Background and purpose
Increased supratentorial white matter hyperintensities volume (S‐WMHV) has been reported to be a predictor of worse outcome in patients with acute ischemic stroke (AIS). ...However, few studies have focused on less common locations, such as brainstem white matter hyperintensities (B‐WMH), and their relationship to S‐WMHV. This study aimed to examine whether B‐WMH affect clinical outcome after AIS or transient ischemic attack (TIA).
Methods
Based on magnetic resonance imaging evidence, B‐WMH were evaluated in 313 prospectively identified patients with AIS/TIA and registered as absent or present. Standardized S‐WMHV was quantified using a validated volumetric image analysis and natural log‐transformed (Log_S‐WMHV). Poor outcome was defined as a modified Rankin Scale score of 3–6 at 3 months after the index event.
Results
Brainstem white matter hyperintensities were detected in 57 (18.2%) patients. In unadjusted analyses for outcome, the presence of B‐WMH was associated with worse outcome, compared with patients without B‐WMH (P = 0.034). In multivariate analysis controlling for age, atrial fibrillation, stroke severity, reperfusion therapies and Log_S‐WMHV, only B‐WMH odds ratio (OR), 2.46; P = 0.021 and stroke severity (OR, 1.23; P < 0.001) remained independently associated with unfavourable 90‐day modified Rankin Scale score. Patients with B‐WMH were older (OR, 1.06; P < 0.001) and tended to have more hyperlipidaemia (OR, 2.21; P = 0.023) and peripheral arterial disease (OR, 2.57; P = 0.031).
Conclusions
Brainstem white matter hyperintensities are an independent predictor of poor outcome after AIS/TIA and this relationship persists after adjustment for important prognostic factors. Our results also show that leukoaraiosis in this location identifies patients with a specific risk factor profile, suggesting differences in the underlying pathogenesis.
Background and purpose
Patients with acute intracerebral hemorrhage (ICH) pretreated with antithrombotic drugs may have increased early hematoma growth, which would increase mortality risk. The ...effect of antiplatelet (AP) and vitamin K antagonist (VKA) pretreatment on ultra‐early hematoma growth (uHG) and its relationship with mortality in patients with acute supratentorial ICH was analyzed.
Methods
This is an observational retrospective study of a prospective register of 197 ICH patients with first computed tomography (CT) scan taken <6 h from ICH symptom onset. ICH volume was calculated by the ABC/2 formula and uHG by the baseline ICH volume/onset‐to‐CT time (ml/h) formula. The uHG analysis took into account the patient's pretreatment (none, AP or VKA) and the relationship between uHG and very‐early (first 24 h) and 3‐month mortality.
Results
In the pretreatment group, 50 (25.4%) patients were treated with AP and 37 (18.8%) with VKA. The median (interquartile range 25–75) uHG was 19.7 ml/h (2.9–44.8) for AP pretreated patients, 16.2 ml/h (5.1–42.5) for VKA pretreated patients and 8.4 ml/h (2.4–21.8) for non‐pretreated patients, P = 0.019. The uHG was higher in patients with very‐early 42.1 ml/h (20.1–79.6) and total 3‐month mortality 28.0 ml/h (15.8–52.5) compared with survivors 3.9 ml/h (1.5–10.4), P < 0.0001. Adjusted by ICH severity and previous functional status, uHG was an independent factor related to very‐early (P = 0.028) and total 3‐month mortality (P = 0.014).
Conclusions
Patients pretreated with antithrombotics have much higher uHG, which would explain the increased mortality in these patients compared to untreated patients.
Background and purpose
Alcohol overuse (AOu) is considered an important risk factor for spontaneous intracerebral hemorrhage (ICH). The clinical and outcome characteristics of these patients ...(AOu‐ICH) are not well known.
Methods
All patients with ICH admitted to a single university tertiary stroke center were prospectively studied from May 2005 to May 2015. Demographic profiles, radiologic characteristics and clinical outcomes of patients with acute ICH and previous AOu (>40 g/day or >300 g/week) were analyzed.
Results
During the study period, 555 patients with spontaneous primary ICH met the inclusion criteria. A total of 81 patients (14.6%) reported AOu (24.3% of men vs. 3.1% of women; P < 0.0001; mean age, 63 years old for AOu vs. 74 years old for non‐AOu; P < 0.0001). Of the classic cardiovascular risk factors, only smoking was associated with AOu (63% vs. 12.2% of non‐AOu; P < 0.0001). Initial severity and hematoma volume were similar in both groups, with no observed differences in stroke care or in‐hospital medical complications. Patients with AOu had worse outcome (modified Rankin Scale score, 3–6 points) than patients without AOu at 3 months odds ratio (OR), 2.50; 95% confidence interval (CI), 1.32–4.75; P = 0.005 and 12 months (OR, 2.47; 95% CI, 1.23–5.00; P = 0.011). A similar trend was observed at 5 years (OR, 2.48; 95% CI, 0.96–6.39; P = 0.059).
Conclusions
Alcohol overuse was present in 14.6% of patients with ICH, who were predominantly male, smokers and a mean of 11 years younger than the non‐AOu group. Despite a lack of differences in initial clinical severity, stroke care and early medical complications, patients with AOu had worse short‐ and long‐term outcomes.
Fibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic ...variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR).
We conducted a GWAS testing ∼7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data.
Our GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 × 10−8) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, β = 0.181, P < 2.18 × 10−42) displayed in two-sample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null.
We identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.
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•Certain GCKR or FGF21 variants are associated with plasma FGF21 level.•The effects of FGF21 on improved lipid profile and liver function were confirmed.•Higher FGF21 levels were associated with lower C-reactive protein levels.•Higher FGF21 levels were associated with higher insulin-like growth factor-I levels.•FGF21 showed null or weak effect on fat mass and cardiometabolic diseases.
OBJECTIVE:To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age b-age) on patient outcomes at 3 months after an ischemic ...stroke.
METHODS:We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis.
RESULTS:After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 95% confidence interval 1.01–1.07), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort.
CONCLUSIONS:B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.
Ischemic stroke is associated with aging. It is possible to predict chronological age by measuring age-related changes in DNA methylation from multiple CpG sites across the genome, known as ...biological age. The difference between biological age and actual chronological age would indicate an individual's level of aging. Our aim was to determine the biological age of ischemic stroke patients and compare their aging with controls of the same chronological age. A total of 123 individuals, 41 controls and 82 patients with ischemic stroke were paired by chronological age, ranging from 39 to 82 years. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites in both groups, and biological age was estimated using methylation values of specific CpGs. Ischemic stroke patients were
an average 2.5 years older than healthy controls (p-value=0.010). Stratified by age tertiles, younger stroke patients (≤57 years old) were biologically older than controls (OR=1.19; 95%CI 1.00-1.41, p-value=0.046). The older groups showed no biological age differences between cases and controls, but were close to reaching the significance level. Ischemic stroke patients are
older than controls. Biological age should be considered as a potential new biomarker of stroke risk.
Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose ...levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels ≥ 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 × 10(-12)); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 × 10(-16)), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c ≥ 7%).
Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently ...associated with stroke outcome.
Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.
A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10
).
Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.
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