Genetics of Cerebral Small Vessel Disease.
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ABSTRACT:
SUBMITTER: Marini S
PROVIDER: S-EPMC7337039 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Genetics of Cerebral Small Vessel Disease.
Marini Sandro S Anderson Christopher D CD Rosand Jonathan J
Stroke 20191122 1
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Project description:Cerebral small vessel disease (SVD) is an important cause of stroke and cognitive impairment among the elderly and is a more frequent cause of stroke in Asia than in the US or Europe. Although traditional risk factors such as hypertension or diabetes mellitus are important in the development of cerebral SVD, the exact pathogenesis is still uncertain. Both, twin and family history studies suggest heritability of sporadic cerebral SVD, while the candidate gene study and the genome-wide association study (GWAS) are mainly used in genetic research. Robust associations between the candidate genes and occurrence of various features of sporadic cerebral SVD, such as lacunar infarction, intracerebral hemorrhage, or white matter hyperintensities, have not yet been elucidated. GWAS, a relatively new technique, overcomes several shortcomings of previous genetic techniques, enabling the detection of several important genetic loci associated with cerebral SVD. In addition to the more common, sporadic cerebral SVD, several single-gene disorders causing cerebral SVD have been identified. The number of reported cases is increasing as the clinical features become clear and diagnostic examinations are more readily available. These include cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1-related cerebral SVD, autosomal dominant retinal vasculopathy with cerebral leukodystrophy, and Fabry disease. These rare single-gene disorders are expected to play a crucial role in our understanding of cerebral SVD pathogenesis by providing animal models for the identification of cellular, molecular, and biochemical changes underlying cerebral small vessel damage.
| S-EPMC4325630 | biostudies-literature
Project description:Cerebral small-vessel disease (cSVD) is a common cause of stroke, functional decline, vascular cognitive impairment, and dementia. Pathological processes in the brain's microcirculation are tightly interwoven with pathology in the brain parenchyma, and this interaction has been conceptualized as the neurovascular unit (NVU). Despite intensive research efforts to decipher the NVU's structure and function to date, molecular mechanisms underlying cSVD remain poorly understood, which hampers the development of cSVD-specific therapies. Important steps forward in understanding the disease mechanisms underlying cSVD have been made using genetic approaches in studies of both monogenic and sporadic SVD. We provide an overview of the NVU's structure and function, the implications for cSVD, and the underlying molecular mechanisms of dysfunction that have emerged from recent genetic studies of both monogenic and sporadic diseases of the small cerebral vasculature.
| S-EPMC6614021 | biostudies-literature
Project description:Cerebral small vessel disease (cSVD) causes lacunar stroke (LS), intracerebral haemorrhage, and is the most common pathology underlying vascular dementia. However, there are few trials examining whether treating conventional cardiovascular risk factors reduce stroke risk in cSVD, as opposed to stroke as a whole. We used Mendelian randomization techniques to investigate which risk factors are causally related to cSVD and to evaluate whether specific drugs may be beneficial in cSVD prevention. We identified genetic proxies for blood pressure traits, lipids, glycaemic markers, anthropometry measures, smoking, alcohol consumption, and physical activity from large-scale genome-wide association studies of European ancestry. We also selected genetic variants as proxies for drug target perturbation in hypertension, dyslipidaemia, hyperglycaemia, and obesity. Mendelian randomization was performed to assess their associations with LS from the GIGASTROKE Consortium (n = 6811) and in a sensitivity analysis in a cohort of patients with MRI-confirmed LS (n = 3306). We also investigated associations with three neuroimaging features of cSVD, namely, white matter hyperintensities (n = 55 291), fractional anisotropy (n = 36 460), and mean diffusivity (n = 36 012). Genetic predisposition to higher systolic and diastolic blood pressure was associated with LS and cSVD imaging markers. Genetically predicted liability to diabetes, obesity, smoking, higher triglyceride levels, and the ratio of triglycerides to high density lipoprotein (HDL) also showed detrimental associations with LS risk, while genetic predisposition to higher HDL concentrations and moderate-to-vigorous physical activity showed protective associations. Genetically proxied blood pressure-lowering through calcium channel blockers (CCBs) was associated with cSVD imaging markers, while genetically proxied HDL-raising through Cholesteryl Ester Transfer Protein (CETP) inhibitors, triglyceride-lowering through lipoprotein lipase (LPL), and weight-lowering through gastric inhibitory polypeptide receptor (GIPR) were associated with lower risk of LS. Our findings highlight the importance of some conventional cardiovascular risk factors, including blood pressure and BMI, in cSVD, but not other e.g. LDL. The findings further demonstrate the potential beneficial effects of CCBs on cSVD imaging markers and CETP inhibitors, LPL enhancement, and GIPR obesity-targeted drugs on LS. They provide useful information for initiating future clinical trials examining secondary prevention strategies in cSVD.
| S-EPMC7617411 | biostudies-literature
Project description:ObjectiveOur aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease.MethodsThe study comprised 1,800 participants (aged 72.5 ± 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors.ResultsPresence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09-2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02-1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04-1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [β] ± standard error: 0.0003 ± 0.0001, p = 0.024; β ± standard error: 0.005 ± 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04-1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69-0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque.ConclusionsIn addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively.
| S-EPMC3590057 | biostudies-literature
Project description:Cerebral small vessel disease (CSVD) is a group of pathological processes with multifarious etiology and pathogenesis that are involved into the small arteries, arterioles, venules, and capillaries of the brain. CSVD mainly contains lacunar infarct or lacunar stroke, leukoaraiosis, Binswanger's disease, and cerebral microbleeds. CSVD is an important cerebral microvascular pathogenesis as it is the cause of 20% of strokes worldwide and the most common cause of cognitive impairment and dementia, including vascular dementia and Alzheimer's disease (AD). It has been well identified that CSVD contributes to the occurrence of AD. It seems that the treatment and prevention for cerebrovascular diseases with statins have such a role in the same function for AD. So far, there is no strong evidence-based medicine to support the idea, although increasing basic studies supported the fact that the treatment and prevention for cerebrovascular diseases will benefit AD. Furthermore, there is still lack of evidence in clinical application involved in specific drugs to benefit both AD and CSVD.
| S-EPMC4629951 | biostudies-literature
Project description:BackgroundWhile hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr-/- mouse model.MethodsWe used Ldlr-/- mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr-/- mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.ResultsWe found a significant increase in the number of erythrocyte stases in 6 months old Ldlr-/- mice compared to all other groups (P < 0.05). Ldlr-/- animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr-/- mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.ConclusionsIn Ldlr-/- mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr-/- mice appear to be an adequate animal model for research into CSVD.
| S-EPMC5552130 | biostudies-literature
Project description:ImportanceThere is increasing recognition that vascular disease, which can be treated, is a key contributor to dementia risk. However, the contribution of specific markers of vascular disease is unclear and, as a consequence, optimal prevention strategies remain unclear.ObjectiveTo disentangle the causal relation of several key vascular traits to dementia risk: (i) white matter hyperintensity (WMH) burden, a highly prevalent imaging marker of covert cerebral small vessel disease (cSVD); (ii) clinical stroke; and (iii) blood pressure (BP), the leading risk factor for cSVD and stroke, for which efficient therapies exist. To account for potential epidemiological biases inherent to late-onset conditions like dementia.Design setting and participantsThis study first explored the association of genetically determined WMH, BP levels and stroke risk with AD using summary-level data from large genome-wide association studies (GWASs) in a two-sample Mendelian randomization (MR) framework. Second, leveraging individual-level data from large longitudinal population-based cohorts and biobanks with prospective dementia surveillance, the association of weighted genetic risk scores (wGRSs) for WMH, BP, and stroke with incident all-cause-dementia was explored using Cox-proportional hazard and multi-state models. The data analysis was performed from July 26, 2020, through July 24, 2022.ExposuresGenetically determined levels of WMH volume and BP (systolic, diastolic and pulse blood pressures) and genetic liability to stroke.Main outcomes and measuresThe summary-level MR analyses focused on the outcomes from GWAS of clinically diagnosed AD (n-cases=21,982) and GWAS additionally including self-reported parental history of dementia as a proxy for AD diagnosis (ADmeta, n-cases=53,042). For the longitudinal analyses, individual-level data of 157,698 participants with 10,699 incident all-cause-dementia were studied, exploring AD, vascular or mixed dementia in secondary analyses.ResultsIn the two-sample MR analyses, WMH showed strong evidence for a causal association with increased risk of ADmeta (OR, 1.16; 95%CI:1.05-1.28; P=.003) and AD (OR, 1.28; 95%CI:1.07-1.53; P=.008), after accounting for genetically determined pulse pressure for the latter. Genetically predicted BP traits showed evidence for a protective association with both clinically defined AD and ADmeta, with evidence for confounding by shared genetic instruments. In longitudinal analyses the wGRSs for WMH, but not BP or stroke, showed suggestive association with incident all-cause-dementia (HR, 1.02; 95%CI:1.00-1.04; P=.06). BP and stroke wGRSs were strongly associated with mortality but there was no evidence for selective survival bias during follow-up. In secondary analyses, polygenic scores with more liberal instrument definition showed association of both WMH and stroke with all-cause-dementia, AD, and vascular or mixed dementia; associations of stroke, but not WMH, with dementia outcomes were markedly attenuated after adjusting for interim stroke.ConclusionThese findings provide converging evidence that WMH is a leading vascular contributor to dementia risk, which may better capture the brain damage caused by BP (and other etiologies) than BP itself and should be targeted in priority for dementia prevention in the population.
| S-EPMC10543241 | biostudies-literature
Project description:Background and Objective: Studies on relations between arterial stiffness and full spectrum of radiological features of cerebral small vessel disease (CSVD) are scarce. We aim to investigate the association of arterial stiffness with lacunes, white matter hyperintensities (WMH), microbleeds (CMBs), dilated perivascular spaces (PVS), and brain atrophy in a community-based sample. Methods: A total of 953 participants (55.7 ± 9.4 years) who underwent brachial-ankle pulse wave velocity (baPWV) and brain magnetic resonance imaging were included. Lacunes, CMBs, and PVS were visually rated. Brain structure and WMH were automatically segmented. Brain parenchyma fraction (BPF), a surrogate index of brain atrophy, was calculated as a ratio of brain parenchyma volume to total intracranial volume. Multivariable logistic and linear regressions were used to investigate the associations between baPWV and CSVD. Subsequently, we explored these associations in strata of age. Results: Increased baPWV was associated with severe PVS in white matter (OR, 1.09; 95%CI, 1.01-1.17; p = 0.022), larger WMH volume (β, 0.08; 95%CI, 0.04-0.12; p < 0.001), lower BPF (β, -0.09; 95%CI, -0.15- -0.03; p = 0.007), and marginally associated with strictly lobar CMBs (OR, 1.11; 95%CI, 1.00-1.23; p = 0.055), but not with lacunes. WMH volume mediated the relation between baPWV and BPF. In age subgroup analysis, the association of baPWV with PVS in white matter was stronger among those aged <55 years, whereas the association with brain atrophy was more prominent among those aged ≥55 years. Increased baPWV was associated with larger WMH volume in both younger and older individuals. Conclusions: Increased arterial stiffness was associated with most of imaging markers of CSVD, including PVS in white matter, larger WMH volume, strictly lobar CMBs, and brain atrophy, but not lacunes. The mechanisms underlying these associations and their potential clinical significances warrant further investigations.
| S-EPMC6121106 | biostudies-literature
Project description:Opinion statementCerebral small vessel disease (SVD) is characterised by damage to deep grey and white matter structures of the brain and is responsible for a diverse range of clinical problems that include stroke and dementia. In this review, we describe advances in neuroimaging published since January 2015, mainly with magnetic resonance imaging (MRI), that, in general, are improving quantification, observation and investigation of SVD focussing on three areas: quantifying the total SVD burden, imaging brain microstructural integrity and imaging vascular malfunction. Methods to capture 'whole brain SVD burden' across the spectrum of SVD imaging changes will be useful for patient stratification in clinical trials, an approach that we are already testing. More sophisticated imaging measures of SVD microstructural damage are allowing the disease to be studied at earlier stages, will help identify specific factors that are important in development of overt SVD imaging features and in understanding why specific clinical consequences may occur. Imaging vascular function will help establish the precise blood vessel and blood flow alterations at early disease stages and, together with microstructural integrity measures, may provide important surrogate endpoints in clinical trials testing new interventions. Better knowledge of SVD pathophysiology will help identify new treatment targets, improve patient stratification and may in future increase efficiency of clinical trials through smaller sample sizes or shorter follow-up periods. However, most of these methods are not yet sufficiently mature to use with confidence in clinical trials, although rapid advances in the field suggest that reliable quantification of SVD lesion burden, tissue microstructural integrity and vascular dysfunction are imminent.
| S-EPMC5486578 | biostudies-literature
Project description:To explore Dawson's fingers in cerebral small vessel disease (CSVD) and factors related to the development of Dawson's finger, we collected and analyzed clinical data of 65 patients with CSVD. We found a venous abnormality feature called Dawson's fingers around the ventricles in magnetic resonance images (MRIs) of 20 out of 65 patients with CSVD (30. 8%). A significant association between Dawson's fingers and diabetes mellitus (DM) was also detected (30 vs. 8.9%, P < 0.05). CSVD patients with Dawson's fingers had significantly increased cerebral microbleeds (CMB) (44.2 vs. 75.0%, p < 0.05), lacunae (66.7 vs. 95.0%, p < 0.05), and white matter hyperintensity (WMH) (p < 0.05) damage, and these patients exhibited significant cognitive domain impairment as assessed via Montreal Cognitive Assessment (MoCA) (18.9 ± 1.8 vs. 24.0 ± 0.8, p < 0.05) and Mini-Mental State Examination (MMSE) (24.5 ± 1.1 vs. 26.6 ± 0.6, p < 0.05). Our results show a distinctly high incidence of Dawson's fingers in CSVD patients and identify a significant association with DM, thus yielding insights about the appropriate use of Dawson's fingers, a venous imaging marker, to explore the basic pathophysiology of CSVD.
| S-EPMC7396560 | biostudies-literature