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1.	Ridker, PM, et al. (author) Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients 2017 In: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 376:16, s. 1527-1539 Journal article (peer-reviewed)
2.	Mishra, A., et al. (author) Stroke genetics informs drug discovery and risk prediction across ancestries 2022 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123 Journal article (peer-reviewed)abstract Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
3.	Franceschini, N., et al. (author) GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes 2018 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1 Journal article (peer-reviewed)abstract Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
4.	Pulit, S. L., et al. (author) Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes 2018 In: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6 Journal article (peer-reviewed)abstract Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
5.	Lind, Lars, et al. (author) Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes 2018 In: Neurology. Genetics. - : LIPPINCOTT WILLIAMS & WILKINS. - 2376-7839. ; 4:6, s. e293- Journal article (peer-reviewed)
6.	Marini, S., et al. (author) Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis 2019 In: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491 Journal article (peer-reviewed)abstract IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
7.	Malik, R, et al. (author) Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes 2018 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:4, s. 524- Journal article (peer-reviewed)
8.	Malik, R, et al. (author) Publisher Correction: Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes 2019 In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51:7, s. 1192-1193 Journal article (other academic/artistic)
9.	van de Munckhof, A., et al. (author) Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase 2022 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 53:10, s. 3206-3210 Journal article (peer-reviewed)abstract Background: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization. Methods: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization). Results: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed). Conclusions: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.
10.	Fischer, U., et al. (author) Early versus Later Anticoagulation for Stroke with Atrial Fibrillation 2023 In: New England Journal of Medicine. - 0028-4793. ; 388:26, s. 2411-2421 Journal article (peer-reviewed)abstract BackgroundThe effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear.MethodsWe performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days.ResultsOf 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days.ConclusionsIn this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, .)
11.	Jaworek, T., et al. (author) Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke 2022 In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16 Journal article (peer-reviewed)abstract Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
12.	Valdes-Marquez, E., et al. (author) Relative effects of LDL-C on ischemic stroke and coronary disease A Mendelian randomization study 2019 In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:11 Journal article (peer-reviewed)abstract Objective To examine the causal relevance of lifelong differences in low-density lipoprotein cholesterol (LDL-C) for ischemic stroke (IS) relative to that for coronary heart disease (CHD) using a Mendelian randomization approach. We undertook a 2-sample Mendelian randomization, based on summary data, to estimate the causal relevance of LDL-C for risk of IS and CHD. Information from 62 independent genetic variants with genome-wide significant effects on LDL-C levels was used to estimate the causal effects of LDL-C for IS and IS subtypes (based on 12,389 IS cases from METASTROKE) and for CHD (based on 60,801 cases from CARDIoGRAMplusC4D). We then assessed the effects of LDL-C on IS and CHD for heterogeneity. A 1 mmol/L higher genetically determined LDL-C was associated with a 50% higher risk of CHD (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.32-1.68, p = 1.1 x 10(-8)). By contrast, the causal effect of LDL-C was much weaker for IS (OR 1.12, 95% CI 0.96-1.30, p = 0.14; p for heterogeneity = 2.6 x 10(-3)) and, in particular, for cardioembolic stroke (OR 1.06, 95% CI 0.84-1.33, p = 0.64; p for heterogeneity = 8.6 x 10(-3)) when compared with that for CHD. In contrast with the consistent effects of LDL-C-lowering therapies on IS and CHD, genetic variants that confer lifelong LDL-C differences show a weaker effect on IS than on CHD. The relevance of etiologically distinct IS subtypes may contribute to the differences observed.
13.	Bakker, M. K., et al. (author) Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors 2020 In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:12, s. 1303-1313 Journal article (peer-reviewed)abstract Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits. Cross-ancestry genome-wide association analyses in individuals of European and East Asian ancestry identify 11 new risk loci for intracranial aneurysms and highlight a polygenic architecture explaining a substantial fraction of disease heritability.
14.	Bonkhoff, A. K., et al. (author) Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome 2022 In: NEUROLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:13 Journal article (peer-reviewed)abstract Background and Objectives To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. Methods MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs lowWMHburden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. Results A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific WMH effects on stroke severity, higher WMH burden increased the odds of unfavorable outcomes independent of lesion location. Discussion Higher WMH burden may be associated with an increased stroke severity in case of stroke lesions involving left-hemispheric insular, opercular, and inferior frontal regions (potentially linked to language functions) and right-hemispheric temporoparietal regions (potentially linked to attention). Our findings suggest that patients with specific constellations of WMH burden and lesion locations may have greater benefits from acute recanalization treatments. Future clinical studies are warranted to systematically assess this assumption and guide more tailored treatment decisions.
15.	Bonkhoff, A. K., et al. (author) Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics 2022 In: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-453X .- 1662-4548. ; 16 Journal article (peer-reviewed)abstract Background purposeA substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methodsAnalyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. ResultsWe analyzed 2,466 patients (age = 63.4 +/- 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio similar to 1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p(FDR) < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p(FDR) = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. ConclusionMultiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only.
16.	Compter, A., et al. (author) Determinants and outcome of multiple and early recurrent cervical artery dissections 2018 In: Neurology. ; 91:8 Journal article (peer-reviewed)abstract Objective To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD). Methods We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed. Results Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29–2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34–2.46), family history of stroke (OR 1.55, 95% CI 1.06–2.25), cervical pain (OR 1.36, 95% CI 1.01–1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01–8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49–5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD. Conclusion Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.
17.	Grond-Ginsbach, C., et al. (author) Genetic Imbalance in Patients with Cervical Artery Dissection 2017 In: Current Genomics. - : Bentham Science Publishers Ltd.. - 1389-2029. ; 18:2, s. 206-213 Journal article (peer-reviewed)abstract Background: Genetic and environmental risk factors are assumed to contribute to the susceptibility to cervical artery dissection (CeAD). To explore the role of genetic imbalance in the etiology of CeAD, copy number variants (CNVs) were identified in high-density microarrays samples from the multicenter CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study and from control subjects from the CADISP study and the German PopGen biobank. Microarray data from 833 CeAD patients and 2040 control subjects (565 subjects with ischemic stroke due to causes different from CeAD and 1475 disease-free individuals) were analyzed. Rare genic CNVs were equally frequent in CeAD-patients (16.4%; n=137) and in control subjects (17.0%; n=346) but differed with respect to their genetic content. Compared to control subjects, CNVs from CeAD patients were enriched for genes associated with muscle organ development and cell differentiation, which suggests a possible association with arterial development. CNVs affecting cardiovascular system development were more common in CeAD patients than in control subjects (p=0.003; odds ratio (OR) =2.5; 95% confidence interval (95% CI) = 1.4-4.5) and more common in patients with a familial history of CeAD than in those with sporadic CeAD (p=0.036; OR=11.2; 95% CI=1.2-107). Conclusion: The findings suggest that rare genetic imbalance affecting cardiovascular system development may contribute to the risk of CeAD. Validation of these findings in independent study populations is warranted.
18.	Ibanez, L., et al. (author) Multi-ancestry GWAS reveals excitotoxicity associated with outcome after ischaemic stroke 2022 In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2394-2406 Journal article (peer-reviewed)abstract During the first hours after stroke onset, neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between the National Institutes of Health Stroke Scale (NIHSS) within 6 h of stroke onset and NIHSS at 24 h. A total of 5876 individuals from seven countries (Spain, Finland, Poland, USA, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of NIHSS at 24 h of variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture from that of stroke risk. Eight loci (1p21.1, 1q42.2, 2p25.1, 2q31.2, 2q33.3, 5q33.2, 7p21.2 and 13q31.1) were genome-wide significant and explained 1.8% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each locus. Expression quantitative trait loci mapping and summary data-based Mendelian randomization indicate that ADAM23 (log Bayes factor = 5.41) was driving the association for 2q33.3. Gene-based analyses suggested that GRIA1 (log Bayes factor = 5.19), which is predominantly expressed in the brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated GNPAT (log Bayes factor = 7.64) ABCB5 (log Bayes factor = 5.97) for the 1p21.1 and 7p21.1 loci. Human brain single-nuclei RNA-sequencing indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a presynaptic protein and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provide the first genetic evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischaemic stroke. Ibanez et al. perform a multi-ancestry meta-analysis to investigate the genetic architecture of early stroke outcomes. Two of the eight genome-wide significant loci identified-ADAM23 and GRIA1-are involved in synaptic excitability, suggesting that excitotoxicity contributes to neurological instability after ischaemic stroke.
19.	Kloss, M., et al. (author) Recurrent versus first cervical artery dissection - a retrospective study of clinical and vascular characteristics 2020 In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 27:11, s. 2185-2190 Journal article (peer-reviewed)abstract Background and purpose Most recurrent cervical artery dissection (CeAD) events occur shortly after the acute first CeAD. This study compared the characteristics of recurrent and first CeAD events and searched for associations between subsequent events of an individual person. Methods Cervical artery dissection patients with a new CeAD event occurring during a 3-6 month follow-up were retrospectively selected in seven specialized stroke centers. Clinical and vascular characteristics of the initial and the recurrent CeADs were compared. Results The study sample included 76 patients. Recurrent CeADs were occlusive in one (1.3%) patient, caused cerebral ischaemia in 13 (17.1%) and were asymptomatic in 39 (51.3%) patients, compared to 29 (38.2%) occlusive, 42 (55.3%) ischaemic and no asymptomatic first CeAD events. In 52 (68.4%) patients, recurrent dissections affected both internal carotid arteries or both vertebral arteries, whilst 24 (31.6%) patients had subsequent dissections in both types of artery. Twelve (28.6%) of 42 patients with an ischaemic first dissection had ischaemic symptoms due to the recurrent CeADs, too. However, only one (1.3%) of 34 patients with a non-ischaemic first CeAD suffered ischaemia upon recurrence. Conclusion Recurrent CeAD typically affects the same site of artery. It causes ischaemic events less often than the first CeAD. The risk that patients who presented with solely non-ischaemic symptoms of a first CeAD will have ischaemic symptoms in the case of a recurrent CeAD seems very small.
20.	Pfeiffer, D., et al. (author) Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke 2019 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 50:2, s. 298-304 Journal article (peer-reviewed)abstract 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.
21.	Pulit, SL, et al. (author) Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. 2016 In: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84 Journal article (peer-reviewed)abstract The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
22.	Seiffge, D. J., et al. (author) Recanalization Therapies in Acute Ischemic Stroke Patients Impact of Prior Treatment With Novel Oral Anticoagulants on Bleeding Complications and Outcome A Pilot Study 2015 In: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 132:13, s. 1261-1269 Journal article (peer-reviewed)abstract Background-We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake <48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). Methods and Results-This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICH any), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICH ECASS-II) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICH NINDS); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8-22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1-1.6). ICH any was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICH ECASS-II and sICH NINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions-IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.
23.	Valdes-Marquez, E, et al. (author) Relative effects of LDL-C on ischemic stroke and coronary disease: A Mendelian randomization study 2019 In: Neurology. - 1526-632X. ; 92:11, s. E1176-E1187 Journal article (peer-reviewed)
24.	Altavilla, R., et al. (author) Anticoagulation After Stroke in Patients With Atrial Fibrillation: To Bridge or Not With Low-Molecular-Weight Heparin? 2019 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 50:8, s. 2093-2100 Journal article (peer-reviewed)abstract Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.
25.	Carrera, C., et al. (author) Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma 2021 In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 2416-2426 Journal article (peer-reviewed)abstract Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.
26.	Claesson, T, et al. (author) The impact of type 1 diabetes on brain volumes in neurologically asymptomatic adults 2021 In: DIABETOLOGIA. - 0012-186X. ; 64:SUPPL 1, s. 337-338 Conference paper (other academic/artistic)
27.	Cole, John W, et al. (author) Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke. 2018 In: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11 Journal article (peer-reviewed)abstract 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.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.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.PROCR polymorphisms are associated with early-onset ischemic stroke in Caucasians.
28.	Engelter, S. T., et al. (author) Cervical Artery Dissection and Sports 2021 In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12 Journal article (peer-reviewed)abstract Cervical artery dissection (CeAD) occurring in the context of sports is a matter of concern for CeAD patients. They seek advice on the role of sports in CeAD and on the safety of resuming sports after CeAD. The scarcity of studies and guidelines addressing these issues poses a challenge. We aimed at summarizing the current knowledge about CeAD and sports in order to provide an informed, comprehensive opinion for counseling CeAD patients. We took into account pathophysiological considerations, observations of cases reports, series, and registries, and conclusions by analogy from aortic dissection or inherited connective tissue syndromes. In summary, practicing active sports as the cause of CeAD seems uncommon. It seems recommendable to refrain from any kind of sports activities for at least 1 month, which can be extended in case of an unfavorable clinical or neurovascular course. We recommend starting with sport activities at low intensity-preferably with types of endurance sports-and to gradually increase the pace in an individually tailored manner, taking into circumstances of the occurrences of the CeAD in the individual patient (particularly in relation to sports), the meaning of sports activities for the individual well-being, the presence or absence of comorbidities and of neurological sequela, neurovascular findings, and whether there are signs of an underlying connective tissue alteration. Major limitations and several forms of bias are acknowledged. Still, in the absence of any better data, the summarized observations and considerations might help clinicians in advising and counseling patients with CeAD in clinical practice.
29.	Filioglo, A, et al. (author) Outcomes after reperfusion therapies in patients with ACA stroke: A multicenter cohort study from the EVATRISP collaboration. 2022 In: Journal of the neurological sciences. - : Elsevier BV. - 1878-5883 .- 0022-510X. ; 432 Journal article (peer-reviewed)abstract Patients with stroke secondary to occlusions of the anterior cerebral artery (ACA) often have poor outcomes. The optimal acute therapeutic intervention for these patients remains unknown.Patients with isolated ACA-stroke were identified from 10 centers participating in the EndoVascular treatment And ThRombolysis in Ischemic Stroke Patients (EVATRISP) prospective registry. Patients treated with endovascular thrombectomy (EVT) were compared to those treated with intravenous thrombolysis (IVT). Odds ratios with 95% confidence intervals (OR; 95%CI) were calculated using multivariate regression analysis.Included were 92 patients with ACA-stroke. Of the 92 ACA patients, 55 (60%) were treated with IVT only and 37 (40%) with EVT (±bridging IVT). ACA patients treated with EVT had more often wake-up stroke (24% vs. 6%, p=0.044) and proximal ACA occlusions (43% vs. 24%, p=0.047) and tended to have higher stroke severity on admission [NIHSS: 10.0 vs 7.0, p=0.054). However, odds for favorable outcome, mortality or symptomatic intracranial hemorrhage did not differ significantly between both groups. Exploration of the effect of clot location inside the ACA showed that in patients with A1 or A2/A3 ACA occlusions the chances of favorable outcome were not influenced by treatment allocation to IVT or EVT.Treatment with either IVT or EVT could be safe with similar effect in patients with ACA-strokes and these effects may be independent of clot location within the occluded ACA.
30.	Gensicke, H., et al. (author) Intravenous thrombolysis and platelet count 2018 In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 90:8 Journal article (peer-reviewed)abstract ObjectiveTo study the effect of platelet count (PC) on bleeding risk and outcome in stroke patients treated with IV thrombolysis (IVT) and to explore whether withholding IVT in PC < 100 x 10(9)/L is supported.MethodsIn this prospective multicenter, IVT register-based study, we compared PC with symptomatic intracranial hemorrhage (sICH; Second European-Australasian Acute Stroke Study [ECASS II] criteria), poor outcome (modified Rankin Scale score 3-6), and mortality at 3 months. PC was used as a continuous and categorical variable distinguishing thrombocytopenia (<150 x 10(9)/L), thrombocytosis (>450 x 10(9)/L), and normal PC (150-450 x 10(9)/L [reference group]). Moreover, PC < 100 x 10(9)/L was compared to PC 100 x 10(9)/L. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) from the logistic regression models were calculated.ResultsAmong 7,533 IVT-treated stroke patients, 6,830 (90.7%) had normal PC, 595 (7.9%) had thrombocytopenia, and 108 (1.4%) had thrombocytosis. Decreasing PC (every 10 x 10(9)/L) was associated with increasing risk of sICH (ORadjusted 1.03, 95% CI 1.02-1.05) but decreasing risk of poor outcome (ORadjusted 0.99, 95% CI 0.98-0.99) and mortality (ORadjusted 0.98, 95% CI 0.98-0.99). The risk of sICH was higher in patients with thrombocytopenic than in patients with normal PC (ORadjusted 1.73, 95% CI 1.24-2.43). However, the risk of poor outcome (ORadjusted 0.89, 95% CI 0.39-1.97) and mortality (ORadjusted 1.09, 95% CI 0.83-1.44) did not differ significantly. Thrombocytosis was associated with mortality (ORadjusted 2.02, 95% CI 1.21-3.37). Forty-four (0.3%) patients had PC < 100 x 10(9)/L. Their risks of sICH (ORunadjusted 1.56, 95% CI 0.48-5.07), poor outcome (ORadjusted 1.63, 95% CI 0.82-3.24), and mortality (ORadjusted 1.38, 95% CI 0.64-2.98) did not differ significantly from those of patients with PC 100 x 10(9)/L.ConclusionLower PC was associated with increased risk of sICH, while higher PC indicated increased mortality. Our data suggest that PC modifies outcome and complications in individual patients, while withholding IVT in all patients with PC < 100 x 10(9)/L is challenged.
31.	Giustozzi, M., et al. (author) Safety of Anticoagulation in Patients Treated with Urgent Reperfusion for Ischemic Stroke Related to Atrial Fibrillation 2020 In: Stroke. - 0039-2499. ; 51:8, s. 2347-2354 Journal article (peer-reviewed)abstract Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02]). Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant. © 2020 Georg Thieme Verlag. All rights reserved.
32.	Heitsch, L., et al. (author) Early Neurological Change After Ischemic Stroke Is Associated With 90-Day Outcome 2021 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 52:1, s. 132-141 Journal article (peer-reviewed)abstract Background and Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSSbaseline - NIHSS24hours = Delta NIHSS6-24h), to examine its relevance to AIS mechanisms and long-term outcomes. Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced Delta NIHSS6-24h. In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on Delta NIHSS6-24h was examined. Finally, the association of Delta NIHSS6-24h with 90-day favorable outcomes (modified Rankin Scale score 0-2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4-16), and median Delta NIHSS6-24h was 2 (interquartile range, 0-5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted Delta NIHSS6-24h (R-2=0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R-2=0.27), but much of the variance remained unexplained. Delta NIHSS6-24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, Delta NIHSS3-24h was similarly associated with 90-day outcomes. Conclusions: The dynamic phenotype, Delta NIHSS6-24h, captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, Delta NIHSS6-24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.
33.	Hong, S. M., et al. (author) Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke 2021 In: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 12 Journal article (peer-reviewed)abstract 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 (beta = 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.
34.	Kahles, T., et al. (author) Repeated Intravenous Thrombolysis for Early Recurrent Stroke Challenging the Exclusion Criterion 2016 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 47:8, s. 2133-2135 Journal article (peer-reviewed)abstract Background and Purpose-Intravenous thrombolysis (IVT) within 4.5 hours from symptom onset improves functional outcome in patients with acute ischemic stroke. Its use in patients with previous stroke within the preceding 3 months is contraindicated because of the assumed higher risk of intracranial hemorrhage. In addition, tissue-type plasminogen activator may itself promote neurotoxicity and blood-brain barrier disruption. However, safety and effectiveness of repeated IVT is essentially unknown in patients with early (<3 months) recurrent stroke (ERS), because they were excluded from thrombolysis trials. This article reports the largest case series of repeated IVT in ERS. Methods-We reviewed databases of prospectively collected patient data of 8 European stroke centers for the presence of patients with ERS, who received IVT for both the index stroke and ERS. Demographics, clinical and radiological data, bleeding complications, and functional outcome were analyzed. Results-We identified 19 subjects with repeated IVT in ERS. Mean age was 68 +/- 12 years, and 37% of them were female. Median interthrombolysis interval was 30 days (interquartile range, 13-50). Functional independence (modified Rankin scale score <= 2) was achieved in 79% of patients after the first and in 47.4% after repeated IV tissue-type plasminogen activator, respectively. There was no symptomatic intracranial hemorrhage. Median final infarct volume after the first IVT was 1.5 cm(3) (interquartile range, 0.5-3.1). Conclusions-Patients with small infarct volumes and robust clinical improvement might be considered for repeated IVT within 3 months. Studies following strict protocols and larger registries incorporating these patients might serve to identify selection criteria for the safe use of repeated IVT in ERS.
35.	Kellert, L., et al. (author) Prognostic significance of pulsatile tinnitus in cervical artery dissection 2016 In: European Journal of Neurology. - : Wiley. - 1351-5101. ; 23:7, s. 1183-1187 Journal article (peer-reviewed)abstract Background and purposeOur aim was to investigate whether pulsatile tinnitus (PT) in cervical artery dissection (CeAD) has prognostic significance. MethodsAll CeAD patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) study with documentation of PT were analysed. The presence of PT was systematically assessed using a standardized questionnaire. Stroke severity at admission was defined according to the National Institutes of Health Stroke Scale (NIHSS). Excellent outcome after 3 months was defined as a modified Rankin Scale of 0-1. ResultsSixty-three of 778 patients (8.1%) reported PT. PT+ patients presented less often with ischaemic stroke (41.3% vs. 63.9%, P < 0.001), more often with dissection in the internal carotid artery (85.7% vs. 64.2%, P = 0.001), less often with vessel occlusion (19.0% vs. 34.1%, P = 0.017) and more often with excellent outcome at 3 months (92.1% vs. 75.4%, P = 0.002). Logistic regression analysis identified PT as an independent predictor of excellent outcome after 3 months [odds ratio (OR) 3.96, 95% confidence interval (CI) 1.22-12.87] adjusted to significant outcome predictors NIHSS on admission (OR 0.82, 95% CI 0.79-0.86), Horner syndrome (OR 1.95, 95% CI 1.16-3.29) and vessel occlusion (OR 0.62, 95% CI 0.40-0.94) and to non-significant predictors age, sex, pain and location of CeAD. ConclusionThe presence of PT in CeAD is associated with a benign clinical course and predicts a favourable outcome.
36.	Kellert, L., et al. (author) University education and cervical artery dissection 2018 In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 265:5, s. 1065-1070 Journal article (peer-reviewed)abstract We investigated whether university education is more likely in cervical artery dissection (CeAD)-patients than in age- and sex-matched patients with ischemic stroke (IS) due to other causes (non-CeAD-IS-patients). Patients from the Cervical Artery Dissection and Ischemic Stroke Patients study with documented self-reported profession before onset of IS due to CeAD (n = 715) or non-CeAD causes (n = 631) were analyzed. In the reported profession, the absence or presence of university education was assessed. Professions could be rated as academic or non-academic in 518 CeAD and 456 non-CeAD patients. Clinical outcome at 3 months was defined as excellent if modified Rankin Scale was 0-1. University education was more frequent in CeAD-patients (100 of 518, 19.3%) than in non-CeAD-IS-patients (61 of 456, 13.4%, p = 0.008). CeAD-patients with and without university education differed significantly with regard to smoking (39 vs. 57%, p = 0.001) and excellent outcome (80 vs. 66%, p = 0.004). In logistic regression analysis, university education was associated with excellent outcome in CeAD-patients (OR 2.44, 95% CI 1.37-5.38) independent of other outcome predictors such as age (OR 0.97, 95% CI 0.84-0.99), NIHSS (OR 0.80, 95% CI 0.76-0.84) and local signs (OR 2.77, 95% CI 1.37-5.57). We observed a higher rate of university education in patients with CeAD compared with non-CeAD patients in our study population. University education was associated with favorable outcome in CeAD-patients. The mechanism behind this association remains unclear.
37.	Ken-Dror, G., et al. (author) Genome-Wide Association Study Identifies First Locus Associated with Susceptibility to Cerebral Venous Thrombosis 2021 In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 90:5, s. 777-788 Journal article (peer-reviewed)abstract 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 x 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 x 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 x 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
38.	Laari, S. P. K., et al. (author) Executive Dysfunction Related to Binge Drinking in Ischemic Stroke 2020 In: Cognitive and Behavioral Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1543-3633. ; 33:1, s. 23-32 Journal article (peer-reviewed)abstract Background: Recent evidence has shown that cognitive dysfunction is associated with a history of binge drinking in adolescents who do not have an alcohol use disorder. Most previous studies with adults, however, have failed to show a link between cognitive dysfunction and subdiagnostic binge drinking, nor have any studies investigated the additive cognitive effect of binge drinking to ischemic stroke. Objective: To examine whether a pattern of cognitive dysfunction, especially executive and memory dysfunction, in patients with a first-ever ischemic stroke is associated with a history of subdiagnostic binge drinking. Methods: We studied 206 first-ever ischemic stroke patients (18-65 years) and 50 healthy, demographically comparable adults-both groups with no alcohol use disorder. After exclusion by matching, 189 patients and 39 healthy participants were included in our study (228 participants). The binge-drinking group included 76 participants; the non-binge-drinking group included 152. A multivariate analysis of covariance was used to compare nine cognitive functions between the two groups, with age, education, and stroke severity used as covariates. Results: Binge drinking had a significant negative effect on executive functions (P<0.001). The non-binge-drinking group outperformed the binge-drinking group on the Stroop Test (P=0.001), Trail Making Test (P=0.002), and a phonemic fluency test (P=0.005). The BingexStroke Severity interaction (P=0.037) indicated that a history of binge drinking increased the negative effect of stroke on executive functions. Conclusions: Subdiagnostic binge drinking may exacerbate the adverse effects of ischemic stroke on executive dysfunction.
39.	Le Grand, Q., et al. (author) Genetic Insights on the Relation of Vascular Risk Factors and Cervical Artery Dissection 2023 In: Journal of the American College of Cardiology. - 0735-1097. ; 82:14, s. 1411-1423 Journal article (peer-reviewed)abstract BACKGROUND The association between vascular risk factors and cervical artery dissections (CeADs), a leading cause of ischemic stroke (IS) in the young, remains controversial. OBJECTIVES This study aimed to explore the causal relation of vascular risk factors with CeAD risk and recurrence and compare it to their relation with non-CeAD IS. METHODS This study used 2-sample Mendelian randomization analyses to explore the association of blood pressure (BP), lipid levels, type 2 diabetes, waist-to-hip ratio, smoking, and body mass index with CeAD and non-CeAD IS. To simulate effects of the most frequently used BP-lowering drugs, this study constructed genetic proxies and tested their association with CeAD and non-CeAD IS. In analyses among patients with CeAD, the investigators studied the association between weighted genetic risk scores of vascular risk factors and the risk of multiple or early recurrent dissections. RESULTS Genetically determined higher systolic BP (OR: 1.51; 95% CI: 1.32-1.72) and diastolic BP (OR: 2.40; 95% CI: 1.92-3.00) increased the risk of CeAD (P < 0.0001). Genetically determined higher body mass index was inconsistently associated with a lower risk of CeAD. Genetic proxies for f3-blocker effects were associated with a lower risk of CeAD (OR: 0.65; 95% CI: 0.50-0.85), whereas calcium-channel blockers were associated with a lower risk of non-CeAD IS (OR: 0.75; 95% CI: 0.63-0.90). Weighted genetic risk scores for systolic BP and diastolic BP were associated with an increased risk of multiple or early recurrent CeAD. CONCLUSIONS These results are supportive of a causal association between higher BP and increased CeAD risk and recurrence and provide genetic evidence for lower CeAD risk under f3-blockers. This may inform secondary prevention strategies and trial design for CeAD. (J Am Coll Cardiol 2023;82:1411-1423) <(c)> 2023 by the American College of Cardiology Foundation.
40.	Lindgren, Erik, 1993, et al. (author) Dural arteriovenous fistulas in cerebral venous thrombosis Data from the International Cerebral Venous Thrombosis Consortium 2022 In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:3, s. 761-770 Journal article (peer-reviewed)abstract Background and purpose To explore the prevalence, risk factors, time correlation, characteristics and clinical outcome of dural arteriovenous fistulas (dAVFs) in a cerebral venous thrombosis (CVT) population. Methods We included patients from the International CVT Consortium registries. Diagnosis of dAVF was confirmed centrally. We assessed the prevalence and risk factors for dAVF among consecutive CVT patients and investigated its impact on clinical outcome using logistic regression analysis. We defined poor outcome as modified Rankin Scale score 3-6 at last follow-up. Results dAVF was confirmed in 29/1218 (2.4%) consecutive CVT patients. The median (interquartile range [IQR]) follow-up time was 8 (5-23) months. Patients with dAVF were older (median [IQR] 53 [44-61] vs. 41 [29-53] years; p < 0.001), more frequently male (69% vs. 33%; p < 0.001), more often had chronic clinical CVT onset (>30 days: 39% vs. 7%; p < 0.001) and sigmoid sinus thrombosis (86% vs. 51%; p < 0.001), and less frequently had parenchymal lesions (31% vs. 55%; p = 0.013) at baseline imaging. Clinical outcome at last follow-up did not differ between patients with and without dAVF. Additionally, five patients were confirmed with dAVF from non-consecutive CVT cohorts. Among all patients with CVT and dAVF, 17/34 (50%) had multiple fistulas and 23/34 (68%) had cortical venous drainage. Of 34 patients with dAVF with 36 separate CVT events, 3/36 fistulas (8%) were diagnosed prior to, 20/36 (56%) simultaneously and 13/36 after (36%, median 115 [IQR 38-337] days) diagnosis of CVT. Conclusions Dural arteriovenous fistulas occur in at least 2% of CVT patients and are associated with chronic CVT onset, older age and male sex. Most CVT-related dAVFs are detected simultaneously or subsequently to diagnosis of CVT.
41.	Malmivaara, A, et al. (author) Comparing ischaemic stroke in six European countries. The EuroHOPE register study 2015 In: European journal of neurology. - : Wiley. - 1468-1331 .- 1351-5101. ; 22:2, s. 284- Journal article (peer-reviewed)
42.	Martinez-Majander, N., et al. (author) Embolic strokes of undetermined source in young adults: baseline characteristics and long-term outcome 2018 In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 25:3, s. 535-541 Journal article (peer-reviewed)abstract Background and purposeEmbolic strokes of undetermined source (ESUS) are a recent entity, not yet thoroughly investigated in young stroke patients. The clinical characteristics and long-term risks of vascular events and all-cause mortality between young-onset ESUS and other aetiological subgroups were compared. MethodsPatients with ESUS were identified amongst the 1008 patients aged 15-49 years with first-ever ischaemic stroke in Helsinki Young Stroke Registry, and primary end-points were defined as recurrent stroke, composite vascular events and all-cause mortality. Cumulative 15-year risks for each end-point were analysed with life tables and adjusted risks were based on Cox proportional hazard analyses. ResultsOf the 971 eligible patients, 203 (20.9%) were classified as ESUS. They were younger (median age 40 years, interquartile range 32-46 vs. 45 years, 39-47), more often female (43.3% vs. 35.7%) and had fewer cardiovascular risk factors than other modified TOAST groups. With a median follow-up time of 10.1 years, ESUS patients had the second lowest cumulative risk of recurrent stroke and composite vascular events and lowest mortality compared to other TOAST groups. Large-artery atherosclerosis and small vessel disease carried significantly higher risk for recurrent stroke than did ESUS, whilst no difference appeared between cardioembolism from high-risk sources and ESUS. ConclusionsIn our cohort, ESUS patients were younger and had milder cardiovascular risk factor burden and generally better long-term outcome compared to other causes of young-onset stroke. The comparable risk of recurrent stroke between ESUS and high-risk sources of cardioembolism might suggest similarities in their pathophysiology.
43.	Martinez-Majander, N., et al. (author) Endothelial Dysfunction is Associated With Early-Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age 2021 In: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 10:14 Journal article (peer-reviewed)abstract Background The aim of this study was to assess the association between endothelial function and early-onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age- and sex-matched (+/- 5 years) stroke-free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high-density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke-free controls. In sex- and age-specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22-10.07) and in patients >= 41 years (OR, 5.78; 95% CI, 1.52-21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high-density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early-onset CIS in men and patients approaching middle age.
44.	Martinez-Majander, N., et al. (author) Markers of early vascular aging are not associated with cryptogenic ischemic stroke in the young: A case-control study 2022 In: Journal of Stroke and Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057. ; 31:9 Journal article (peer-reviewed)abstract Background and Purpose: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study. Methods: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS. Results: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women). Conclusions: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS. © 2022 The Author(s)
45.	Muino, E., et al. (author) RP11-362K2.2:RP11-767I20.1 Genetic Variation Is Associated with Post-Reperfusion Therapy Parenchymal Hematoma. A GWAS Meta-Analysis 2021 In: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 10:14 Journal article (peer-reviewed)abstract Stroke is one of the most common causes of death and disability. Reperfusion therapies are the only treatment available during the acute phase of stroke. Due to recent clinical trials, these therapies may increase their frequency of use by extending the time-window administration, which may lead to an increase in complications such as hemorrhagic transformation, with parenchymal hematoma (PH) being the more severe subtype, associated with higher mortality and disability rates. Our aim was to find genetic risk factors associated with PH, as that could provide molecular targets/pathways for their prevention/treatment and study its genetic correlations to find traits sharing genetic background. We performed a GWAS and meta-analysis, following standard quality controls and association analysis (fastGWAS), adjusting age, NIHSS, and principal components. FUMA was used to annotate, prioritize, visualize, and interpret the meta-analysis results. The total number of patients in the meta-analysis was 2034 (216 cases and 1818 controls). We found rs79770152 having a genome-wide significant association (beta 0.09, p-value 3.90 x 10(-8)) located in the RP11-362K2.2:RP11-767I20.1 gene and a suggestive variant (rs13297983: beta 0.07, p-value 6.10 x 10(-8)) located in PCSK5 associated with PH occurrence. The genetic correlation showed a shared genetic background of PH with Alzheimer's disease and white matter hyperintensities. In addition, genes containing the ten most significant associations have been related to aggregated amyloid-beta, tau protein, white matter microstructure, inflammation, and matrix metalloproteinases.
46.	Paciaroni, M., et al. (author) Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin-K Oral Anticoagulants (RAF-NOACs) Study 2017 In: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 6:12 Journal article (peer-reviewed)abstract Background-The optimal timing to administer non-vitamin K oral anticoagulants (NOACs) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and theirtiming in patients with acute ischemic stroke and atrial fibrillation who received NOACs for secondary prevention. Methods and Results-Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA(2)DS(2)-VASc score >4 and less reduced renal function. Thirty-two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOACs within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated > 14 days after acute stroke. Conclusions-In patients with acute ischemic stroke and atrial fibrillation, treatment with NOACs was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.
47.	Paciaroni, M., et al. (author) Hemorrhagic transformation in patients with acute ischemic stroke and atrial fibrillation: Time to initiation of oral anticoagulant therapy and outcomes 2018 In: Journal of the American Heart Association. - 2047-9980. ; 7:22 Journal article (peer-reviewed)abstract Background—In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation (HT). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT, (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results—HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT. Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT; 53.1% of patients with HT were deceased or disabled compared with 35.8% of those without HT. On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions—In patients with HT, anticoagulation was initiated about 12 days later than patients without HT. This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability. © 2018 The Authors.
48.	Paciaroni, M., et al. (author) Prediction of Early Recurrent Thromboembolic Event and Major Bleeding in Patients With Acute Stroke and Atrial Fibrillation by a Risk Stratification Schema The ALESSA Score Study 2017 In: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 48:3, s. 726-732 Journal article (peer-reviewed)abstract Background and Purposes-This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods-The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00-1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08-2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30-1.00). We assigned to age 80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632-0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493-0.678; P=0.10) for major bleedings. Results-The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529-0.763; P=0.009) for ischemic outcome events and 0.407 (0.275-0.540; P=0.14) for hemorrhagic outcome events. Conclusions-In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings.
49.	Paciaroni, M., et al. (author) Timing of initiation of oral anticoagulants in patients with acute ischemic stroke and atrial fibrillation comparing posterior and anterior circulation strokes 2020 In: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. Journal article (peer-reviewed)abstract Introduction: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. Materials and Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80). Discussion: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. Conclusions: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.
50.	Scutelnic, A., et al. (author) Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19 2023 In: European Stroke Journal. - 2396-9873. ; 8:4, s. 1001-1010 Journal article (peer-reviewed)abstract Introduction: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. Patients and methods: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. Results: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28-54) vs 45 (28-56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x10(9)/L (28-79) vs 68 (30-125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19-62) vs 53 (20-92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. Discussion and conclusions: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.

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