Cerebral small vessel disease and risk of incident stroke, dementia and depression, and all-cause mortality: A systematic review and meta-analysis.
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SUBMITTER: Rensma SP
PROVIDER: S-EPMC6123527 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and objectivesCerebral small vessel disease is a major cause of stroke and dementia. Metabolomics can help identify novel risk factors to better understand pathogenesis and predict disease progression and severity.MethodsWe analyzed baseline metabolomic profiles from 118,021 UK Biobank participants. We examined cross-sectional associations of 325 metabolites with MRI markers of small vessel disease, evaluated longitudinal associations with incident stroke and dementia, and ascertained causal relationships using Mendelian randomization.ResultsIn cross-sectional analyses, lower levels of apolipoproteins, free cholesterol, cholesteryl esters, fatty acids, lipoprotein particle concentrations, phospholipids, and triglycerides were associated with increased white matter microstructural damage on diffusion tensor MRI. In longitudinal analyses, lipoprotein subclasses of very large high-density lipoprotein cholesterol (HDL) were associated with an increased risk of stroke, and acetate and 3-hydroxybutyrate were associated with an increased risk of dementia. Mendelian randomization analyses identified strong evidence supporting causal relationships for many findings. A few metabolites had consistent associations across multiple analysis types. Increased total lipids in very large HDL and increased HDL particle size were associated with increased white matter damage (lower fractional anisotropy: OR: 1.44, 95% CI 1.07-1.95, and OR: 1.19, 95% CI 1.06-1.34, respectively; mean diffusivity: OR: 1.49, 95% CI 1.11-2.01, and OR: 1.24, 95% CI 1.11-1.40, respectively) and an increased risk of incident all stroke (HR: 4.04, 95% CI 2.13-7.64, and HR: 1.54, 95% CI 1.20-1.98, respectively) and ischemic stroke (HR: 3.12, 95% CI 1.53-6.38; HR: 1.37, 95% CI 1.04-1.81). Valine was associated with decreased mean diffusivity (OR: 0.51, 95% CI 0.30-0.88) and had a protective association with all-cause dementia (HR: 0.008, 95% CI 0.002-0.035). Increased levels of cholesterol in small HDL were associated with a decreased risk of incident all stroke (HR: 0.17, 95% CI 0.08-0.39) and ischemic stroke (HR: 0.19, 95% CI 0.08-0.46) and were supported by evidence of a causal association with MRI-confirmed lacunar stroke (OR: 0.96, 95% CI 0.93-0.99).DiscussionIn this large-scale metabolomics study, we found multiple metabolites associated with stroke, dementia, and MRI markers of small vessel disease. Further studies may help inform the development of personalized prediction models and provide insights into mechanistic pathways and future treatment approaches.
| S-EPMC10401678 | biostudies-literature
Project description: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.
| S-EPMC4758558 | biostudies-literature
Project description:ObjectiveTo investigate the relation between baseline cerebral small vessel disease (SVD) and the risk of incident parkinsonism using different MRI and diffusion tensor imaging (DTI) measures.MethodsIn the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, a prospective cohort study, 503 elderly participants with SVD and without parkinsonism were included in 2006. During follow-up (2011-2012), parkinsonism was diagnosed according to UK Brain Bank criteria. Cox regression analysis was used to investigate the association between baseline imaging measures and incident all-cause parkinsonism and vascular parkinsonism (VP). Tract-based spatial statistics analysis was used to identify differences in baseline DTI measures of white matter (WM) tracts between participants with VP and without parkinsonism.ResultsFollow-up was available from 501 participants (mean age 65.6 years; mean follow-up duration 5.2 years). Parkinsonism developed in 20 participants; 15 were diagnosed with VP. The 5-year risk of (any) parkinsonism was increased for those with a high white matter hyperintensity (WMH) volume (hazard ratio [HR] 1.8 per SD increase, 95% confidence interval [CI] 1.3-2.4) and a high number of lacunes (HR 1.4 per number increase, 95% CI 1.1-1.8) at baseline. For VP, this risk was also increased by the presence of microbleeds (HR 5.7, 95% CI 1.9-16.8) and a low gray matter volume (HR 0.4 per SD increase, 95% CI 0.2-0.8). Lower fractional anisotropy values in bifrontal WM tracts involved in movement control were observed in participants with VP compared to participants without parkinsonism.ConclusionsSVD at baseline, especially a high WMH volume and a high number of lacunes, is associated with incident parkinsonism. Our findings favor a role of SVD in the etiology of parkinsonism.
| S-EPMC4642143 | biostudies-literature
Project description:Background and purposeThe recently developed total cerebral small-vessel disease (CSVD) score might appropriately reflect the total burden or severity of CSVD. We investigated whether the total CSVD score is associated with long-term outcomes during follow-up in patients with acute ischemic stroke.MethodsIn total, 1,096 consecutive patients with acute ischemic stroke who underwent brain magnetic resonance imaging were enrolled. We calculated the total CSVD score for each patient after determining the burden of cerebral microbleeds (CMBs), high-grade white-matter hyperintensities (HWHs), high-grade perivascular spaces (HPVSs), and asymptomatic lacunar infarctions (ALIs). We recorded the date and cause of death for all of the patients using data from the Korean National Statistical Office. We compared the long-term mortality rate with the total CSVD score using Cox proportional-hazards models.ResultsCMBs were found in 26.8% of the subjects (294/1,096), HWHs in 16.4% (180/1,096), HPVSs in 19.3% (211/1,096), and ALIs in 38.0% (416/1,096). After adjusting for age, sex, and variables that were significant at p<0.1 in the univariate analysis, the total CSVD score was independently associated with long-term death from all causes [hazard ratio (HR)=1.18 per point, 95% confidence interval (CI)=1.07-1.30], ischemic stroke (HR=1.20 per point, 95% CI=1.01-1.42), and hemorrhagic stroke (HR=2.05 per point, 95% CI=1.30-3.22), but not with fatal cardiovascular events (HR=1.17 per point, 95% CI=0.82-1.67).ConclusionsThe total CSVD score is a potential imaging biomarker for predicting mortality during follow-up in patients with acute ischemic stroke.
| S-EPMC5392462 | biostudies-literature
Project description:Objective: To investigate the application of optical coherence tomography angiography (OCTA) in cerebral small vessel disease (SVD), ischemic stroke and dementia. Methods: We conducted a systematic search in MEDLINE (from inception) and EMBASE (from 1980) to end 2019 for human studies that measured retinal parameters in cerebral SVD, ischemic stroke, and dementia using OCTA. Results: Fourteen articles (n = 989) provided relevant data. Ten studies included patients with Alzheimer disease (AD) and mild cognitive impairment (n = 679), two investigated pre-symptomatic AD participants (n = 154), and two investigated monogenic SVD patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (n = 32) and Fabry disease (n = 124). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial methodological variations between studies precluded a formal meta-analysis. Quantitative measurements revealed significant yet inconclusive changes in foveal avascular zone, perfusion density, and vessel density (VD) in AD, presymptomatic AD, and SVD patients. Two (n = 160) of three studies (n = 192) showed association between decreased VD and increased white matter hyperintensities. In three (n = 297) of seven studies (n = 563), better cognitive function was associated with increased VD. One study (n = 52) suggested increased VD was associated with increased ganglion cell-inner plexiform layer thickness in AD yet with no covariate adjustment. Conclusions: Changes in retinal microvasculature identified using OCTA are associated with monogenic SVD and different stages of AD, but data are limited and partly confounded by methodological differences. Larger studies with risk factors adjustment and more consistent OCTA methods are needed to fully exploit this technology. PROSPERO registration number: CRD42020166929.
| S-EPMC7511809 | biostudies-literature
Project description:Background Results of several longitudinal cohort studies suggested an association between cerebral small-vessel disease and depression. Therefore, we performed a meta-analysis to explore whether cerebral small-vessel disease imparts increased risk for incident depression. Methods and Results We searched prospective cohort studies relevant to the relationship between cerebral small-vessel disease and incident depression published through September 6, 2019, which yielded 16 cohort studies for meta-analysis based on the relative odds ratio (OR) calculated with fixed- and random-effect models. Baseline white matter hyperintensities (WMHs) (pooled OR, 1.37; 95% CI, 1.14-1.65), enlarged perivascular spaces (pooled OR, 1.33; 95% CI, 1.03-1.71), and cerebral atrophy (pooled OR, 2.83; 95% CI, 1.54-5.23) were significant risk factors for incident depression. Presence of deep WMHs (pooled OR, 1.47; 95% CI, 1.05-2.06) was a stronger predictor of depression than were periventricular WMHs (pooled OR, 1.31; 95% CI, 0.93-1.86). What's more, the pooled OR increased from 1.20 for the second quartile to 1.96 for the fourth quartile, indicating that higher the WMH severity brings greater risk of incident depression (25th-50th: pooled OR, 1.20; 95% CI, 0.68-2.12; 50th-75th; pooled OR, 1.42; 95% CI, 0.81-2.46; 75th-100th: OR, 1.96; 95% CI, 1.06-3.64). These results were stable to subgroup analysis for age, source of participants, follow-up time, and methods for assessing WMHs and depression. Conclusions Cerebral small-vessel disease features such as WMHs, enlarged perivascular spaces, and cerebral atrophy, especially the severity of WMHs and deep WMHs, are risk factors for incident depression.
| S-EPMC7792262 | biostudies-literature
Project description:ObjectiveTo determine whether a simple small vessel disease (SVD) score, which uses information available on rapid visual assessment of clinical MRI scans, predicts risk of cognitive decline and dementia, above that provided by simple clinical measures.MethodsThree prospective longitudinal cohort studies (SCANS [St George's Cognition and Neuroimaging in Stroke], RUN DMC [Radboud University Nijmegen Diffusion Imaging and Magnetic Resonance Imaging Cohort], and the ASPS [Austrian Stroke Prevention Study]), which covered a range of SVD severity from mild and asymptomatic to severe and symptomatic, were included. In all studies, MRI was performed at baseline, cognitive tests repeated during follow-up, and progression to dementia recorded prospectively. Outcome measures were cognitive decline and onset of dementia during follow-up. We determined whether the SVD score predicted risk of cognitive decline and future dementia. We also determined whether using the score to select a group of patients with more severe disease would reduce sample sizes for clinical intervention trials.ResultsIn a pooled analysis of all 3 cohorts, the score improved prediction of dementia (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.81-0.89) compared with that from clinical risk factors alone (AUC, 0.76; 95% CI, 0.71-0.81). Predictive performance was higher in patients with more severe SVD. Power calculations showed selecting patients with a higher score reduced sample sizes required for hypothetical clinical trials by 40%-66% depending on the outcome measure used.ConclusionsA simple SVD score, easily obtainable from clinical MRI scans and therefore applicable in routine clinical practice, aided prediction of future dementia risk.
| S-EPMC7274929 | biostudies-literature
Project description:IntroductionCerebral small vessel disease (SVD) predicts all-cause mortality in Eastern Asian and Caucasian populations. However, little is known about SVD impact in individuals of different races/ethnic groups. In this study, we sought to estimate the mortality risk according to the total SVD (tSVD) score in older adults of Amerindian ancestry.MethodsParticipants aged ≥60 years from the prospective population-based Atahualpa Project cohort underwent brain MRI between June 2012 and June 2017. The tSVD score was calculated based on the presence of moderate-to-severe white matter hyperintensities, enlarged perivascular spaces, one or more lacune, and one or more cerebral microbleed. We ascertained all-cause mortality during post-MRI follow-up. Poisson regression and Cox-proportional hazards models adjusted for demographics and cardiovascular risk were obtained to estimate mortality risk according to the tSVD score.ResultsAnalysis included 375 participants with available brain MRI and clinical data (mean age 69.0 ± 8.3 years, 56.3% women). The tSVD score was 0 point in 216 individuals (57.6%), 1 point in 71 (18.9%), 2 points in 53 (14.1%), and 3-4 points in 35 (9.3%). Increasing tSVD score was associated with advancing age, hypertension, low level of education, and physical inactivity. Using tSVD score of 0 as reference, a multivariate Poisson regression model showed an increased mortality for individuals with a tSVD score 3-4 points (IRR: 2.27; 95% CI: 1.20-4.28). Likewise, in the Cox-proportional model adjusted for demographics and cardiovascular risk, participants with a tSVD score 3-4 maintained a greater than two-fold mortality risk when compared to those with tSVD score of 0 points (HR: 2.32; 95% CI: 1.23-4.39).ConclusionsHigh-burden SVD as determined by the tSVD score predicts mortality in community-dwelling older adults of Amerindian ancestry. Incidental diagnosis of covert SVD should prompt aggressive control of cardiovascular health.
| S-EPMC8948511 | biostudies-literature
Project description:Background and purposeTo investigate the association of different status of cerebral small vessel disease (CSVD) and infarction number with recurrence after acute minor stroke and transient ischaemic attack (TIA).MethodsThis study was a post hoc analysis of the Clopidogrel in High-risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, and includes 886 patients with acute minor stroke and TIA. The status of CSVD and infarction number was recorded for each individual. Infarction number were classified as multiple acute infarctions (MAIs≥2), single acute infarction (SAI =1), and non-acute infarction (NAI =0). The CSVD burden were grouped into non-CSVD (0 score) and CSVD (1-4 score). The primary outcome was a recurrent stroke at the 1-year follow-up. The secondary outcomes were recurrent ischaemic stroke, composite vascular event (CVE), and TIA. We analyzed the relationships between different status of CSVD burden and infarction pattern with the risk of outcomes using multivariable Cox regression models.ResultsAmong all 886 patients included in present analysis, recurrent stroke was occurred in 93 (10.5%) patients during 1-year follow-up. After adjusted for all potential covariates, compared with patients with non-CSVD and NAI, patients with CSVD and MAIs were associated with approximately 9.5-fold increased risk of recurrent stroke at 1 year (HR 9.560, 95% CI 1.273-71.787, p=0.028). Similar results observed in ischaemic stroke and CVE.ConclusionThe status of CSVD and infarction number predicted recurrent stroke in patients with acute minor stroke and TIA, especially for those with coexistent CSVD and MAIs.
| S-EPMC9349065 | biostudies-literature
Project description:ObjectiveTo study the long-term prevalence of small vessel disease after young stroke and to compare this to healthy controls.MethodsThis prospective cohort study comprises 337 patients with an ischemic stroke or TIA, aged 18-50 years, without a history of TIA or stroke. In addition, 90 age- and sex-matched controls were included. At follow-up, lacunes, microbleeds, and white matter hyperintensity (WMH) volume were assessed using MRI. To investigate the relation between risk factors and small vessel disease, logistic and linear regression were used.ResultsAfter mean follow-up of 9.9 (SD 8.1) years, 337 patients were included (227 with an ischemic stroke and 110 with a TIA). Mean age of patients was 49.8 years (SD 10.3) and 45.4% were men; for controls, mean age was 49.4 years (SD 11.9) and 45.6% were men. Compared with controls, patients more often had at least 1 lacune (24.0% vs 4.5%, p < 0.0001). In addition, they had a higher WMH volume (median 1.5 mL [interquartile range (IQR) 0.5-3.7] vs 0.4 mL [IQR 0.0-1.0], p < 0.001). Compared with controls, patients had the same volume WMHs on average 10-20 years earlier. In the patient group, age at stroke (β = 0.03, 95% confidence interval [CI] 0.02-0.04) hypertension (β = 0.22, 95% CI 0.04-0.39), and smoking (β = 0.18, 95% CI 0.01-0.34) at baseline were associated with WMH volume.ConclusionsPatients with a young stroke have a higher burden of small vessel disease than controls adjusted for confounders. Cerebral aging seems accelerated by 10-20 years in these patients, which may suggest an increased vulnerability to vascular risk factors.
| S-EPMC5035980 | biostudies-literature