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Background: Inflammation promotes atherogenesis. Randomized controlled trials of anti-inflammatory therapies for prevention after stroke have not yet demonstrated clear benefit. IL-6 (interleukin-6) and hsCRP (high-sensitivity C-reactive protein) are independently associated with major adverse cardiovascular events poststroke and may guide patient selection in future randomized controlled trials. Optimal timing of hsCRP/IL-6 measurement poststroke is unknown, as early blood levels may be confounded by the inflammatory response to brain infarction., Methods: Using individual-participant data from a systematic review, we performed a time-course analysis to investigate the association between hsCRP/IL-6 and recurrent events stratified by timing of sampling. The prespecified coprimary end points after sample measurement were: (1) recurrent major adverse cardiovascular events (first major coronary event, recurrent stroke, or vascular death) and (2) recurrent stroke (ischemic, hemorrhagic, or unspecified). The poststroke dynamics of IL-6/hsCRP were analyzed by plotting their median (interquartile interval) concentrations within each tenth of the sampling timeframe. Acute/postacute phases were defined for each biomarker according to the shape of this relationship., Results: There were data for 9798 patients from 11 studies (19 891 person-years follow-up, 10 observational cohorts, and 1 randomized trial). Each marker was measured once. IL-6 was markedly elevated <24 hours poststroke compared with postacute levels (≥24 hours; 11.6 versus 3.02 pg/mL; P <0.001). HsCRP was elevated for 10 days. IL-6 was associated with recurrent major adverse cardiovascular events in the postacute phase (≥24 hours; risk ratio, 1.30 [CI, 1.19-1.41], per unit log e IL-6), but not in the acute phase (<24 hours; risk ratio, 1.10 [CI, 0.98-1.25]; P interaction unit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP.e unit (risk ratio, 1.16 [CI, 1.05-1.66]) and per quarter increase (risk ratio, 1.55 [CI, 1.19-2.02]; Q4 versus Q1), but not if measured acutely. Similar findings were observed for recurrent stroke. There was no evidence of time-dependent interaction with hsCRP., Conclusions: Timing of sample measurement after stroke modifies the association with recurrent major adverse cardiovascular events for IL-6 but not hsCRP. These data inform future randomized controlled trial designs incorporating biomarker-based selection of patients for anti-inflammatory therapies., Competing Interests: Dr McCabe is supported by grant funding from Irish Institute for Clinical Neuroscience. Dr Woodward performs consultancy work for Freeline. Dr Katan received funding from the Swiss national Science Foundation; grants from the Swiss Heart Foundation and USZ Foundation; participated on advisory boards and speaker honoraria for Medtronic, BMS Pfizer/Jansen, and Astra Zeneca; and in kind contributions from Roche Diagnostics, and Brahms Thermo Fisher Scientific. Dr Rothwell performed consultancy work for Abbott, Bayer, and Sanofi; and data/safety monitoring for Bristol-Myers Squibb. Dr Sudlow received grant support from Asthma Lung UK, British Heart Foundation, Medical Research Council, Kidney Research UK, the Stroke Association, and Diabetes UK. Dr Whiteley performed consultancy work for Bayer and Viatris, data/safety monitoring for several clinical trials (CATIS-ICAD [Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease], TEMPO-2 [Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion], PROTECT-U [Prospective Randomized Open-Label Trial to Evaluate Risk Factor Management in Patients With Unruptured Intracranial Aneurysms], and INTERACT-3 [The Third Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial]); and received compensation from UK Courts for expert witness services. Dr Kelly is the principal investigator of the CONVINCE trial (Colchicine for Prevention of Vascular Inflammation in Non-cardio Embolic Stroke). The other authors report no conflicts.

Background: Mosaic loss of chromosome Y (LOY) is associated with cardiovascular and neurodegenerative diseases in men, and genetic predisposition to LOY is associated with poor poststroke outcome. We, therefore, tested the hypothesis that LOY itself is associated with functional outcome after ischemic stroke., Methods: The study comprised male patients with ischemic stroke from the cohort studies SAHLSIS2 (Sahlgrenska Academy Study on Ischemic Stroke Phase 2; n=588) and LSR (Lund Stroke Register; n=735). We used binary logistic regression to analyze associations between LOY, determined by DNA microarray intensity data, and poor 3-month functional outcome (modified Rankin Scale score, >2) in each cohort separately and combined. Patients who received recanalization therapy were excluded from sensitivity analyses., Results: LOY was associated with about 2.5-fold increased risk of poor outcome in univariable analyses ( P <0.001). This association withstood separate adjustment for stroke severity and diabetes in both cohorts but not age. In sensitivity analyses restricted to the nonrecanalization group (n=987 in the combined cohort), the association was significant also after separate adjustment for age (odds ratio, 1.6 [95% CI, 1.1-2.4]) and when additionally adjusting for stroke severity and diabetes (odds ratio, 1.6 [95% CI, 1.1-2.5])., Conclusions: We observed an association between LOY and poor outcome after ischemic stroke in patients not receiving recanalization therapy. Future studies on LOY and other somatic genetic alterations in larger stroke cohorts are warranted., Competing Interests: Disclosures Dr Dumanski is a cofounder and shareholder in Cray Innovation AB. Dr Lindgren reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novo Nordisk, Pfizer, and Portola Pharmaceuticals. The other authors report no conflicts.

Background: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines., Methods: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis., Results: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase log e IL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase log e hsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43])., Conclusions: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Background: Inflammation contributes both to the pathogenesis of stroke and the response to brain injury. We aimed to identify proteins reflecting the acute-phase response and proteins more likely to reflect proinflammatory processes present before stroke by broadly profiling inflammation-related plasma proteins in a longitudinal ischemic stroke study., Methods: Participants were from a Swedish ischemic stroke cohort (SAHLSIS [Sahlgrenska Academy Study on Ischemic Stroke], n=600 cases and n=600 controls). Plasma levels of 65 proteins including chemokines, interleukins, surface molecules, and immune receptors were measured once in controls and at 3× in cases: during the acute phase, after 3 months, and for a subgroup (n=223) at 7-year follow-up. Associations between proteins and ischemic stroke or subtype were investigated in multivariable binary regression models corrected for age, sex, vascular risk factors, and multiple testing., Results: In the acute phase, 48 proteins were significantly and independently associated with ischemic stroke (false discovery rate adjusted P <0.05). At 3-month follow-up, 51 proteins and at 7-year follow-up 50 proteins were associated with ischemic stroke. The majority of proteins were upregulated in cases compared with controls (n=34 at all time points) and the most upregulated were CXCL5 (CXC chemokine ligand 5) and OSM (oncostatin M). Generally, large artery and cardioembolic stroke had the highest protein levels. However, several interesting subtype-specific differences were also detected at each time point., Conclusions: We found inflammation-related proteins that were differentially regulated in ischemic stroke cases compared with controls only in the acute phase and others that remained elevated also at later time points. This latter group of proteins could reflect underlying pathophysiological processes of relevance. Future studies both in terms of disease risk and prognostication are warranted.

Background and Purpose- Psychosocial factors can have implications for ischemic stroke risk and recovery. This study investigated the effect of genetically determined risk of depression on these outcomes using the Mendelian randomization (MR) framework. Methods- Genetic instruments for risk of depression were identified in a discovery genome-wide association study of 246 363 cases and 561 190 controls and further replicated in a separate population of 474 574 cases and 1 032 579 controls. Corresponding genetic association estimates for risk of ischemic stroke were taken from 60 341 cases and 454 450 controls, with those for functional outcome 3 months after ischemic stroke taken from an analysis of 6021 patients. Following statistical power calculation, inverse-variance weighted MR was performed to pool estimates across different instruments. The Cochran Q heterogeneity test, weighted median MR, and MR pleiotropy residual sum and outlier were used to explore possible bias relating to inclusion of pleiotropic variants. Results- There was no MR evidence for an effect of genetically determined risk of depression on ischemic stroke risk. Although suffering low statistical power, the main inverse-variance weighted MR analysis was suggestive of a detrimental effect of genetically determined risk of depression on functional outcome after ischemic stroke (odds ratio of poor outcome [modified Rankin Scale, ≥3] per 1-SD increase in genetically determined risk of depression, 1.81; 95% CI, 0.98-3.35; P=0.06). There was no evidence of heterogeneity between MR estimates produced by different instruments (Q P=0.26). Comparable MR estimates were obtained with weighted median MR (odds ratio, 2.57; 95% CI, 1.05-6.25; P=0.04) and MR pleiotropy residual sum and outlier (odds ratio, 1.81; 95% CI, 0.95-3.46; P=0.08). Conclusions- We found no MR evidence of genetically determined risk of depression affecting ischemic stroke risk but did find consistent MR evidence suggestive of a possible effect on functional outcome after ischemic stroke. Given the widespread prevalence of depression-related morbidity, these findings could have implications for prognostication and personalized rehabilitation after stroke.

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm 3 (0.9-16.6 cm 3 ). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Background and Purpose: Brain-derived neurotrophic factor (BDNF) plays important roles in brain plasticity and repair, and it influences stroke outcomes in animal models. Circulating BDNF concentrations are lowered in patients with traumatic brain injury, and low BDNF predicts poor recovery after this injury. We sought to investigate whether circulating concentrations of BDNF are altered in the acute phase of ischemic stroke and whether they are associated with short- or long-term functional outcome., Methods: Serum concentrations of BDNF were measured in the Sahlgrenska Academy Study on Ischemic Stroke. The main outcomes were modified Rankin Scale (mRS) good (mRS score of 0-2) versus poor (mRS score of 3-6) at 3 months and 2 years after stroke, and good (mRS score of 0-2) versus poor (mRS score of 3-5) at 7 years after stroke., Results: Acute concentrations of BDNF were significantly lower in ischemic stroke cases (n=491) compared with controls (n=513). BDNF concentrations were not significantly associated with 3-month outcome. However, patients with BDNF in the lowest tertile had an increased risk of experiencing a poor outcome both at 2-year and 7-year follow-up, and these associations were independent of vascular risk factors and stroke severity (odds ratio, 2.6; confidence intervals, 1.4-4.9; P=0.002 and odds ratio, 2.1; confidence intervals, 1.1-3.9; P=0.028, respectively)., Conclusions: Circulating concentrations of BDNF protein are lowered in the acute phase of ischemic stroke, and low levels are associated with poor long-term functional outcome. Further studies are necessary to confirm these associations and to determine the predictive value of BDNF in stroke outcomes., (© 2016 American Heart Association, Inc.)

Background and Purpose: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years., Methods: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls., Results: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2., Conclusions: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke., (© 2016 American Heart Association, Inc.)

Background and Purpose: The consequences for the family of stroke survivor are generally studied in a short-term perspective. The aim of this study was to assess long-term aspects of health-related quality of life among spouses of stroke survivors., Methods: Data on stroke survivors, controls, and spouses were collected from the 7-year follow-up of the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The health-related quality of life of spouses was assessed by the Short Form-36, and the characteristics of stroke survivors were assessed using the National Institutes of Health Stroke Scale, the Mini-Mental State Examination, the Hospital Anxiety and Depression Scale, the Barthel Index, and the modified Rankin Scale., Results: Dyads of 248 stroke survivors aged <70 at stroke onset and 245 dyads of matched controls were included. Spouses of stroke survivors and spouses of controls had a median age of 64 and 65, respectively; proportion of men was 35% and 34%, respectively. The spouses of stroke survivors reported lower scores in all the mental domains (P=0.045; P<0.001), as well as in the domains of general health (P=0.013) and physical role (P=0.006), compared with the spouses of controls. Predictors of poor physical health of the spouses were their own age and the level of global disability of the stroke survivor. Predictors of poor mental health of the spouses were depressive symptoms, cognitive impairment, and global disability among the stroke survivors., Conclusions: The health-related quality of life of spouses of stroke survivors is reduced not only during the first years but also in the long-term perspective., (© 2015 American Heart Association, Inc.)

Background and Purpose: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium., Methods: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases., Results: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75)., Conclusions: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke., (© 2014 American Heart Association, Inc.)

Background and Purpose: The purpose of the present study was to investigate the 4-year mortality risk among patients<55 years with a first ischemic stroke during 1987-2006., Methods: A total of 17,149 cases (37.4% women) aged 18 to 54 years who survived≥28 days after a first ischemic stroke were identified in the Swedish Inpatient Register from 1987 to 2006. All patients were followed for 4 years or until death. The standardized mortality ratio was calculated by comparing the mortality rates with those of the general population of equivalent age, sex, and calendar year., Results: During the period, there were 1265 deaths. Long-term survival improved over time in both men and women. Among men, the mortality risk decreased by 32% (hazard ratio=0.68 [95% confidence interval, 0.56-0.82]) from the first 5-year period to the last 5-year period (1987-1991 versus 2002-2006), and among women, the mortality risk decreased by 45% (0.55 [0.41-0.75]). Despite an overall decrease in mortality, the standardized mortality ratios for the last 5-year period remained high: 5.88 (95% confidence interval, 5.10-6.71) for men and 5.91 (4.68-7.29) for women with an absolute excess risk of 1.60 and 0.97 per 100 person-years, respectively, with nearly half of all deaths related to cardiovascular disease., Conclusions: During the 20-year period, 4-year mortality decreased by one third but was still 6-fold higher than that of the general population in the most recent period, emphasizing the importance of secondary prevention in young persons who have had a stroke.

Background and Purpose: Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke., Methods: The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10,296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14,549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research-generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived., Conclusions: The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

Background and Purpose: The incidence of stroke in Sweden increased between 1989 and 2000 among people aged ≤65 years, but more recent data on those aged >65 years are lacking., Methods: Through the Swedish Hospital Discharge and Cause of Death registries, we identified all cases of nonfatal and fatal ischemic stroke (IS) among people aged 18 to 84 years during 1987-2010 in Sweden., Results: Of the 391 081 stroke cases identified, 1.6% were 18 to 44 years, 16.7% were 45 to 64 years, and 81.7% were 65 to 84 years. Among people aged 18 to 44 years, there was a continuous increase in the incidence of stroke of 1.3% (95% confidence interval, 0.8%-1.8%) per year for men and 1.6% (1.0%-2.3%) per year for women. Among men and women aged 45 to 64 years, slightly declining rates were observed from the late 1990s, with a mean annual decrease of 0.4% (0.1%-0.7%) among men and 0.6% (0.2%-1.0%) among women. Among men aged 65 to 84 years, a decrease of 3.7% in IS (3.4%-4.0%) per year was observed from the late 1990s. This was more marked in women, where an initial decrease of 2.5% (2.1%-2.9%) per year was followed by an accelerated decrease of 5.1% (4.4%-5.8%) after 2005. Mortality from IS decreased markedly in all age groups., Conclusions: The incidence of IS in elderly people in Sweden is now decreasing, whereas the decline in IS incidence in the middle-aged people is much less steep. The increasing incidence of stroke in the young, particularly if carried forward to an older age, is concerning.

Background and Purpose: Evidence is emerging that inflammation plays a key role in the pathophysiology of ischemic stroke (IS). The aim of this study was to investigate whether genetic variation in the interleukin-1α, interleukin-1β, and interleukin-1 receptor antagonist genes (IL1A, IL1B, and IL1RN) is associated with IS and/or any etiologic subtype of IS., Methods: Twelve tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which comprises 844 patients with IS and 668 control subjects. IS subtypes were defined according to the Trial of Org 10172 in Acute Stroke Treatment criteria in SAHLSIS. The Lund Stroke Register and the Malmö Diet and Cancer study were used as a replication sample for overall IS (in total 3145 patients and 1793 control subjects)., Results: The single nucleotide polymorphism rs380092 in IL1RN showed an association with overall IS in SAHLSIS (OR, 1.21; 95% CI, 1.02-1.43; P=0.03), which was replicated in the Lund Stroke Register and the Malmö Diet and Cancer study sample. An association was also detected in all samples combined (OR, 1.12; 95% CI, 1.04-1.21; P=0.03). Three single nucleotide polymorphisms in IL1RN (including rs380092) were nominally associated with the subtype of cryptogenic stroke in SAHLSIS, but the statistical significance did not remain after correction for multiple testing. Furthermore, increased plasma levels of interleukin-1 receptor antagonist were observed in the subtype of cryptogenic stroke compared with controls., Conclusions: This comprehensive study, based on a tagSNP approach and replication, presents support for the role of IL1RN in overall IS.

Background and Purpose: in a genome-wide association study and subsequent case-control studies, the single-nucleotide polymorphism rs12425791 on chromosome 12p13 was reported to be associated with ischemic stroke, but this could not be validated in a recent well-powered study. We therefore investigated whether an association between ischemic stroke and rs12425791 could be detected in 3 different case-control studies from the southwest of Sweden., Methods: we examined 3606 patients with ischemic stroke and 2528 controls from 3 independent case-controls studies., Results: no significant association between ischemic stroke and the single-nucleotide polymorphism rs12425791 was detected in any of the 3 case-control samples or in the samples combined. The odds ratio for ischemic stroke for the minor allele in the combined sample was 1.02 (95% CI, 0.93 to 1.13)., Conclusions: the single-nucleotide polymorphism rs12425791 does not confer a substantial risk for ischemic stroke in our population. Our results support a recent large study including other European populations.

Background and Purpose: Genome-wide association studies recently identified 2 variants on chromosome 4q25 as susceptibility factors for atrial fibrillation. Interestingly, these variants were subsequently also shown to be associated with stroke. However, it remains unclear whether 4q25 associates with all the stroke subtypes or with cardioembolic stroke in particular, which is often attributable to atrial fibrillation., Methods: We performed a large case-control association study in 4199 ischemic stroke patients, all subtyped according to Trial of Org 10172 in Acute Stroke Treatment criteria, and 3750 controls derived from 6 studies conducted in Australia, Austria, Belgium, Poland, Spain, and Sweden. Two variants on chromosome 4q25, rs1906591 and rs10033464, were genotyped., Results: Within cases, the A-allele of rs1906591 was associated with atrial fibrillation (odds ratio, 1.64 [95% CI, 1.43 to 1.90]; P=9.2 . 10(-12)), whereas rs10033464 was only marginally associated. There was an association between overall ischemic stroke and rs1906591 (odds ratio, 1.20 [95% CI, 1.09 to 1.32]; P=1.2 . 10(-4)). However, this was probably caused by the large effect of stroke of cardioembolic etiology because no relation was obtained in any other subgroup of stroke. The rs10033464 variant failed to show any relationship with ischemic stroke., Conclusions: We replicated the association of the rs1906591 variant on chromosome 4q25 with atrial fibrillation and ischemic stroke of cardioembolic etiology. The 4q25 locus failed to associate with noncardiac subtypes of ischemic stroke.

Background and Purpose: C-reactive protein (CRP) has evolved as an inflammatory risk marker of cardiovascular disease. Several single-nucleotide polymorphisms at the CRP locus have been found to be associated with CRP levels. The aim of the present study was to investigate CRP levels and genetic variants in etiological subtypes of ischemic stroke., Methods: The Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) comprises 600 consecutive ischemic stroke cases (18 to 69 years) and 600 matched controls from western Sweden. Stroke subtypes were defined by the TOAST classification. Serum CRP levels were determined by a high-sensitivity immunometric assay., Results: CRP levels were significantly higher for all ischemic stroke subtypes compared with controls, both in the acute phase and at the 3-month follow-up. After adjustment for traditional risk factors, CRP at follow-up was related to higher odds ratios (ORs) of overall ischemic stroke (OR, 1.25; 95% CI, 1.09 to 1.43) and large-vessel disease (OR, 1.48; 95% CI, 1.09 to 2.00). The CRP -286C>T>A, 1059G>C, and 1444C>T single-nucleotide polymorphisms showed significant associations with CRP levels. However, neither CRP genotypes nor haplotypes showed an association to overall ischemic stroke., Conclusions: This is the first large study on CRP in different TOAST subtypes in a young ischemic stroke population. CRP levels differed between etiological subtypes of ischemic stroke both in the acute phase and at the 3-month follow-up. CRP at follow-up was associated with overall ischemic stroke and the large-vessel disease subtype. Genetic variants at the CRP locus were associated with CRP levels, but no association was detected for overall ischemic stroke.

Background and Purpose: The tissue-type plasminogen activator (tPA) -7351C>T and the plasminogen activator inhibitor type 1 (PAI-1) -675 4G>5G polymorphisms influence transcriptional activity. Both variants have been associated with myocardial infarction, with increased risk for the T and 4G allele, respectively. In this study we investigated the possible association between these polymorphisms, the respective plasma protein levels, and ischemic stroke., Methods: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), 600 patients with acute ischemic stroke aged 18 to 69 years and 600 matched community controls were recruited. Stroke subtype was determined using Trial of Org 10172 in Acute Treatment criteria., Results: There were no associations between individual genetic variants and ischemic stroke. The multivariate-adjusted odds ratio for overall ischemic stroke was 1.11 (95% CI 0.87 to 1.43) for tPA T allele carriers, and 0.84 (95% CI, 0.64 to 1.11) for subjects homozygous for the PAI-1 4G allele. When genotypes were combined, a protective effect for the tPA CC/PAI-1 4G4G genotype combination was observed (odds ratio 0.65, 95% CI 0.43 to 0.98; P<0.05). Plasma levels of tPA and PAI-1 antigen at follow-up were independently associated with overall ischemic stroke. tPA-antigen differed by stroke subtype and was highest among those with large-vessel disease and cardioembolic stroke., Conclusions: Neither the tPA -7351C>T nor the PAI-1 to 675 4G>5G polymorphism showed significant association with ischemic stroke. For the tPA CC/PAI-1 4G4G genotype combination, a protective effect was observed. Collectively, these results are consistent with a more complex role for tPA and PAI-1 in the brain as compared with the heart.

Background and Purpose: Results from twin and family history studies of ischemic stroke suggest that future molecular genetic studies should focus on strictly defined stroke subtypes and younger cases. Accordingly, we investigated stroke subtypes, vascular risk factors, and family history in a large study of patients with ischemic stroke onset before age 70 years., Methods: Six hundred consecutive white participants with ischemic stroke (18 to 69 years) and 600 age- and sex-matched controls were examined for vascular risk factors and family history of stroke and myocardial infarction (MI). Stroke subtype was defined using Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria., Results: Family history of stroke was associated with overall ischemic stroke (multivariate odds ratio [OR], 1.75; 95% confidence interval [CI], 1.26 to 2.43), large-vessel disease (LVD) (OR, 1.88; 95% CI, 1.02 to 3.44), small-vessel disease (SVD, OR, 1.79; 95% CI, 1.13 to 2.84), and cryptogenic stroke (OR, 1.70; 95% CI, 1.13 to 2.56), but not with cardioembolic stroke. Family history of MI was strongly associated with LVD (OR, 3.25; 95% CI, 1.74 to 6.07), whereas no significant association were observed for other subtypes. We also found an independent association between family history of stroke and a favorable outcome after 3 months., Conclusion: Family history of stroke is an independent risk factor for ischemic stroke with onset before age 70 years. For the first time to our knowledge, we report this association not only for LVD and SVD but also for cryptogenic stroke, implying that future studies of the genetics of ischemic stroke should target these 3 subtypes.

Background and Purpose: Data on the association between obesity and stroke are still limited. We examined the possible association between mid-life body mass index (BMI) and risk of stroke in the prospective Multifactor Primary Prevention Study in Göteborg, Sweden., Methods: 7402 apparently healthy men aged 47 to 55 at baseline were followed-up over a 28-year period. Incidence of fatal and nonfatal stroke was recorded in a local stroke registry through the Swedish National Register on Cause of Death and the Swedish Hospital Discharge Registry., Results: A total of 873 first strokes were recorded, including 495 ischemic, 144 hemorrhagic, and 234 unspecified strokes. Compared with men with low normal weight (BMI, 20.0 to 22.49 kg/m2), men with BMI >30.0 kg/m2 had a multiple adjusted hazard ratio of 1.93 (95% CI, 1.44 to 2.58) for total stroke, 1.78 (95% CI, 1.22 to 2.60) for ischemic stroke, and 3.91 (95% CI, 2.10 to 7.27) for unspecified stroke. There was no significant association between BMI and hemorrhagic stroke. Adjustment for potential mediators, eg, hypertension, diabetes and serum cholesterol levels, attenuated but did not eliminate the risk., Conclusions: In this prospective population-based study of men, increased BMI in mid-life was associated with an increased risk for total, ischemic, and unspecified stroke, but not with hemorrhagic stroke. The result supports the role of mid-life BMI as a risk factor for stroke later in life and suggests a differentiated effect on stroke subtypes.