scholarly journals New insights into mechanisms of small vessel disease stroke from genetics

2017 ◽  
Vol 131 (7) ◽  
pp. 515-531 ◽  
Author(s):  
Rhea Tan ◽  
Matthew Traylor ◽  
Loes Rutten-Jacobs ◽  
Hugh Markus
Keyword(s):  
Small Vessel Disease ◽  
Association Studies ◽  
Small Vessel ◽  
Monogenic Disease ◽  
Genome Wide Association Studies ◽  
Stroke Patients ◽  
Genetic Studies ◽  
Vessel Disease ◽  
Disease Mechanisms ◽  
Shed Light

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood–brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and ‘sporadic’ SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in ‘sporadic’ SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in ‘sporadic’ SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.

scholarly journals Hypertension and Cerebral Microangiopathy (Cerebral Small Vessel Disease): Genetic and Epigenetic Aspects of Their Relationship

Acta Naturae ◽  
2018 ◽  
Vol 10 (2) ◽  
pp. 4-15 ◽  
Author(s):  
L. A. Dobrynina ◽  
M. R. Zabitova ◽  
L. A. Kalashnikova ◽  
E. V. Gnedovskaya ◽  
M. A. Piradov
Keyword(s):  
Antihypertensive Therapy ◽  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Cerebral Injury ◽  
Small Vessel ◽  
Genome Wide Association Studies ◽  
Vessel Disease ◽  
Cerebral Complications ◽  
Cerebral Microangiopathy

Hypertension (HT) and its cerebral complications are extremely vexing medical and social problems. Despite the obvious association between hypertension and the clinical and neuroimaging features of cerebral microangiopathy (CMA) (also known as cerebral small vessel disease), the causal links between them remain ambiguous. Besides, antihypertensive therapy as the only way to manage these patients does not always prevent brain damage. Knowledge about the key factors and mechanisms involved in HT and CMA development is important for predicting the risk of cerebral complications and developing new approaches to their prevention and treatment. At present, genome-wide association studies and other approaches are used to investigate the common hereditary mechanisms of HT and CMA development, which will explain a large number of CMA cases not associated with hypertension, lack of a correlation between HT severity and the degree of cerebral injury, and failure of antihypertensive therapy to prevent CMA progression. Epigenetic markers likely play a modulating role in the development of these diseases.

scholarly journals Association of common genetic variants with brain microbleeds

Neurology ◽  
2020 ◽  
Vol 95 (24) ◽  
pp. e3331-e3343 ◽  
Author(s):  
Maria J. Knol ◽  
Dongwei Lu ◽  
Matthew Traylor ◽  
Hieab H.H. Adams ◽  
José Rafael J. Romero ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Genome Wide Association Studies ◽  
Vessel Disease ◽  
Genome Wide ◽  
Common Genetic Variants

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case–control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21–1.45]; p = 2.5 × 10−10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19–1.50]; p = 1.0 × 10−6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86–1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

scholarly journals Genetic factors in cerebral small vessel disease and their impact on stroke and dementia

2015 ◽  
Vol 36 (1) ◽  
pp. 158-171 ◽  
Author(s):  
Christof Haffner ◽  
Rainer Malik ◽  
Martin Dichgans
Keyword(s):  
Small Vessel Disease ◽  
Association Studies ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Genome Wide Association Studies ◽  
Major Theme ◽  
Vessel Disease ◽  
Type Iv ◽  
Genome Wide ◽  
Substantial Progress

Cerebral small vessel disease (SVD) is among the most frequent causes of both stroke and dementia. There is a growing list of genes known to be implicated in Mendelian forms of SVD. Also, genome-wide association studies have identified common variants at a number of genetic loci that are associated with manifestations of SVD, among them loci for white matter hyperintensities, small vessel stroke, and deep intracerebral hemorrhage. Driven by these discoveries and new animal models substantial progress has been made in elucidating the molecular, cellular, and physiologic mechanisms underlying SVD. A major theme emerging from these studies is the extracellular matrix (ECM). Recent findings include a role of structural constituents of the ECM such as type IV collagens in hereditary and sporadic SVD, the sequestration of proteins with a known role in ECM maintenance into aggregates of NOTCH3, and altered signaling through molecules known to interact with the ECM. Here, we review recent progress in the identification of genes involved in SVD and discuss mechanistic concepts with a particular focus on the ECM.

Homocysteine, small-vessel disease, and atherosclerosis: An MRI study of 825 stroke patients

Neurology ◽  
2014 ◽  
Vol 83 (8) ◽  
pp. 695-701 ◽  
Author(s):  
S.-B. Jeon ◽  
D.-W. Kang ◽  
J. S. Kim ◽  
S. U. Kwon
Keyword(s):  
Small Vessel Disease ◽  
Small Vessel ◽  
Stroke Patients ◽  
Vessel Disease ◽  
Mri Study

scholarly journals Accelerated development of cerebral small vessel disease in young stroke patients

Neurology ◽  
2016 ◽  
Vol 87 (12) ◽  
pp. 1212-1219 ◽  
Author(s):  
Renate M. Arntz ◽  
Steffen M.A. van den Broek ◽  
Inge W.M. van Uden ◽  
Mohsen Ghafoorian ◽  
Bram Platel ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Stroke Patients ◽  
Young Stroke ◽  
Vessel Disease

scholarly journals Prevalence and Effect of Cerebral Small Vessel Disease in Stroke Patients With Aspirin Treatment Failure–A Hospital-Based Stroke Secondary Prevention Registry

2021 ◽  
Vol 12 ◽  
Author(s):  
Ping-Song Chou ◽  
Pi-Shan Sung ◽  
Chi-Hung Liu ◽  
Yueh-Feng Sung ◽  
Ray-Chang Tzeng ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Ischemic Stroke ◽  
Treatment Failure ◽  
Rating Scale ◽  
Small Vessel Disease ◽  
Demographic Data ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Stroke Patients ◽  
Vessel Disease

Background: Breakthrough strokes during treatment with aspirin, termed clinical aspirin treatment failure (ATF), is common in clinical practice. The burden of cerebral small vessel disease (SVD) is associated with an increased recurrent ischemic stroke risk. However, the association between SVD and ATF remains unclear. This study investigated the prevalence and clinical characteristics of SVD in stroke patients with ATF.Methods: Data from a prospective, and multicenter stroke with ATF registry established in 2018 in Taiwan were used, and 300 patients who developed ischemic stroke concurrent with regular use of aspirin were enrolled. White matter lesions (WMLs) and cerebral microbleeds (CMBs) were identified using the Fazekas scale and Microbleed Anatomical Rating Scale, respectively. Demographic data, cardiovascular comorbidities, and index stroke characteristics of patients with different WML and CMB severities were compared. Logistic regression analyses were performed to explore the factors independently associated with outcomes after ATF.Results: The mean patient age was 69.5 ± 11.8 years, and 70.0% of patients were men. Among all patients, periventricular WML (PVWML), deep WML (DWML), and CMB prevalence was 93.3, 90.0, and 52.5%, respectively. Furthermore, 46.0% of the index strokes were small vessel occlusions. Severe PVWMLs and DWMLs were significantly associated with high CMB burdens. Patients with moderate-to-severe PVWMLs and DWMLs were significantly older and had higher cardiovascular comorbidity prevalence than did patients with no or mild WMLs. Moreover, patients with favorable outcomes exhibited significantly low prevalence of severe PVWMLs (p = 0.001) and DWMLs (p = 0.001). After logistic regression was applied, severe WMLs predicted less favorable outcomes independently, compared with those with no to moderate PVWMLs and DWMLs [odds ratio (OR), 0.47; 95% confidence interval (CI), 0.25–0.87 for severe PVWMLs; OR, 0.40; 95% CI, 0.21–0.79 for severe DWMLs].Conclusions: SVD is common in stroke patients with ATF. PVWMLs and DWMLs are independently associated with functional outcomes in stroke patients with ATF. The burden of SVD should be considered in future antiplatelet strategies for stroke patients after ATF.

scholarly journals Cerebral small vessel disease MRI features do not improve the prediction of stroke outcome

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011208
Author(s):  
Coutureau Juliette ◽  
Asselineau Julien ◽  
Perez Paul ◽  
Kuchcinski Gregory ◽  
Sagnier Sharmila ◽  
...  
Keyword(s):  
Predictive Accuracy ◽  
Small Vessel Disease ◽  
Added Value ◽  
Psychological Status ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Stroke Outcome ◽  
Stroke Patients ◽  
Vessel Disease ◽  
Mri Features

Objective:To determine whether the total small vessel disease (SVD) score adds information to the prediction of stroke outcome compared to validated predictors, we tested different predictive models of outcome in stroke patients.Methods:White matter hyperintensity, lacunes, perivascular spaces, microbleeds, and atrophy were quantified in two prospective datasets of 428 and 197 first-ever stroke patients, using MRI collected 24-to-72 hours after stroke onset. Functional, cognitive, and psychological status were assessed at the 3–6 month follow-up. The predictive accuracy (in terms of calibration and discrimination) of age, baseline NIHSS, and infarct volume was quantified (model-1) on dataset-1, the total SVD score was added (model-2), and the improvement in predictive accuracy was evaluated. These two models were also developed in dataset-2 for replication. Finally, in model-3, the MRI features of cerebral SVD were included rather than the total SVD score.Results:Model-1 showed excellent performance for discriminating poor vs. good functional outcomes (AUC=0.915), and fair performance for identifying cognitively impaired and depressed patients (AUCs, 0.750 and 0.688 respectively). A higher SVD score was associated with a poorer outcome (odds ratio=1.30 [1.07, 1.58], p=0.0090 at best for functional outcome). However, adding the total SVD score (model-2) or individual MRI features (model-3) did not improve the prediction over model-1. Results for dataset-2 were similar.Conclusions:Cerebral SVD was independently associated with functional, cognitive, and psychological outcomes, but had no clinically relevant added value to predict the individual outcomes of patients when compared to the usual predictors, such as age and baseline NIHSS.

scholarly journals Pre-micro RNA polymorphism detection in small versus large vessel disease in stroke patients

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
H H Elkhawas ◽  
H H Afify ◽  
H Shokri ◽  
E Hassan ◽  
A Alzahaby
Keyword(s):  
Small Vessel Disease ◽  
Susceptibility Gene ◽  
Large Vessel ◽  
Small Vessel ◽  
Stroke Patients ◽  
Functional Polymorphisms ◽  
Vessel Disease ◽  
Stroke Subtypes ◽  
Micro Rnas ◽  
Large Vessel Disease

Abstract Article Outline Abstract Introduction Patients and methods Procedure Statistical analysis Results Discussion Conclusion References Background Cerebrovascular accidents are the second leading cause of death and the third leading cause of disability worldwide. The methods currently available for diagnosis and prognosis of cerebral ischaemia still require further improvements. Micro-RNAs (small non-coding RNAs) have been recently reported as useful biomarkers in diseases such as cancer and diabetes. Further research concerned with microRNA (miRNA) profiling from peripheral blood to detect and identify characteristic patterns in ischaemic stroke is crucial. Aim of the work This study aims to investigate the association between three potentially functional polymorphisms in pre-miRNAs and stroke subtypes (small vessel disease and large vessel disease) in a sample of Egyptian stroke patients. Patients and Methods This is a cross sectional study conducted in Ain Shams University Hospitals in which 81 patients presenting with cerebrovascular stroke fulfilling criteria of small vessel disease (SVD) or large vessel disease (LVD) according to TOAST [2] classification in the period from March 2018 to August 2018 were included. Blood samples were withdrawn for DNA extraction to investigate the association between three potentially functional polymorphisms (rs2910164, rs11614913, and rs3746444) in pre-miRNAs (hsamiR-146a, hsa-miR-196a2, and hsa-miR-499, respectively). Results Smoking, hypertension and diabetes were significant value in both stroke subtypes. Meanwhile, age and gender showed no significance between both stroke subtypes. Conclusion Ischemic stroke has polygenic basis, but identification of stroke susceptibility gene and quantification of associated risks has been hindered by conflicting results from different studies.

Abstract P549: Total Small Vessel Disease Burden Not Associated With Functional Independence After Endovascular Treatment in Acute Ischemic Stroke Patients

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Lina Zheng ◽  
Xinyi Leng ◽  
Ximing Nie ◽  
Hongyi Yan ◽  
Thomas W Leung ◽  
...  
Keyword(s):  
Endovascular Treatment ◽  
Primary Outcome ◽  
Small Vessel Disease ◽  
Functional Independence ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Stroke Patients ◽  
Vessel Occlusion ◽  
Vessel Disease ◽  
Secondary Outcomes

Background: Individual small vessel disease (SVD) markers had been associated with outcomes of endovascular treatment (EVT) in acute stroke patients. We aimed to investigate the associations between total SVD burden and outcomes in such patients. Methods: In a nation-wide multicenter registration study, we enrolled stroke patients with anterior circulation large vessel occlusion (LVO) receiving EVT, who had undergone 3T MRI. Presence of lacunes, white matter hyperintensities, cerebral microbleeds and perivascular spaces in both hemispheres were assessed in MRI and each marker was assigned a score of 0 or 1 by presence. A total SVD burden score (0-4) was calculated by summing up the individual scores, which was dichotomized as none-to-mild (score 0-2) and moderate-to-severe (score 3-4). The primary outcome was 90-day functional independence, defined as modified Rankin Scale (mRS) of 0-2. Secondary outcomes included change in NIHSS from baseline to 7 days, early neurological deterioration (END), symptomatic intracranial hemorrhage and 90-day mortality. We investigated the associations of dichotomized total SVD burden score with the outcomes using binary logistic regression analyses. Results: Of the 202 patients (65.38% male; mean age 65.54 ± 11.93 years) enrolled, 176 patients had none-to-mild and 26 had moderate-to-severe total SVD burden. Those with moderate-to-severe SVD were older (mean age 69.8 versus 64.7; P=0.043) and more of them had a prior stroke (42.31% versus 23.3%; P=0.039), compared with otherwise. Dichotomized total SVD burden was not significantly associated with the primary outcome, 90-day functional independence (moderate-to-severe versus none-to-mild SVD burden: 53.85% versus 47.13%; OR 0.76, 95% CI 0.33-1.75; P=0.523). Although moderate-to-severe total SVD burden was associated with a higher rate of END (15.38% versus 3.43%; OR 5.12; 95% CI 1.34-19.58; P=0.017), no significant association was detected between the total SVD burden and other secondary outcomes. Conclusions: The total SVD burden as assessed in MRI was not significantly associated with the chance of obtaining functional independence at 90 days in LVO-stroke patients receiving EVT. A higher total SVD burden may not be an exclusion criteria for clinical decision for EVT.

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