in CADASIL: Relationships to Cognitive Dysfunctions

Stroke ◽

10.1161/str.52.suppl_1.p332 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Dorothee Schoemaker ◽

Yesica Zuluaga ◽

Lina Velilla ◽

Carolina Ospina ◽

Francisco Lopera ◽

...

Keyword(s):

Small Vessel Disease ◽

Structural Mri ◽

Vascular Cognitive Impairment ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Perivascular Spaces ◽

Cerebrovascular Injury ◽

Vessel Disease ◽

History Of

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease (cSVD) linked to NOTCH3 mutations and leading to the early onset of stroke and vascular cognitive impairment. Neuroimaging features of CADASIL include extensive white matter hyperintensity, lacunes, cerebral microbleeds and enlarged perivascular spaces. Researchers from the Rotterdam study recently proposed a MRI-based cSVD Score reflecting the overall burden of cerebrovascular injury (Yilmaz et al., 2018). Here, we explored the relevance of this cSVD Score in distinguishing CADASIL subjects from non-carriers and its relationships to cognition. We evaluated 26 NOTCH3 mutation carriers and 25 non-carriers from large Colombian families. Of the CADASIL subjects, 4 had previous strokes (symptomatic) and 22 had no history of strokes (asymptomatic). All subjects underwent a 3T MRI and a neuropsychological evaluation. Structural MRI markers of cSVD, as well as the cSVD Score, were quantified in each subject following established protocols. Demographic, cognitive and neuroimaging features across groups are presented in Table 1. The cSVD Score significantly differed between groups, after adjusting for age (Figure 1-A). In CADASIL subjects, the cSVD Score was negatively related to performance in Memory, Processing Speed, Executive Function, after accounting for age and education (Figure 1-B). These results suggest that the cSVD Score could be a useful marker of disease severity in CADASIL. Longitudinal studies are now needed to determine if this score allows predicting clinical outcomes in CADASIL, such as stroke or dementia.

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Total Cerebral Small Vessel Disease Burden on MRI Correlates With Cognitive Impairment in Outpatients With Amnestic Disorders

Frontiers in Neurology ◽

10.3389/fneur.2021.747115 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yangyi Fan ◽

Yicheng Xu ◽

Ming Shen ◽

Huailian Guo ◽

Zhaoxu Zhang

Keyword(s):

Linear Regression ◽

Regression Model ◽

Linear Regression Model ◽

Small Vessel Disease ◽

Multiple Linear Regression Model ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Perivascular Spaces ◽

Vessel Disease ◽

Moca Score

Objectives: The main markers of cerebral small vessel disease (cSVD) on MRI may be entered into a scoring system, with the total score representing the overall burden of cSVD. An association between total cSVD score and cognitive dysfunction has been reported in several cohorts. The present study aimed to investigate this association in outpatients with amnestic disorders.Materials and Methods: Outpatients with amnestic complaints in a memory clinic (n = 289) were recruited retrospectively. All the patients had undergone clinical and cognitive evaluation at first presentation. Cognitive function was assessed by Montreal Cognitive Assessment (MoCA) scale. The total cSVD score was based on the following markers on MRI: lacune; white matter hyperintensities, microbleed, and enlarged perivascular spaces. The association between total cSVD score and MoCA score was tested via Spearman's analysis and a linear regression model.Results: Among the 289 patients, rates for 0–4 cSVD markers respectively ranged from 30.4 to 2.8%. A multiple linear regression model revealed an inverse correlation between the total cSVD score and MoCA score. The association remained significant after adjusting for gender, age, education, levels of medial temporal lobe atrophy, and classical vascular risk factors [β = −0.729, 95% CI (−1.244, −0.213); P = 0.006]. When individual markers were individually analyzed after adjusting for the same factors, only microbleed associated with MoCA score [β = −3.007, 95% CI (−4.533, −1.480), P < 0.001].Conclusions: A significant association was demonstrated between total cSVD score and cognitive performance in the outpatients with amnestic disorders.

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Enlarged Perivascular Spaces on MRI Are a Feature of Cerebral Small Vessel Disease

Stroke ◽

10.1161/strokeaha.109.564914 ◽

2010 ◽

Vol 41 (3) ◽

pp. 450-454 ◽

Cited By ~ 275

Author(s):

Fergus N. Doubal ◽

Alasdair M.J. MacLullich ◽

Karen J. Ferguson ◽

Martin S. Dennis ◽

Joanna M. Wardlaw

Keyword(s):

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Perivascular Spaces ◽

Vessel Disease

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Arterial Stiffness Is Associated With Basal Ganglia Enlarged Perivascular Spaces and Cerebral Small Vessel Disease Load

Stroke ◽

10.1161/strokeaha.118.020163 ◽

2018 ◽

Vol 49 (5) ◽

pp. 1279-1281 ◽

Cited By ~ 15

Author(s):

Iolanda Riba-Llena ◽

Joan Jiménez-Balado ◽

Xavier Castañé ◽

Anna Girona ◽

Antonio López-Rueda ◽

...

Keyword(s):

Basal Ganglia ◽

Arterial Stiffness ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Perivascular Spaces ◽

Vessel Disease

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Abstract WMP59: White Matter Hyperintensities Play a Pivotal Role in Progression of Cerebral Small Vessel Disease: A 7-Year Chinese Urban Community Study

Stroke ◽

10.1161/str.51.suppl_1.wmp59 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yiwei Xia ◽

Yi Shen ◽

Yi Wang ◽

Lumeng Yang ◽

Yiqing Wang ◽

...

Keyword(s):

Executive Function ◽

Small Vessel Disease ◽

Urban Community ◽

Cerebral Small Vessel Disease ◽

Pivotal Role ◽

Small Vessel ◽

Community Study ◽

Perivascular Spaces ◽

Vessel Disease ◽

Increased Risk

Objective: To explore the role of WMH in progression of CSVD in an urban community in China over a period of 7 years, and to investigate associations between WMH volume (baseline & progression) and cognitive impairment. Methods: CSVD markers and neuropsychological tests at baseline and follow-up of 191 participants of the Shanghai Aging Study (SAS) were assessed. WMH volume were assessed by automatic segmentation based on U-net model. Lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (ePVS) were rated manually. SVD score was rated as the total burden of CSVD markers. We performed multivariate linear regression and binominal logistic regression. We plotted progression of markers by baseline WMH volume in tertile. Results: Participants with higher baseline WMH volume developed more progression of WMH volume, increased risk of incident lacunes, incident CMBs, and ePVS progression. Mean change of WMH volume over 7 years was 4.27mL (0.62mL/y) for all participants, 3.21mL for participants with 1st tertile WMH volume at baseline, 4.19mL for those with 2nd tertile WMH, and 5.43mL for those with 3rd tertile WMH. Incident lacunes and incident CMBs were predominantly seen in participants with 2nd and 3rd tertile WMH. WMH (baseline & progression) were associated with decline of executive function. Conclusions: WMH play a pivotal role in progression of cerebral small vessel disease and are associated with decline of executive function in a Chinese urban community study over a period of 7 years.

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