Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants.
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ABSTRACT:
SUBMITTER: Persyn E
PROVIDER: S-EPMC7195435 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
Publications
Genome-wide association study of MRI markers of cerebral small vessel disease in 42,310 participants.
Persyn Elodie E Hanscombe Ken B KB Howson Joanna M M JMM Lewis Cathryn M CM Traylor Matthew M Markus Hugh S HS
Nature communications 20200501 1
Cerebral small vessel disease is a major cause of stroke and dementia, but its genetic basis is incompletely understood. We perform a genetic study of three MRI markers of the disease in UK Biobank imaging data and other sources: white matter hyperintensities (N = 42,310), fractional anisotropy (N = 17,663) and mean diffusivity (N = 17,467). Our aim is to better understand the disease pathophysiology. Across the three traits, we identify 31 loci, of which 21 were previously unreported. We perfor ...[more]
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Project description:Intracerebral haemorrhage and small vessel ischaemic stroke (SVS) are the most acute manifestations of cerebral small vessel disease, with no established preventive approaches beyond hypertension management. Combined genome-wide association study (GWAS) of these two correlated diseases may improve statistical power to detect novel genetic factors for cerebral small vessel disease, elucidating underlying disease mechanisms that may form the basis for future treatments. Because intracerebral haemorrhage location is an adequate surrogate for distinct histopathological variants of cerebral small vessel disease (lobar for cerebral amyloid angiopathy and non-lobar for arteriolosclerosis), we performed GWAS of intracerebral haemorrhage by location in 1813 subjects (755 lobar and 1005 non-lobar) and 1711 stroke-free control subjects. Intracerebral haemorrhage GWAS results by location were meta-analysed with GWAS results for SVS from MEGASTROKE, using 'Multi-Trait Analysis of GWAS' (MTAG) to integrate summary data across traits and generate combined effect estimates. After combining intracerebral haemorrhage and SVS datasets, our sample size included 241 024 participants (6255 intracerebral haemorrhage or SVS cases and 233 058 control subjects). Genome-wide significant associations were observed for non-lobar intracerebral haemorrhage enhanced by SVS with rs2758605 [MTAG P-value (P) = 2.6 × 10-8] at 1q22; rs72932727 (P = 1.7 × 10-8) at 2q33; and rs9515201 (P = 5.3 × 10-10) at 13q34. In the GTEx gene expression library, rs2758605 (1q22), rs72932727 (2q33) and rs9515201 (13q34) are significant cis-eQTLs for PMF1 (P = 1 × 10-4 in tibial nerve), NBEAL1, FAM117B and CARF (P < 2.1 × 10-7 in arteries) and COL4A2 and COL4A1 (P < 0.01 in brain putamen), respectively. Leveraging S-PrediXcan for gene-based association testing with the predicted expression models in tissues related with nerve, artery, and non-lobar brain, we found that experiment-wide significant (P < 8.5 × 10-7) associations at three genes at 2q33 including NBEAL1, FAM117B and WDR12 and genome-wide significant associations at two genes including ICA1L at 2q33 and ZCCHC14 at 16q24. Brain cell-type specific expression profiling libraries reveal that SEMA4A, SLC25A44 and PMF1 at 1q22 and COL4A1 and COL4A2 at 13q34 were mainly expressed in endothelial cells, while the genes at 2q33 (FAM117B, CARF and NBEAL1) were expressed in various cell types including astrocytes, oligodendrocytes and neurons. Our cross-phenotype genetic study of intracerebral haemorrhage and SVS demonstrates novel genome-wide associations for non-lobar intracerebral haemorrhage at 2q33 and 13q34. Our replication of the 1q22 locus previous seen in traditional GWAS of intracerebral haemorrhage, as well as the rediscovery of 13q34, which had previously been reported in candidate gene studies with other cerebral small vessel disease-related traits strengthens the credibility of applying this novel genome-wide approach across intracerebral haemorrhage and SVS.
| S-EPMC6763741 | biostudies-literature
Project description:ObjectiveTo determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD).MethodsIn the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined.ResultsOver 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85.ConclusionsThis longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.
| S-EPMC5664300 | biostudies-literature
Project description:Frailty is a common syndrome in older individuals that is associated with poor cognitive outcome. The underlying brain correlates of frailty are unclear. The aim of this study was to investigate the association between frailty and MRI features of cerebral small vessel disease in a group of non-demented older individuals. We included 170 participants who were classified as frail (n = 30), pre-frail (n = 85) or non-frail (n = 55). The association of frailty and white matter hyperintensity volume and shape features, lacunar infarcts and cerebral perfusion was investigated by regression analyses adjusted for age and sex. Frail and pre-frail participants were older, more often female and showed higher white matter hyperintensity volume (0.69 [95%-CI 0.08 to 1.31], p = 0.03 respectively 0.43 [95%-CI: 0.04 to 0.82], p = 0.03) compared to non-frail participants. Frail participants showed a non-significant trend, and pre-frail participants showed a more complex shape of white matter hyperintensities (concavity index: 0.04 [95%-CI: 0.03 to 0.08], p = 0.03; fractal dimensions: 0.07 [95%-CI: 0.00 to 0.15], p = 0.05) compared to non-frail participants. No between group differences were found in gray matter perfusion or in the presence of lacunar infarcts. In conclusion, increased white matter hyperintensity volume and a more complex white matter hyperintensity shape may be structural brain correlates of the frailty phenotype.
| S-EPMC6683288 | biostudies-literature
Project description:Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.
| S-EPMC4758545 | biostudies-literature
Project description:BackgroundThis study investigated the relationships of neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with cerebral small vessel disease (CSVD).MethodsA total of 3052 community-dwelling residents from the Poly-vasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study were involved in this cross-sectional study. CSVD burden and imaging markers, including white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS), were assessed according to total CSVD burden score. The associations of NC, NLR and SII with CSVD and imaging markers were evaluated using logistic regression models. Furthermore, two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of NC on CSVD. The prognostic performances of NC, NLR and SII for the presence of CSVD were assessed.ResultsAt baseline, the mean age was 61.2 ± 6.7 years, and 53.5% of the participants were female. Higher NC was suggestively associated with increased total CSVD burden and modified total CSVD burden (Q4 vs. Q1: common odds ratio (cOR) 1.33, 95% CI 1.05-1.70; cOR 1.28, 95% CI 1.02-1.60) and marginally correlated with the presence of CSVD (OR 1.29, 95% CI 1.00-1.66). Furthermore, elevated NC was linked to a higher risk of lacune (OR 2.13, 95% CI 1.25-3.62) and moderate-to-severe BG-EPVS (OR 1.67, 95% CI 1.14-2.44). A greater NLR was related to moderate-to-severe BG-EPVS (OR 1.68, 95% CI 1.16-2.45). Individuals with a higher SII had an increased risk of modified WMH burden (OR 1.35, 95% CI 1.08-1.69) and moderate-to-severe BG-EPVS (OR 1.70, 95% CI 1.20-2.41). MR analysis showed that genetically predicted higher NC was associated with an increased risk of lacunar stroke (OR 1.20, 95% CI 1.04-1.39) and small vessel stroke (OR 1.21, 95% CI 1.06-1.38). The addition of NC to the basic model with traditional risk factors improved the predictive ability for the presence of CSVD, as validated by the net reclassification index and integrated discrimination index (all p < 0.05).ConclusionsThis community-based population study found a suggestive association between NC and CSVD, especially for BG-EPVS and lacune, and provided evidence supporting the prognostic significance of NC.
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Project description:BackgroundCerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers.MethodsCross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI.ResultsThe eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010-0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803-1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896-1.242], p value 0.52).ConclusionA compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.
| S-EPMC8811003 | 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:BackgroundIncreased arterial resistance is a potential pathological mechanism of cerebral small vessel disease (cSVD).AimIn this study, we aimed to investigate the association between pulsatility index (PI) representing cerebral arterial resistance and subtypes of cSVD in patients with lacunar stroke.MethodsWe included consecutive lacunar stroke patients between 2010 and 2013. White matter hyperintensity (WMH) volume was rated using semi-automated quantitative methods. Additionally, the presence of old lacunar infarct (OLI), cerebral microbleed (CMB), or enlarged perivascular space (EPVS) was also evaluated. The relationship between PI, measured in each middle cerebral artery, and the subtype/burden of cSVD was analyzed in the relevant hemisphere.ResultsA total of 206 lacunar patients were included and 412 hemispheres were analyzed (mean age: 64 years, male: 68.4%). In multivariable analysis, PI was positively associated with the WMH volume [beta = 1.372, 95% confidence interval (CI) = 0.624 to 2.120, P < 0.001] after adjusting for confounders. PI was also related to the presence of OLI (adjusted odds ratio = 11.37, 95% CI = 2.55-48.56, P = 0.001); however, this relationship was not significant in CMB or EPVS. Regarding the cSVD burden, PI increased according to the WMH tertiles (P for trend < 0.001), the burden of OLI (P for trend < 0.001), and EPVS tertiles (P for trend < 0.001), showing a quantitative relationship.ConclusionsIpsilateral PI is closely associated with cSVD in patients with lacunar stroke. Furthermore, this association is different between subtypes of cSVD, which is suggestive of underlying pathophysiological differences.
| S-EPMC7365409 | biostudies-literature
Project description:Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological-pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied. Exact pathological findings of in vivo MRI-detected lesions were revealed. The ischaemic lesion after 17 days from onset showed positivity for peroxiredoxin, cluster of differentiation 204 and glial fibrillary acidic protein, indicating sterile inflammation and neuroprotective reaction. Cortical microinfarcts beneath the cortical superficial siderosis were associated with inflammation from the superficial layer in a patient with cerebral amyloid angiopathy; in this patient, a bilinear track-like appearance of the cortical superficial siderosis on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II-III. An in vivo MRI-detected cerebral microbleed was revealed to be heterogeneous. An in vivo MRI-detected cerebral microbleed was revealed to be a venous angioma. Furthermore, a neuropathologically confirmed embolic cerebral microbleed was firstly detected using this method. Our results suggest that in vivo MRI-detected lobar cerebral microbleeds can be caused by non-cerebral amyloid angiopathy aetiologies, such as microembolism and venous angioma. Venous angioma and embolic microbleeds may mimic cerebral amyloid angiopathy markers on in vivo MRI. To clarify the clinical importance of these lesions, we should investigate their rate and frequency in a large cohort of healthy individuals and patients with cardiac risk factors. Thus, we provide evidence that ex vivo micro-MRI improves the clinical diagnosis of small vessel diseases.
| S-EPMC8111066 | biostudies-literature
Project description:A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B₁-insensitive R₁ measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R₁ and R₂* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24⁻30 h and (iv) one month. Absolute and blood-normalised changes in R₁ and R₂* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R₁ measurements were accurate across a wide range of values. R₁ (p < 0.05) and R₂* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24⁻30 h. R₂* returned to baseline at one month. Blood-normalised R₁ and R₂* changes post-infusion and at 24⁻30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R₂* than for R₁ mapping. R₁ and R₂* changes were correlated at 24⁻30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R₂* appears to be more sensitive to USPIO than R₁. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.
| S-EPMC6387454 | biostudies-literature