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Background and Objectives: To test the hypothesis that a predisposition to acquired genetic alterations is associated with ischemic stroke outcome by investigating the association between a polygenic risk score (PRS) for mosaic loss of chromosome Y (mLOY) and outcome in a large international data set., Methods: We used data from the genome-wide association study performed within the Genetics of Ischemic Stroke Functional Outcome network, which included 6,165 patients (3,497 men and 2,668 women) with acute ischemic stroke of mainly European ancestry. We assessed a weighted PRS for mLOY and examined possible associations with the modified Rankin Scale (mRS) score 3 months poststroke in logistic regression models. We investigated the whole study sample as well as men and women separately., Results: Increasing PRS for mLOY was associated with poor functional outcome (mRS score >2) with an odds ratio (OR) of 1.11 (95% confidence interval [CI] 1.03-1.19) per 1 SD increase in the PRS after adjustment for age, sex, ancestry, stroke severity (NIH Stroke Scale), smoking, and diabetes mellitus. In sex-stratified analyses, we found a statistically significant association in women (adjusted OR 1.20, 95% CI 1.08-1.33). In men, the association was in the same direction (adjusted OR 1.04, 95% CI 0.95-1.14), and we observed no significant genotype-sex interaction., Discussion: In this exploratory study, we found associations between genetic variants predisposing to mLOY and stroke outcome. The significant association in women suggests underlying mechanisms related to genomic instability that operate in both sexes. These findings need replication and mechanistic exploration., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Cerebral venous thrombosis (CVT) is an uncommon form of stroke affecting mostly young individuals. Although genetic factors are thought to play a role in this cerebrovascular condition, its genetic etiology is not well understood., Methods: A genome-wide association study was performed to identify genetic variants influencing susceptibility to CVT. A 2-stage genome-wide study was undertaken in 882 Europeans diagnosed with CVT and 1,205 ethnicity-matched control subjects divided into discovery and independent replication datasets., Results: In the overall case-control cohort, we identified highly significant associations with 37 single nucleotide polymorphisms (SNPs) within the 9q34.2 region. The strongest association was with rs8176645 (combined p = 9.15 × 10 -24 ; odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.76-2.31). The discovery set findings were validated across an independent European cohort. Genetic risk score for this 9q34.2 region increases CVT risk by a pooled estimate OR = 2.65 (95% CI = 2.21-3.20, p = 2.00 × 10 -16 ). SNPs within this region were in strong linkage disequilibrium (LD) with coding regions of the ABO gene. The ABO blood group was determined using allele combination of SNPs rs8176746 and rs8176645. Blood groups A, B, or AB, were at 2.85 times (95% CI = 2.32-3.52, p = 2.00 × 10 -16 ) increased risk of CVT compared with individuals with blood group O., Interpretation: We present the first chromosomal region to robustly associate with a genetic susceptibility to CVT. This region more than doubles the likelihood of CVT, a risk greater than any previously identified thrombophilia genetic risk marker. That the identified variant is in strong LD with the coding region of the ABO gene with differences in blood group prevalence provides important new insights into the pathophysiology of CVT. ANN NEUROL 2021;90:777-788., (© 2021 American Neurological Association.)

Background and Purpose: This cross-sectional cohort study aims at investigating young ischaemic stroke survivors with good physical recovery 7 years post-stroke in order to analyze the relation between late cognitive ability and employment., Methods: Consecutive ischaemic stroke survivors participating in the Sahlgrenska Academy Study on Ischemic Stroke, <55 years of age at stroke onset, and with no or minimal persisting neurological deficits corresponding to a score ≤2 on the National Institutes of Health Stroke Scale at long-term follow-up 7 years post-stroke were included. At this follow-up, the participants were assessed with respect to general cognitive function, processing speed, executive functions, cardiovascular risk factors, self-reported employment, cognitive difficulties, fatigue, depressive symptoms, anxiety and physical function., Results: Seven years post-stroke 112/142 (79%) had part-time or full-time work and 30/142 (21%) had full-time disability pension or sick leave. Compared to those with full-time disability pension or sick leave, participants with current employment demonstrated significantly better performance with respect to general cognitive function and processing speed, and significantly lower self-ratings for cognitive difficulties, physical limitations, fatigue and depressed mood. Multivariable logistic regression selected self-rated memory (odds ratio [OR] 2.61, 95% confidence interval [CI] 1.61-4.21), processing speed (OR 3.50, 95% CI 1.67-7.33) and self-rated communication skills (OR 3.46, 95% CI 1.75-6.85) as most important correlates (area under the curve 0.83-0.87) of having current employment., Conclusion: This study indicates that cognitive dysfunction is an important contributor to long-term work disability amongst young stroke survivors with good physical recovery., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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., Competing Interests: AR was employed by Centogene AG, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hong, Giese, Schirmer, Bonkhoff, Bretzner, Rist, Dalca, Regenhardt, Etherton, Donahue, Nardin, Mocking, McIntosh, Attia, Benavente, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Roquer, Kittner, Lemmens, Levi, McDonough, Meschia, Phuah, Rolfs, Ropele, Rosand, Rundek, Sacco, Schmidt, Enzinger, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Wasselius, Woo, Zand, McArdle, Worrall, Wu, Jern, Lindgren, Maguire, Tomppo, Golland, Rost and the MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium.)

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data., (© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes., Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA)., Results: Radiomic features were predictive of WMH burden ( R 2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p -values CV 1 - 6 < 0.001, p -value CV 7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes., Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients' brain health., Competing Interests: AR was employed by the company Centogene GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bretzner, Bonkhoff, Schirmer, Hong, Dalca, Donahue, Giese, Etherton, Rist, Nardin, Marinescu, Wang, Regenhardt, Leclerc, Lopes, Benavente, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Kittner, Lemmens, Levi, McArdle, McDonough, Meschia, Phuah, Rolfs, Ropele, Rosand, Roquer, Rundek, Sacco, Schmidt, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Wasselius, Woo, Wu, Zand, Worrall, Maguire, Lindgren, Jern, Golland, Kuchcinski and Rost.)

Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n = 503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.

Insulin-like growth factor-II (IGF-II) regulates prenatal brain development, but the role in adult brain function and injury is unclear. Here, we determined whether serum levels of IGF-II (s-IGF-II) are associated with mortality and functional outcome after ischemic stroke (IS). The study population comprised ischemic stroke cases (n = 492) and controls (n = 514) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Functional outcome was evaluated after 3 months and 2 years using the modified Rankin Scale (mRS), and additionally, survival was followed at a minimum of 7 years or until death. S-IGF-II levels were higher in IS cases both in the acute phase and at 3-month follow-up compared to controls ( p < 0.05 and p < 0.01, respectively). The lowest quintile of acute s-IGF-II was, compared to the four higher quintiles, associated with an increased risk of post-stroke mortality (median follow-up 10.6 years, crude hazard ratio (HR) 2.34, 95% confidence interval (CI) 1.56-3.49, and fully adjusted HR 1.64, 95% CI 1.02-2.61). In contrast, crude associations with poor functional outcome (mRS 3-6) lost significance after full adjustment for covariates. In conclusion, s-IGF-II was higher in IS cases than in controls, and low acute s-IGF-II was an independent risk marker of increased mortality.

Complex diseases represent a number of common disorders such as allergic conditions, cardiovascular, metabolic and chronic inflammatory diseases. These diseases are caused by a combination of genetic, environmental and lifestyle factors. This complex etiology creates challenges when it comes to diagnostics, follow-up programs and treatment. Although exact disease mechanisms are yet to be elucidated for most complex diseases, key genetic determinants have been mapped and omics profiling has unraveled involved pathways. Using this wealth of data, precision medicine applications have started to appear also for common, complex diseases. In this article, we review current precision medicine applications from a clinical point of view and outline briefly a roadmap ahead for further clinical implementation of precision medicine in complex diseases.

DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood-liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 ≤  r  < 0.75) were detected for 6% and strong correlations ( r  ≥ 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood-liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease., Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation., Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke., Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk., Funding: British Heart Foundation., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap., Methods: Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data., Results: The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism., Conclusion: The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The cause of ischemic stroke remains unknown, cryptogenic, in 25% of young and middle-aged patients. We hypothesized that if atherosclerosis is prominent in cryptogenic stroke, it would have a similar proinflammatory protein signature as large artery atherosclerosis (LAA) stroke., Materials & Methods: Blood was collected in the acute phase and after 3 months from cryptogenic (n = 162) and LAA (n = 73) stroke patients aged 18-69 years and once from age-matched controls (n = 235). Cryptogenic stroke was divided into Framingham Risk Score (FRS) quartiles to compare low and high risk of atherosclerosis. Plasma concentrations of 25 proteins were analyzed using a Luminex multiplex assay. The discriminating properties were assessed with discriminant analysis and C-statistics., Results: We identified proteins that separated cryptogenic and LAA stroke from controls (area under the curves, AUCs ≥ 0.85). For both subtypes, RANTES, IL-4, and IFN-γ contributed the most at both time points. These associations were independent of risk factors of atherosclerosis. We also identified proteins that separated cryptogenic strokes in the lowest quartile of FRS from those in the highest, and from LAA stroke (AUCs ≥ 0.76), and here eotaxin and MCP-1 contributed the most., Conclusions: The protein signature separating cases from controls was different from the signature separating cryptogenic stroke with low risk of atherosclerosis from those with high risk and from LAA stroke. This suggests that increased RANTES, IL-4, and IFN-γ in stroke may not be primarily related to atherosclerosis, whereas increased eotaxin and MCP-1 in cryptogenic stroke may be markers of occult atherosclerosis as the underlying cause., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: To examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS)., Methods: For the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool-based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes., Results: Patients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm 3 (interquartile range 2.18-14.61 cm 3 ) and differed significantly across CCS subtypes ( p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus ( p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes ( p < 0.001)., Conclusion: In this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke., (© 2020 American Academy of Neurology.)

Background: Magnetic resonance imaging (MRI) serves as a cornerstone in defining stroke phenotype and etiological subtype through examination of ischemic stroke lesion appearance and is therefore an essential tool in linking genetic traits and stroke. Building on baseline MRI examinations from the centralized and structured radiological assessments of ischemic stroke patients in the Stroke Genetics Network, the results of the MRI-Genetics Interface Exploration (MRI-GENIE) study are described in this work. Methods: The MRI-GENIE study included patients with symptoms caused by ischemic stroke ( N = 3,301) from 12 international centers. We established and used a structured reporting protocol for all assessments. Two neuroradiologists, using a blinded evaluation protocol, independently reviewed the baseline diffusion-weighted images (DWIs) and magnetic resonance angiography images to determine acute lesion and vascular occlusion characteristics. Results: In this systematic multicenter radiological analysis of clinical MRI from 3,301 acute ischemic stroke patients according to a structured prespecified protocol, we identified that anterior circulation infarcts were most prevalent (67.4%), that infarcts in the middle cerebral artery (MCA) territory were the most common, and that the majority of large artery occlusions 0 to 48 h from ictus were in the MCA territory. Multiple acute lesions in one or several vascular territories were common (11%). Of 2,238 patients with unilateral DWI lesions, 52.6% had left-sided infarct lateralization ( P = 0.013 for χ 2 test). Conclusions: This large-scale analysis of a multicenter MRI-based cohort of AIS patients presents a unique imaging framework facilitating the relationship between imaging and genetics for advancing the knowledge of genetic traits linked to ischemic stroke., (Copyright © 2020 Drake, Frid, Hansen, Wu, Giese, Schirmer, Donahue, Cloonan, Irie, Bouts, McIntosh, Mocking, Dalca, Sridharan, Xu, Giralt-Steinhauer, Holmegaard, Jood, Roquer, Cole, McArdle, Broderick, Jiménez-Conde, Jern, Kissela, Kleindorfer, Lemmens, Meschia, Rundek, Sacco, Schmidt, Sharma, Slowik, Thijs, Woo, Worrall, Kittner, Mitchell, Rosand, Golland, Lindgren, Rost and Wassélius.)

Background: The association of serum insulin-like growth factor I (s-IGF-I) with favorable outcome after ischemic stroke (IS) beyond 2 years is unknown. We investigated whether the levels of s-IGF-I 3 months post-stroke were associated with functional recovery up to 7 years after IS, considering also mortality and recurrent strokes., Methods: Patients (N=324; 65% males; mean age, 55 years) with s-IGF-I levels assessed 3 months after the index IS were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The modified Rankin Scale (mRS) was used to evaluate outcomes at 3 months, 2 and 7 years after IS, and recovery was defined as an improvement, no change, or deterioration in the shifts of mRS score. Baseline stroke severity was determined using the National Institutes of Health Stroke Scale (NIHSS)., Results: The mRS score distributions were better in the above-median s-IGF-I group (>146.7 ng/ml). The s-IGF-I level was not associated with recurrent stroke (N=79) or death (N=44), although it correlated with recovery (r=0.12, P=0.035). In the regression analysis, s-IGF-I associated with recovery between 3 months and 7 years (but not between 2 and 7 years). The associations did not withstand adjustment for age and sex. For comparison, the corresponding associations between 3 months and 2 years withstood all adjustments., Conclusion: The association for s-IGF-I with long-term post-stroke recovery persists after 7 years, which is also reflected in the mRS score distributions at all time-points. The effects are however modest, and not driven by mortality or recurrent stroke., Competing Interests: No conflict of interest has been declared by the authors., (Eigentümer und Copyright ©Georg Thieme Verlag KG 2019.)

Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS)., Patients and Methods: This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission., Results: Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm 3 ) was associated with age (β -0.3 [per 14.4 years]), male sex (β 1.0), and prior stroke (β -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (β -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes., Conclusion: Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Vascular endothelial growth factor (VEGF) acts in angiogenesis and neuroprotection, although the beneficial effects on experimental ischemic stroke (IS) have not been replicated in clinical studies. We investigated serum VEGF (s-VEGF) in the acute stage (baseline) and 3 months post-stroke in relation to stroke severity and functional outcome., Methods: The s-VEGF and serum high-sensitivity C-reactive protein (hs-CRP) concentrations were measured in patients enrolled in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) at the acute time-point (median 4 days, N = 492, 36% female; mean age, 57 years) and at 3 months post-stroke (N = 469). Baseline stroke severity was classified according to the National Institutes of Health Stroke Scale (NIHSS), and functional outcomes (3 months and 2 years) were evaluated using the modified Rankin Scale (mRS), dichotomized into good (mRS 0-2), and poor (mRS 3-6) outcomes. Multivariable logistic regression analyses were adjusted for covariates., Results: The baseline s-VEGF did not correlate with stroke severity but correlated moderately with hs-CRP (r = .17, P < .001). The baseline s-VEGF was 39.8% higher in total anterior cerebral infarctions than in lacunar cerebral infarctions. In binary logistic regression analysis, associations with 3-month functional outcome were non-significant. However, an association between the 3-month s-VEGF and poor 2-year outcome withstood adjustments for age, sex, cardiovascular covariates, and stroke severity (per 10-fold increase in s-VEGF, odds ratio [OR], 2.56, 95% confidence interval [CI] 1.12-5.82) or hs-CRP (OR 2.53, CI 1.15-5.55)., Conclusions: High 3-month s-VEGF is independently associated with poor 2-year functional outcome but not with 3-month outcome., (© 2020 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: Lateralized inattention is a typical sign of neglect and related to poor functional outcome. Knowledge of the long-term course of this phenomenon is limited. The purpose of this study was to investigate presence and predictors for signs of lateralized inattention 7 years after stroke., Methods: From a cohort of acute ischemic stroke patients, aged 18-69 years (n = 297), a consecutive series of 188 survivors without recurrent stroke at follow-up 7 years later were included. Within the first week after stroke onset, stroke severity was assessed according to the Scandinavian Stroke Scale. Target omissions, asymmetry of omissions, and perceptual speed according to Star- and Letter Cancellation Tests were also assessed. Presence of lateralized inattention at the 7-year follow-up was investigated with the Star- and Letter Cancellation Tests and with the neglect item in the National Institutes of Health Stroke Scale., Results: At the follow-up, 22 (11.7%) participants had lateralized inattention and the multivariable regression showed that independent significant baseline predictors were total omissions in target cancellations (P < .001) and inferior baseline performance on visual processing speed (P = .008)., Conclusion: About one of ten individuals exhibited signs of lateralized inattention 7 years after stroke. Baseline performance in perceptual processing speed and target omissions independently predicted presence of late signs of lateralized inattention. This is the first time processing speed is recognized as a significant predictor of lateralized inattention several years after the stroke incidence, indicating that the longitudinal course of processing speed following stroke is a critical subject for future research., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Physical activity (PA) and insulin-like growth factor I (IGF-I) have beneficial effects for patients who have suffered an ischemic stroke (stroke). However, the relationship between the levels of PA and IGF-I after stroke has not been explored in detail. We investigated the pre-stroke PA level in relation to the post-stroke serum IGF-I (s-IGF-I) level, at baseline and at 3 months after the index stroke, and calculated the change that occurred between these two time-points (ΔIGF-I). Patients ( N = 380; 63.4% males; mean age, 54.7 years) with data on 1-year leisure-time pre-stroke PA and post-stroke s-IGF-I levels were included from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Pre-stroke, leisure-time PA was self-reported as PA1-4, with PA1 representing sedentary and PA2-4 indicating progressively higher PA levels. Associations between s-IGF-I and PA were evaluated by multiple linear regressions with PA1 as the reference and adjustments being made for sex, age, history of previous stroke or myocardial infarctions, cardiovascular risk factors, and stroke severity. PA correlated with baseline s-IGF-I and ΔIGF-I, but not with the 3-month s-IGF-I. In the linear regressions, there were corresponding associations that remained as a tendency (baseline s-IGF-I, p = 0.06) or as a significant effect (ΔIGF-I, p = 0.03) after all the adjustments. Specifically, for each unit of PA, ΔIGF-I increased by 9.7 (95% CI 1,1-18.4) ng/mL after full adjustment. This supports the notion that pre-stroke PA is independently related to ΔIGF-I.

Objective: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS., Methods: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression., Results: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions., Conclusion: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Characterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Systematic studies on increased muscle tone and spasticity late after ischemic stroke, without any selection, are limited. Therefore, we aimed to determine the prevalence of increased muscle tone, classical spasticity and contracture and predictors of increased muscle tone seven years after stroke., Methods: Consecutive patients with acute ischemic stroke <70 years of age (n = 411) were recruited to the Sahlgrenska Academy Study on Ischemic Stroke. Symptoms at index stroke were assessed using the Scandinavian Stroke Scale. Seven years after stroke, survivors (n = 358) were invited for follow-up assessments, of whom 292 agreed to participate and 288 contributed data. Muscle tone according to the Modified Ashworth scale, classical spasticity, and contracture was assessed by a neurologist. The associations between increased muscle tone and characteristics at index stroke and recurrent strokes during follow-up were investigated using logistic regression analysis., Results: Increased muscle tone was recognized in 99 participants (34%): 94 (33%) in the upper limbs, and 72 (25%) in the lower limbs. Classical spasticity was found in 51 participants (18%) and contracture in 26 (9%). Age (odds ratio [OR] 1.03 [95% confidence interval [CI] 1.00-1.06]), arm paresis (OR 1.76 [95% CI 1.40-2.2]), aphasia (OR 1.68 [95% CI 1.12-2.51]), and facial palsy (OR 2.12 [95% CI 1.10-4.07]) were independent predictors of increased muscle tone., Conclusions: One-third of patients with ischemic stroke before 70 years of age showed increased muscle tone at 7-year follow-up. Half of them also had classical spasticity. Age, arm paresis, aphasia, and facial palsy at index stroke were predictors of increased muscle tone poststroke., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Purpose: To assess long-term incidence and predictors of post-stroke epilepsy (PSE) and to evaluate the antiepileptic drug (AED) treatment in a well characterized cohort of middle-aged patients., Methods: The study is based on the Sahlgrenska Study on Ischemic stroke, and included 1066 adult patients with first-ever or recurrent acute ischemic stroke (AIS) before the age of 70. Early seizures (ES) were defined as seizures within one week and PSE as unprovoked seizures occurring more than one week from index stroke. Cardiovascular risk factors, subtype of AIS, and stroke severity were determined at baseline. ES, PSE, treatment with AEDs, recurrent stroke and mortality were assessed through national registers and medical records. Cox regression models were used for identifying predictors of PSE., Results: Twenty-six patients (2.4 %) developed ES. After a median follow-up of 8.0 (IQR 4.1-10.9) years, 84 (7.9 %) had PSE, and 160 (15.0 %) had experienced a non-fatal recurrent stroke. Stroke location (total anterior and partial anterior circulation infarct, both P < 0.001), ES (P < 0.001), stroke recurrence (P < 0.001), artery dissection (P < 0.002), and previous coronary heart disease (P < 0.006) were independent predictors of PSE. Only 10 (11.9 %) had the first seizure more than four years after index stroke. In 24 (30 %) PSE patients, seizure control was not achieved., Conclusions: In addition to well-known risk factors for PSE development, our data also identified stroke recurrence, artery dissection and established coronary disease. Seizure control was less common than expected and in a significant proportion of patients AEDs had not been adjusted despite continuing seizures., Competing Interests: Declaration of Competing Interest The authors declare no financial or other conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

High aerobic fitness, more moderate to vigorous physical activity (MVPA) and less sedentary behavior (SED) have all been suggested to promote cognitive functions, but it is unclear whether they are independent predictors of specific cognitive domains. This study aimed to investigate to what extent aerobic fitness MVPA and SED are independently associated with cognitive performance among middle-aged Swedish adults. We acquired device-based measures of aerobic fitness, cognitive performance and percent daily time spent in MVPA and SED in Swedish adults ( n = 216; 54-66 years old). Aerobic fitness was associated with better performance at one out of two tests of speed/attention and one out of four tests of executive attention, and with worse performance at one of seven tests of memory. Increasing %MVPA was associated with better performance at one out of seven tests of memory and two out of three tests of verbal ability, whereas increasing %SED was associated with better performance at all four tests of executive attention and four out of seven tests of memory. These findings suggest that aerobic fitness, %MVPA and %SED are partly independent correlates of cognitive performance. To fully understand the association between SED and performance at several tests of cognitive function, future investigations might attempt to investigate intellectually engaging SED (such as reading books) separately from mentally undemanding SED (such as watching TV).

Introduction: Worldwide, 2 million patients aged 18-50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients., Methods and Analysis: The Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18-50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence., Ethics and Dissemination: Ethical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Neurofilament light chain (NfL) is a marker of neuroaxonal damage. We aimed to study associations between serum NfL (sNfL) concentrations at different time points after ischemic stroke and outcomes., Methods: We prospectively included ischemic stroke cases (n = 595, mean age 59 years, 64% males) and assessed outcomes by both the modified Rankin Scale (mRS) and the NIH stroke scale (NIHSS) at 3 months and by mRS at 2 years. In a subsample, long-term (7-year) outcomes were also assessed by both mRS and NIHSS. We used the ultrasensitive single-molecule array assay to measure sNfL in the acute phase (range 1-14, median 4 days), after 3 months and 7 years in cases and once in controls (n = 595)., Results: Acute-phase sNfL increased by the time to blood-draw and highest concentrations were observed at 3 months post-stroke. High sNfL associated to stroke severity and poor outcomes, and both associations were strongest for 3-month sNfL. After adjusting for age, previous stroke, stroke severity, and day of blood draw, 3-month sNfL was significantly associated to both outcomes at all time points (p < 0.01 throughout). For all main etiological subtypes, both acute phase and 3-month sNfL were significantly higher than in controls, but the dynamics of sNfL differed by stroke subtype., Conclusions: The results from this study inform on sNfL in ischemic stroke and subtypes over time, and show that sNfL predicts short- and long-term neurological and functional outcomes. Our findings suggest a potential utility of sNfL in ischemic stroke outcome prediction.

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: Insulin resistance (IR) in relation to diabetes is a risk factor for ischemic stroke (IS), whereas less is known about non-diabetic IR and outcome after IS., Methods: In non-diabetic IS (n = 441) and controls (n = 560) from the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), IR was investigated in relation to IS severity and functional outcome. IR was evaluated acutely and after 3 months using the Homeostasis model assessment of IR (HOMA-IR). Stroke severity was assessed by the National Institutes of Health Stroke Scale (NIHSS). Functional outcome was evaluated using the modified Rankin Scale (mRS) after 3 months, 2 and 7 years. Associations were evaluated by logistic regression., Results: Higher acute and 3-month HOMA-IR was observed in IS compared to the controls (both p < 0.001) and in severe compared to mild IS (both p < 0.05). High acute HOMA-IR was associated with poor outcome (mRS 3-6) after 3 months and 7 years [crude Odds ratios (ORs), 95% confidence intervals (CIs) 1.50, 1.07-2.11 and 1.59, 1.11-2.30, respectively], but not after 2 years. These associations lost significance after adjustment for all covariates including initial stroke severity. In the largest IS subtype (cryptogenic stroke), acute HOMA-IR was associated with poor outcome after 2 years also after adjustment for age and stroke severity (OR 2.86, 95% CI 1.01-8.12)., Conclusions: In non-diabetic IS patients, HOMA-IR was elevated and related to stroke severity, but after adjustment for IS severity, the associations between HOMR-IR and poor outcome lost significance. This could suggest that elevated IR mostly is a part of the acute IS morbidity. However, in the subgroup of cryptogenic stroke, the associations with poor outcome withstood correction for stroke severity.

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.

Objective:  Elucidating the genetic basis underlying hepatic hemostatic gene expression variability may contribute to unraveling genetic factors contributing to thrombotic or bleeding disorders. We aimed to identify novel cis -regulatory variants involved in regulating hemostatic genes by analyzing allele-specific expression (ASE) in human liver samples., Study Design:  Biopsies of human liver tissue and blood were collected from adults undergoing liver surgery at the Sahlgrenska University Hospital ( n  = 20). Genomic deoxyribonucleic acid (gDNA) and total ribonucleic acid (RNA) were isolated. A targeted approach was used to enrich and sequence 35 hemostatic genes for single nucleotide polymorphism (SNP) analysis (gDNAseq) and construct individualized genomes for transcript alignment. The allelic ratio of transcripts from targeted RNAseq was determined via ASE analysis. Public expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data were used to assess novelty and importance of the ASE SNPs (and proxies, r 2  ≥ 0.8) for relevant traits/diseases., Results:  Sixty percent of the genes studied showed allelic imbalance across 53 SNPs. Of these, 7 SNPs were previously validated in liver eQTL studies. For 32 with eQTLs in other cell/tissue types, this is the first time genotype-specific expression is demonstrated in liver, and for 14 ASE SNPs, this is the first ever reported genotype-expression association. A total of 29 ASE SNPs were previously associated with the respective plasma protein levels and 17 ASE SNPs to other relevant GWAS traits including venous thromboembolism, coronary artery disease, and stroke., Conclusion:  Our study provides a comprehensive ASE analysis of hemostatic genes and insights into the regulation of hemostatic genes in human liver., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: With an upward trend in the number of people who return home to independent living after stroke, the ability to perform more complex activities is becoming an increasingly important long-term outcome after stroke. Although associations between Instrumental Activities of Daily Living (IADL) and cognitive dysfunction, emotional problems, and fatigue have been reported, less is known about the long-term impact of these stroke consequences on the performance of everyday activities in young and middle-aged stroke survivors., Objective: To explore the impact of cognitive dysfunction, emotional problems, and fatigue on long-term performance of instrumental activities of daily living in young and middle-aged stroke survivors., Method: Data on stroke survivors, aged 18-69 at index stroke, were collected from the Sahlgrenska Academy Study on Ischaemic Stroke. IADL outcome was assessed using the Frenchay Activities Index (FAI), and the impact of chosen variables was assessed using Spearman´s rank-order correlation and logistic regression., Results: Seven years after index stroke, 296 stroke survivors (median age of 64) were included in this study. Cognitive dysfunction showed the strongest correlations with FAI outcome and independently explained worse outcome on FAI summary score and the domain of work/leisure activities. Fatigue was independently explanatory of worse outcome on FAI summary score and domestic chores, while depressive symptoms independently explained worse outcome on work/leisure activities. In a subgroup with only those participants who had no or minimal residual neurological deficits at follow-up (NIHSS score 0), cognitive dysfunction independently explained worse outcome on FAI summary score and work/leisure activities. Depressive symptoms independently explained worse outcome on FAI summary score and domestic chores., Conclusion: Our results show that in young and middle-aged stroke survivors, cognitive dysfunction, depressive symptoms, and fatigue negatively impact performance of IADL even at seven years post stroke onset. Further, we have shown that an impact of both cognitive dysfunction and depressive symptoms can be found also among stroke survivors with mild or no remaining neurological deficits., Competing Interests: The authors have declared that no competing interests exist.

Objective: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study., Methods: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10 -8 ., Results: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10 -9 ). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21 , which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome ( p < 10 -5 ), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4 , TEK , and PTCH1 )., Conclusions: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach., Methods: Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases)., Results: In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 -4 ) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 -4 ) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype., Conclusions: This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts., Methods: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI., Results: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 -8 ; and LINC00539/ZDHHC20, p = 5.82 × 10 -9 . Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 -25 ; p [SSBI] = 5.23 × 10 -14 for hypertension), smoking ( p [BI] = 4.4 × 10 -10 ; p [SSBI] = 1.2 × 10 -4 ), diabetes ( p [BI] = 1.7 × 10 -8 ; p [SSBI] = 2.8 × 10 -3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 -18 ; p [SSBI] = 2.3 × 10 -7 ), stroke ( p [BI] = 3.9 × 10 -69 ; p [SSBI] = 3.2 × 10 -24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 -157 ; p [SSBI] = 3.16 × 10 -106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy., Conclusion: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Rationale: 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., Objective: 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., Methods and Results: 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 -9 )., Conclusions: 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.

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Studies on long-term progression of white matter hyperintensities (WMH) after ischemic stroke are scarce. Here, we sought to investigate this progression and its predictors in a cohort presenting with ischemic stroke before 70 years of age., Materials and Methods: Participants in the Sahlgrenska Academy Study on Ischemic Stroke who underwent magnetic resonance imaging (MRI) of the brain at index stroke were examined by MRI again after 7 years (n = 188, mean age 53 years at index stroke, 35% females). WMH at index stroke and progression were assessed according to Fazekas' grades and the WMH change scale. Stroke subtype was classified according to TOAST., Results: Marked WMH at index stroke were present in 20% of the participants and were significantly associated with age, hypertension, and subtype. Progression of WMH after 7 years was observed in 63% and 35% of the participants for subcortical and periventricular locations, respectively. Significant independent predictors of progression were age and marked WMH at baseline for both locations, whereas no significant associations were detected for vascular risk factors or subtype in multivariable analyses. In participants with no or only mild WMH at baseline, 20% showed marked WMH at follow-up. Age and hypertension, but not subtype, were independently associated with this acquisition of marked WMH., Conclusions: Age and marked WMH at index stroke, but not stroke subtype, predicted long-term WMH progression after ischemic stroke before 70 years of age, whereas age and hypertension predicted acquisition of marked WMH in those with no or only mild WMH at baseline., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Purpose: Polymorphisms in coagulation genes have been associated with early-onset ischemic stroke. Here we pursue an a priori hypothesis that genetic variation in the endothelial-based receptors of the thrombomodulin-protein C system (THBD and PROCR) may similarly be associated with early-onset ischemic stroke. We explored this hypothesis utilizing a multi-stage design of discovery and replication., Methods: Discovery was performed in the Genetics-of-Early-Onset Stroke (GEOS) Study, a biracial population-based case-control study of ischemic stroke among men and women aged 15-49 including 829 cases of first ischemic stroke (42.2% African-American) and 850 age-comparable stroke-free controls (38.1% African-American). Twenty-four single-nucleotide-polymorphisms (SNPs) in THBD and 22 SNPs in PROCR were evaluated. Following LD pruning (r2≥0.8), we advanced uncorrelated SNPs forward for association analyses. Associated SNPs were evaluated for replication in an early-onset ischemic stroke population (onset-age<60 years) consisting of 3676 cases and 21118 non-stroke controls from 6 case-control studies. Lastly, we determined if the replicated SNPs also associated with older-onset ischemic stroke in the METASTROKE data-base., Results: Among GEOS Caucasians, PROCR rs9574, which was in strong LD with 8 other SNPs, and one additional independent SNP rs2069951, were significantly associated with ischemic stroke (rs9574, OR = 1.33, p = 0.003; rs2069951, OR = 1.80, p = 0.006) using an additive-model adjusting for age, gender and population-structure. Adjusting for risk factors did not change the associations; however, associations were strengthened among those without risk factors. PROCR rs9574 also associated with early-onset ischemic stroke in the replication sample (OR = 1.08, p = 0.015), but not older-onset stroke. There were no PROCR associations in African-Americans, nor were there any THBD associations in either ethnicity., Conclusion: PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians., Competing Interests: Drs. Cole, Mitchell, Kittner, Longstreth, and Worrall are supported by research grants from National Institutes of Health (NIH). Dr Cole is supported by a research grants from the American Heart Association and Bayer Pharmaceuticals. Dr. Worrall is Deputy Editor for AAN/Neurology. Dr. Boncoraglio is supported by a research grant from the Fondazione IRCCS Istituto Neurologico Carlo Besta. Dr. Metso is supported by grants from the Finnish Medical Foundation, the Orion Farmos Research Foundation, the Maud Kuistila Memorial Foundation, and the Emil Aaltonen Foundation. Dr. Danesh serves on advisory boards for Novartis, Merck Sharp & Dohme UK, Sanofi, the Medical Research Council, and Wellcome Trust and is a consultant for Takeda. These do not alter the authors adherence to PLOS ONE policies on sharing data and materials. The other authors report no disclosures.

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity., Summary: Background Factor VII-activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low-frequency missense variant Marburg-I (rs7080536) in the FSAP-encoding gene HABP2, determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome-wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. HABP2 was also significant in the gene-based analysis, and remained significant after exclusion of Marburg-I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. Results and Conclusions This study verified the Marburg-I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity., (© 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Background: Insulin-like growth factor I (IGF-I) has neuroprotective effects in experimental ischemic stroke (IS). However, in patients who have suffered IS, various associations between the levels of serum IGF-I (s-IGF-I) and clinical outcome have been reported, probably reflecting differences in sampling time-points and follow-up periods. Since changes in the levels of post-stroke s-IGF-I have not been extensively explored, we investigated whether decreases in the levels of s-IGF-I between the acute time-point (median, 4 days) and 3 months (ΔIGF-I, further transformed into ΔIGF-I-quintiles, ΔIGF-I-q) are associated with IS severity and outcome., Methods: In the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) conducted in Gothenburg, Sweden, patients with IS who had s-IGF-I measurements available were included (N = 354; 65% males; mean age, 55 years). Baseline stroke severity was evaluated using the National Institutes of Health Stroke Scale (NIHSS) and converted into NIHSS-quintiles (NIHSS-q). Outcomes were assessed using the modified Rankin Scale (mRS) at 3 months and 2 years., Results: In general, the levels of s-IGF-I decreased (positive ΔIGF-I), except for those patients with the most severe NIHSS-q. After correction for sex and age, the 3rd ΔIGF-I-q showed the strongest association to mRS 0-2 [Odds Ratio (OR) 5.11, 95% confidence interval (CI) 2.18-11.9], and after 2 years, the 5th ΔIGF-I-q (OR 3.63, 95% CI 1.40-9.38) showed the strongest association to mRS 0-2. The associations remained significant after multivariate correction for diabetes, smoking, hypertension, and hyperlipidemia after 3 months, but were not significant (p = 0.057) after 2 years. The 3-month associations withstood additional correction for baseline stroke severity (p = 0.035), whereas the 2-year associations were further attenuated (p = 0.31)., Conclusions: Changes in the levels of s-IGF-I are associated primarily with temporally near 3-month outcomes, while associations with long-term 2-year outcomes are weakened and attenuated by other factors. The significance of the change in post-stroke s-IGF-I is compatible with a positive role for IGF-I in IS recovery. However, the exact mechanisms are unknown and probably reflects combinations of multiple peripheral and central actions.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Background: Although stroke prevalence is increasing and large proportions of stroke survivors are expected to live many years after stroke onset, research on the long-term consequences of stroke for instrumental activities of daily living (IADL) is limited., Aim: To explore performance of IADL seven years post-stroke onset and identify predictors of long-term IADL performance based on commonly employed acute measures and demographic characteristics in young and middle-aged stroke survivors., Methods: Data on stroke survivors were collected from SAHLSIS. IADL performance was assessed at 7 years using the Frenchay Activities Index (FAI). Demographic data and baseline measures were assessed as predictors of FAI outcome, using logistic regression., Results: 237 stroke survivors with a median age of 63 at follow-up were included. Participants had predominantly suffered a mild stroke and >90% lived at home with no community services. Mean FAI was 25.7(score range 0-45), indicating reduced levels of participation in IADL. Frequency of performance of IADL was lowest for work/leisure activities. Gender, cohabitation status, initial stroke severity and baseline score on mRS were independently associated with IADL outcome., Conclusions: Reduced levels of participation in IADL persist many years after stroke onset and indicate a need to adapt a long-term perspective on stroke rehabilitation.

Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a central role in haemostasis, and plasma TAFI concentrations are heritable. Candidate gene studies have identified several variants within the gene encoding TAFI, CPB2 , that explain part of the estimated heritability. Here, we describe an exploratory genome-wide association study to identify novel variants within and outside of the CPB2 locus that influence plasma concentrations of intact TAFI and/or the extent of TAFI activation (measured by released TAFI activation peptide, TAFI-AP) amongst 3,260 subjects from Southern Sweden. We also explored the role of rare variants on the HumanExome BeadChip. We confirmed the association with previously reported common variants in CPB2 for both intact TAFI and TAFI-AP, and discovered novel associations with variants in putative CPB2 enhancers. We identified a gene-based association with intact TAFI at CPB2 ( P SKAT-O  = 2.8 × 10 -8 ), driven by two novel rare nonsynonymous single nucleotide polymorphisms (SNPs; I420N and D177G). Carriers of the rare variant of D177G (rs140446990; MAF 0.2%) had lower intact TAFI and TAFI-AP concentrations compared with non-carriers (intact TAFI, geometric mean 53 vs. 78%, P T-test   =  5 × 10 -7 ; TAFI-AP 63 vs. 99%, P T-test  = 7.2 × 10 -4 ). For TAFI-AP, we identified a genome-wide significant association at an intergenic region of chromosome 3p14.1 and five gene-based associations (all P SKAT-O  < 5 × 10 -6 ). Using well-characterized assays together with a genome-wide association study and a rare-variant approach, we verified CPB2 to be the primary determinant of TAFI concentrations and identified putative secondary loci (candidate variants and genes) associated with intact TAFI and TAFI-AP that require independent validation., Competing Interests: There are no direct or indirect conflicts of interest to declare., (Schattauer GmbH Stuttgart.)

Background: Cognitive impairment is frequent after stroke, and young patients may live with this consequence for a long time. Predictors of cognitive outcomes after stroke represent a current gap of knowledge., Objectives: To investigate levels of three hemostatic biomarkers as predictors of long-term cognitive function after stroke., Methods: This longitudinal study included consecutively recruited patients with ischemic stroke at 18-69 years (n = 268). Blood was collected 3 months after index stroke and analyzed for plasma concentrations of fibrinogen, von Willebrand factor (VWF) and tissue-type plasminogen activator (t-PA) antigen. Cognitive function 7 years after index stroke was assessed by the Barrow Neurological Institute Screen for Higher Cerebral Functions (BNIS). Participants with stroke <50 years of age were also examined by the Trail Making Test A and B (n = 41). Associations between biomarker concentrations and cognitive scales were assessed in the whole group and in participants with stroke <50 years of age., Results: The hemostatic biomarkers fibrinogen, VWF and t-PA, were all correlated to total BNIS score, but these associations did not withstand adjustment for confounding factors in the whole group. However, in patients <50 years, we found an independent association between fibrinogen concentrations and total BNIS score (β std  = -.27, 95% confidence interval [CI], -0.47 to -0.07) and to performance on the Trail Making Test A (β std  = .31, 95% CI, 0.03-0.58). No such association was seen for the Trail Making Test B., Conclusion: High convalescent fibrinogen concentrations were associated with worse long-term cognitive outcomes in ischemic stroke <50 years of age. We propose further investigations of fibrinogen in relation to cognitive function in stroke in the young.

Background and Purpose: Visuospatial inattention (VSI) and language impairment (LI) are often present early after stroke and associations with an unfavorable short-term functional outcome have been reported. The purpose of this study was to investigate whether a screening of VSI and LI as indicators of cortical symptoms early after stroke could predict long-term functional outcomes., Methods: A consecutive cohort of 375 patients with ischemic stroke was assessed for the occurrence of VSI at a median of 7 days after admission (interquartile range, 1-5 days) using the Star Cancellation Test and for LI (within the first 7 days) with the language item in the Scandinavian Stroke Scale. Seven years later, functional outcomes were assessed by the modified Rankin scale and Frenchay Activities Index in 235 survivors without recurrent stroke. Relationships between baseline predictors and functional outcome at 7 years were analyzed with bivariate correlations and multiple categorical regressions with optimal scaling., Results: The regression model significantly explained variance in the modified Rankin scale (R 2 = 0.435, P < 0.001) and identified VSI (P = 0.001) and neurological deficits (P < 0.001; Scandinavian Stroke Scale score without the language item) as the significant independent predictors. The model for Frenchay Activities Index was also significant (R 2 = 0.269, P < 0.001) with VSI (P = 0.035) and neurological deficits (P < 0.001) as significant independent predictors., Conclusions: Visuospatial inattention at acute stroke has an independent impact on long-term functional outcomes. Early recognition may enable targeted rehabilitative interventions., (© 2017 EAN.)