Replication of Top Loci From COL4A1/2 Associated With White Matter Hyperintensity Burden in Patients With Ischemic Stroke.
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ABSTRACT: Background and purpose
The purpose of this study was to replicate the top loci associated with white matter hyperintensity (WMH) phenotypes identified by large genome-wide association studies and the loci identified from the previous candidate gene studies.Methods
A total of 946 Geisinger MyCode patients with acute ischemic stroke with validated European ancestry and magnetic resonance imaging data were included in this study. Log-transformed WMH volume, as a quantitative trait, was calculated by a fully automated quantification process. The genome-wide association studies was carried out by a linear mixed regression model (GEMMA). A candidate-single nucleotide polymorphism analysis by including known single nucleotide polymorphisms, reported from a meta-analysis and several large GWAS for WMH, was conducted in all cases and binary converted extreme cases.Results
No genome-wide significantly associated variants were identified. In a candidate-single nucleotide polymorphism study, rs9515201 (COL4A2) and rs3744028 (TRIM65), 2 known genetic loci, showed nominal or trend of association with the WMH volume (β=0.13 and P=0.001 for rs9515201; β=0.094 and P=0.094 for rs3744028), and replicated in a subset of extreme cases versus controls (odds ratio=1.78, P=7.74×10-4 for rs9515201; odds ratio=1.53, P=0.047 for rs3744028, respectively). MTHFR677 cytosine/thymine (rs1801133) also showed an association with the binary WMH with odds ratio=1.47 for T allele (P=0.019).Conclusions
Replication of COL4A1/2 associated with WMH reassures that the genetic risk factors for monogenic and polygenic ischemic stroke are shared at gene level.
SUBMITTER: Li J
PROVIDER: S-EPMC8336687 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionTo determine the influence of white matter hyperintensity (WMH) burden on functional outcome, rate of symptomatic intracerebral hemorrhage (sICH), and procedural success in patients with acute ischemic stroke (AIS) treated by mechanical thrombectomy (MT) with current stentriever/aspiration devices.MethodsPatients with AIS due to large vessel occlusion (LVO) from the Thrombectomie des Artères Cérébrales (THRACE) trial and prospective cohorts from 2 academic comprehensive stroke centers treated with MT were pooled and retrospectively analyzed. WMH volumes were obtained by semiautomated planimetric segmentation and tested in association with the rate of favorable outcome (90-day functional independence), substantial recanalization after MT, and sICH.ResultsA total of 496 participants were included between 2015 and 2018 (50% female, mean age 68.1 ± 15.0 years). Overall, 434 (88%) patients presented with detectable WMH (mean ± SD 4.93 ± 7.7). Patients demonstrated increasingly worse outcomes with increasing WMH volumes (odds ratio [aOR]1.05 per 1-cm3 increase for unfavorable outcome, 95% confidence interval [CI] 1.01-1.06, p = 0.014). Fifty-seven percent of patients in the first quartile of WMH volume vs 28% in the fourth quartile demonstrated favorable outcome (p < 0.001). WMH severity was not associated with sICH rate (aOR 0.99, 95% CI 0.93-1.04, p = 0.66), nor did it influence recanalization success (aOR 0.99, 95% CI 0.96-1.02, p = 0.84).ConclusionOur study provides evidence that in patients with AIS due to LVO and high burden of WMH as assessed by pretreatment MRI, the safety and efficacy profiles of MT are similar to those in patients with lower WMH burden and confirms that they are at higher risk of unfavorable outcome. Because more than a quarter of patients in the highest WMH quartile experienced favorable 3 months outcome, WMH burden may not be a good argument to deny MT.Clinicaltrialsgov identifierNCT01062698.
| S-EPMC6815208 | biostudies-literature
Project description:Prior intracerebral hemorrhage (ICH) is associated with increased risk of ischemic stroke. Since white matter hyperintensity (WMH) is associated with ischemic stroke and ICH, this study aimed to evaluate the relationship between ICH and the risk of recurrent stroke by WMH severity. From a prospective multicenter database comprising 1454 noncardioembolic stroke patients with cerebral small-vessel disease, patients were categorized by presence or absence of prior ICH and WMH severity: mild-moderate WMH (reference); advanced WMH; ICH with mild-moderate WMH; and ICH with advanced WMH. Among patients with ICH, the association with stroke outcomes by WMH burden was further assessed. The primary endpoint was ischemic stroke and hemorrhagic stroke. The secondary endpoint was major adverse cardiovascular events (MACE): stroke/coronary heart disease/vascular death. During the mean 1.9-year follow-up period, the ischemic stroke incidence rate per 100 person-years was 2.7, 4.0, 2.5, and 8.1 in increasing severity, and the rate of hemorrhagic stroke was 0.7, 1.3, 0.6, and 2.1, respectively. The risk of ischemic stroke was higher in ICH with advanced WMH (adjusted HR 2.62; 95% CI 1.22-5.60) than the reference group, while the risk of hemorrhagic stroke trended higher (3.75, 0.85-16.53). The risk of MACE showed a similar pattern in ICH with advanced WMH. Among ICH patients, compared with mild WMH, the risk of ischemic stroke trended to be higher in advanced WMH (HR 3.37; 95% CI 0.90‒12.61). Advanced WMH was independently associated with an increased risk of hemorrhagic stroke (HR 33.96; 95% CI 1.52-760.95). Given the fewer rate of hemorrhagic stroke, the risk of hemorrhagic stroke might not outweigh the benefits of antiplatelet therapy for secondary prevention.
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Project description:White matter hyperintensities of presumed vascular origin (WMH) are a prevalent form of cerebral small-vessel disease and an important risk factor for post-stroke cognitive dysfunction. Despite this prevalence, it is not well understood how WMH contributes to post-stroke cognitive dysfunction. Preliminary findings suggest that increasing WMH volume is associated with total hippocampal volume in chronic stroke patients. The hippocampus, however, is a complex structure with distinct subfields that have varying roles in the function of the hippocampal circuitry and unique anatomical projections to different brain regions. For these reasons, an investigation into the relationship between WMH and hippocampal subfield volume may further delineate how WMH predispose to post-stroke cognitive dysfunction. In a prospective study of acute ischemic stroke patients with moderate/severe WMH burden, we assessed the relationship between quantitative WMH burden and hippocampal subfield volumes. Patients underwent a 3T MRI brain within 2-5 days of stroke onset. Total WMH volume was calculated in a semi-automated manner. Mean cortical thickness and hippocampal volumes were measured in the contralesional hemisphere. Total and subfield hippocampal volumes were measured using an automated, high-resolution, ex vivo computational atlas. Linear regression analyses were performed for predictors of total and subfield hippocampal volumes. Forty patients with acute ischemic stroke and moderate/severe white matter hyperintensity burden were included in this analysis. Median WMH volume was 9.0 cm3. Adjusting for intracranial volume and stroke laterality, age (β = -3.7, P < 0.001), hypertension (β = -44.7, P = 0.04), WMH volume (β = -0.89, P = 0.049), and mean cortical thickness (β = 286.2, P = 0.006) were associated with total hippocampal volume. In multivariable analysis, age (β = -3.3, P < 0.001) and cortical thickness (β = 205.2, P = 0.028) remained independently associated with total hippocampal volume. In linear regression for predictors of hippocampal subfield volume, increasing WMH volume was associated with decreased hippocampal-amygdala transition area volume (β = -0.04, P = 0.001). These finding suggest that in ischemic stroke patients, increased WMH burden is associated with selective hippocampal subfield degeneration in the hippocampal-amygdala transition area.
| S-EPMC7649326 | biostudies-literature
Project description:BackgroundFew prospective cohort studies collect detailed information on stroke characteristics among individuals who experience ischemic stroke, including white matter hyperintensity volume, and thus cannot explore how prospectively collected biomarkers prior to the stroke influence white matter hyperintensity volume. We explored the association between a large panel of prospectively collected lipid and inflammatory biomarkers and white matter hyperintensity volume among participants in the Women's Health Study with incident ischemic stroke.MethodsAmong Women's Health Study participants with first ischemic stroke who had baseline serum biomarkers and available magnetic resonance imaging, we measured white matter hyperintensity volume using a validated semi-automated method. Linear regression was used to explore the associations between biomarkers and log-transformed white matter hyperintensity volume.ResultsAfter multivariate adjustment, a 1% increment in HbA1c% was associated with an increase in white matter hyperintensity volume (P value = .05). Evidence of a nonlinear association between high density lipoprotein cholesterol levels and ApoA1 levels with white matter hyperintensity volume was noted (P values for nonlinearity = .01 and .001, respectively). No other biomarkers were significantly associated with white matter hyperintensity volume.ConclusionsChronic hyperglycemia as evidenced by HbA1c levels measured years prior to stroke is associated with white matter hyperintensity volume at the time of stroke. Additional research is needed to explain why low levels of high density lipoprotein cholesterol levels and ApoA1 may be associated with similar white matter hyperintensity volume as high levels.
| S-EPMC7170752 | biostudies-literature
Project description:GoalsThere are no validated biomarkers that allow for reliable distinction between TIA and other transient neurological symptoms that mimic TIA. We sought to determine whether the degree of pre-existing white matter hyperintensity (WMH) lesion burden relates to the diagnostic certainty of TIA in a cohort of patients presenting with transient neurological symptoms.Materials and methodsWe retrospectively analyzed 144 consecutive patients with available brain MRI to quantify and normalize the WMH volume for brain atrophy (adjusted white matter hyperintensity [aWMHV]). We first stratified subjects to probable (n = 62) versus possible (n = 82) TIA as per existing guidelines. Receiver-operating characteristic curves were used to determine a critical aWMHV-threshold (7.8 mL) that best differentiated probable from possible TIA. We then further stratified patients with possible TIA to likely (n = 52) versus unlikely (n = 30) TIA after independent chart review and adjudication. Finally, multivariable logistic and multinomial regression was used to determine whether the defined aWMHV independently related to probable and likely TIA after adjustment for pertinent confounders.FindingsWith the exception of age (P < .001) and use of antiplatelets (P = .017), baseline characteristics were similar between patients with probable, likely, and unlikely TIA. In the fully adjusted multinomial model, the aWMHV cut-off greater than 7.8 mL (odds ratio 3.8, 95% confidence interval 1.3-10.9, P = .012) was significantly more frequent in patients with a probable TIA as compared to those with an unlikely TIA diagnosis.ConclusionsWe provide proof-of-principle that WMH may serve as a neuroimaging marker of diagnostic certainty of TIA after neurological workup has been completed.
| S-EPMC6441369 | biostudies-literature
Project description:Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.
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Project description:ObjectivesWe aimed to investigate effects of deep white matter hyperintensity (DWMH) and periventricular hyperintensity (PVH) on the efficacy of intravenous thrombolysis (IVT) in patients with acute ischemic stroke (AIS).MethodsA total of 113 AIS patients with WMH were categorized into the PVH group and the DWMH group according to the lesion location, with the division of two subgroups based on whether or not they received IVT treatment: the thrombolysis group and the control group. Kaplan-Meier analysis was used for proportional hazards of recurrent stroke. Further, multivariate Cox regression analysis was employed.ResultsOf total patients, there were 62 PVH patients and 51 DWMH patients: 27 of PVH patients and 22 of DWMH patients received IVT, and the remaining patients only received routine treatment. DWMH patients had a higher risk of END (36.4% vs. 11.1%; p = 0.034) and HT (22.7% vs. 3.7%; p = 0.038) than PVH patients in the thrombolysis group. Moreover, DWMH patients undergoing IVT also had a higher risk of END (36.4% vs. 10.3%; x2 = 5.050; p = 0.025) and HT (22.7% vs. 3.4%; x2 = 4.664; p = 0.031) than DWMH patients without IVT. Again, PVH patients had a higher rate of recurrent stroke (20.0% vs. 3.4%; p = 0.034) than DWMH patients in the control group after 90-day follow-up. Kaplan-Meier analysis showed a significant difference in cumulative probability of no major endpoint events (p = 0.039). Further, multivariate Cox regression revealed that PVH is an independent risk factor for stroke recurrence in AIS patients after adjusting confounding factors.ConclusionsThe location of WMH is closely associated with the efficacy of IVT in AIS patients.
| S-EPMC6305931 | biostudies-literature
Project description:Background and purposeThe relationship between plasma level of total homocysteine (tHcy) and white matter hyperintensities (WMHs), especially in patients with acute ischemic stroke (AIS), is controversial. The present study investigated the association between these two as well as WMH locations in a large cohort of patients with AIS.MethodsConsecutive patients were reviewed from a prospective ischemic stroke database. Clinical data, including tHcy level and WMHs, were assessed. WMHs were assessed using the Fazekas scale and Age-Related White Matter Changes (ARWMC) visual grading scale. The association between tHcy and WMH locations was investigated by using multivariate logistic regression analyses.ResultsA total of 923 out of 1,205 patients were examined. The average age was 58.9 ± 11.9 years; 31.6% were female. Elevated tHcy level was significantly associated with WMHs. For the highest tHcy quartile, the odds ratio (OR) (95% confidence interval; CI) was 1.891 (1.257; 2.843) according to the Fazekas scale and 1.781 (1.185; 2.767) according to the ARWMC scale when compared to the lowest quartile. However, in a subgroup analysis, only WMHs in the periventricular area and left or right frontal areas were found to be independently associated with tHcy level. For the highest tHcy quartile, the OR (95% CI) was 1.761 (1.172; 2.648) for the periventricular WMHs, 1.768 (1.134; 2.756)for the left frontal WMHs, and 1.890 (1.206; 2.960)for the right frontal WMHs.ConclusionsIn patients with AIS, plasma tHcy level is related to WMHs, especially WMHs distributed within the periventricular and frontal areas.
| S-EPMC4671668 | biostudies-literature
Project description:Background and purposeFinding of white matter hyperintensity (WMH) has been associated with an increased risk of parenchymal hematoma and poor clinical outcomes after mechanical thrombectomy using old-generation endovascular devices. Currently, no data exist with regard to the risk of mechanical thrombectomy using stentriever devices in patients with significant WMH. We hypothesized that WMH volume will not affect the hemorrhagic and clinical outcome in patients with acute ischemic stroke undergoing thrombectomy using new-generation devices.MethodsA retrospective cohort of consecutive acute ischemic stroke patients >18-year-old receiving mechanical thrombectomy with stentriever devices at a single academic center was examined. WMH volume was assessed by a semiautomated volumetric analysis on T2 fluid attenuated inversion recovery-magnetic resonance imaging. Outcomes included the rate of any intracerebral hemorrhage, 90-day modified Rankin Score (mRS), the rate of good outcome (discharge mRS ≤2), and the rate of successful reperfusion (thrombolysis in cerebral ischemia score 2b or 3).ResultsBetween June 2012 and December 2015, 56 patients with acute ischemic stroke met the study criteria. Median WMH volume was 6.76 cm3 (4.84-16.09 cm3). Increasing WMH volume did not significantly affect the odds of good outcome (odds ratio [OR], 0.811; 95% confidence interval [CI], 0.456-1.442), intracerebral hemorrhage (OR, 1.055; 95% CI, 0.595-1.871), parenchymal hematoma (OR, 0.353; 95% CI, 0.061-2.057), successful recanalization (OR, 1.295; 95% CI, 0.704-2.383), or death (OR, 1.583; 95% CI, 0.84-2.98).ConclusionsMechanical thrombectomy using stentrievers seems to be safe in selected patients with acute ischemic stroke with large vessel occlusion, nonwithstanding the severity of WMH burden in this population. Larger prospective studies are warranted to validate these findings.
| S-EPMC5659291 | biostudies-literature
Project description:Background and purposeRecently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke.MethodsWe quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke.ResultsSingle-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke.ConclusionsThis study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.
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