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3.
  • Thijs, Vincent, et al. (författare)
  • Family History in Young Patients With Stroke.
  • 2015
  • Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 46:7, s. 1975-1978
  • Tidskriftsartikel (refereegranskat)abstract
    • Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke.
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4.
  • Williams, Frances M. K., et al. (författare)
  • Ischemic stroke is associated with the ABO locus : the EuroCLOT study
  • 2013
  • Ingår i: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 73:1, s. 16-31
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Methods: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Results: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 x 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 x 10(-186)), rs10665 with FVII (p = 2.4 x 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 x 10(-57)) and factor VIII (p = 1.2 x 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). Interpretation: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.
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5.
  • Bellenguez, Celine, et al. (författare)
  • Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
  • 2012
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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6.
  • Malik, Rainer, et al. (författare)
  • Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration
  • 2016
  • Ingår i: Neurology. - 1526-632X. ; 86:13, s. 26-1217
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
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7.
  • McCabe, John J., et al. (författare)
  • C-Reactive Protein, Interleukin-6, and Vascular Recurrence According to Stroke Subtype
  • 2024
  • Ingår i: Neurology. - 1526-632X. ; 102:2
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND OBJECTIVES: Anti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention. METHODS: Using individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by stroke mechanism, per quarter and per biomarker unit increase after loge transformation. We then did study-level meta-analysis with comparable published studies not providing IPD. Preferred Reporting Items for Systematic Review and Meta-Analyses IPD guidelines were followed. RESULTS: IPD was obtained from 10 studies (8,420 patients). After adjustment for vascular risk factors and statins/antithrombotic therapy, IL-6 was associated with recurrent MACE in stroke caused by large artery atherosclerosis (LAA) (risk ratio [RR] 2.30, 95% CI 1.21-4.36, p = 0.01), stroke of undetermined cause (UND) (RR 1.78, 1.19-2.66, p = 0.005), and small vessel occlusion (SVO) (RR 1.71, 0.99-2.96, p = 0.053) (quarter 4 [Q4] vs quarter 1 [Q1]). No association was observed for stroke due to cardioembolism or other determined cause. Similar results were seen for recurrent stroke and when analyzed per loge unit increase for MACE (LAA, RR 1.26 [1.06-1.50], p = 0.009; SVO, RR 1.22 [1.01-1.47], p = 0.04; UND, RR 1.18 [1.04-1.34], p = 0.01). High-sensitivity CRP was associated with recurrent MACE in UND stroke only (Q4 vs Q1 RR 1.45 [1.04-2.03], p = 0.03). Findings were consistent on study-level meta-analysis of the IPD results with 2 other comparable studies (20,136 patients). DISCUSSION: Our data provide new evidence for the selection of patients in future RCTs of anti-inflammatory therapy in stroke due to large artery atherosclerosis, small vessel occlusion, and undetermined etiology according to inflammatory marker profile.
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8.
  • Mccabe, John J., et al. (författare)
  • Plasma fibrinogen and risk of vascular recurrence after ischaemic stroke: An individual participant and summary-level data meta-analysis of 11 prospective studies
  • 2024
  • Ingår i: EUROPEAN STROKE JOURNAL. - 2396-9873 .- 2396-9881.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Inflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear. Materials and Methods: We did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup analysis according to timing of phlebotomy after the index event. Results: Eleven studies were included (14,002 patients, 42,800 follow-up years), of which seven provided IPD. Fibrinogen was associated with recurrent MACE on unadjusted (RR 1.35, 95% CI 1.17-1.57, supra-median vs sub-median) and adjusted models (RR 1.21, 95% CI 1.06-1.38). Fibrinogen was associated with recurrent stroke on univariate analysis (RR 1.19, 95% CI 1.03-1.39), but not after adjustment (RR 1.11, 95% CI 0.94-1.31). The association with recurrent MACE was consistently observed in patients with post-acute (>14 days) fibrinogen measures (RR 1.29, 95% CI 1.16-1.45), but not in those with early phlebotomy (<14 days) (RR 0.98, 95% CI 0.82-1.18) (Pinteraction = 0.01). Similar associations were observed for recurrent stroke. Discussion and Conclusion: Fibrinogen was independently associated with recurrence after stroke, but the association was modified by timing of phlebotomy. Fibrinogen measurements might be useful to identify patients who are more likely to derive benefit from anti-inflammatory therapies after stroke. Graphical abstract
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9.
  • Vishram, Julie K.K., et al. (författare)
  • Blood pressure variability predicts cardiovascular events independently of traditional cardiovascular risk factors and target organ damage : a LIFE substudy
  • 2015
  • Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598. ; 33:12, s. 2422-2430
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Assessment of antihypertensive treatment is normally based on the mean value of a number of blood pressure (BP) measurements. However, it is uncertain whether high in-treatment visit-to-visit BP variability may be harmful in hypertensive patients with left ventricular hypertrophy (LVH).Methods: In 8505 patients randomized to losartan vs. atenolol-based treatment in the LIFE study, we tested whether BP variability assessed as SD and range for BP6-24months measured at 6, 12, 18 and 24 months of treatment was associated with target organ damage (TOD) defined by LVH on ECG and urine albumin/creatinine ratio at 24 months, and predicted the composite endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction (MI) or stroke occurring after 24 months (CEP=630 events).Results: In multiple regression models adjusted for mean BP6-24months and treatment allocation, neither high BP6-24months SD nor wide range were related to TOD at 24 months, except for a weak association between Sokolow-Lyon voltage and DBP6-24months SD and range (both b=0.04, P<0.01). Independently of mean BP6-24months, treatment allocation, TOD and baseline characteristics in Cox regression models, CEP after 24 months was associated with DBP6-24months SD [hazard ratio per 1mmHg increase1.04, 95% confidence interval (95% CI) 1.01-1.06, P=0.005], range (hazard ratio 1.02, 95% CI 1.01-1.03, P=0.004), SBP6-24months SD (hazard ratio 1.01, 95% CI 0.99-1.02, P=0.07) and range (hazard ratio 1.006, 95% CI 1.001-1.01, P=0.04). Adjusted for the same factors, stroke was associated with DBP6-24months SD (hazard ratio 1.06, 95% CI 1.02-1.10, P=0.001), range (hazard ratio 1.03, 95% CI 1.01-1.04, P=0.001), SBP6-24months SD (hazard ratio 1.02, 95% CI 1.002-1.04, P=0.04) and range (hazard ratio 1.008, 95% CI 1.001-1.02, P=0.05), but MI was not.Conclusion: In LIFE patients, higher in-treatment BP6-24months variability was independently of mean BP6-24months associated with later CEP and stroke, but not with MI or TOD after 24 months.
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10.
  • von Sarnowski, Bettina, et al. (författare)
  • Lifestyle Risk Factors for Ischemic Stroke and Transient Ischemic Attack in Young Adults in the Stroke in Young Fabry Patients Study
  • 2013
  • Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:1, s. 119-125
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose-Although many stroke patients are young or middle-aged, risk factor profiles in these age groups are poorly understood. Methods-The Stroke in Young Fabry Patients (sifap1) study prospectively recruited a large multinational European cohort of patients with cerebrovascular events aged 18 to 55 years to establish their prevalence of Fabry disease. In a secondary analysis of patients with ischemic stroke or transient ischemic attack, we studied age-and sex-specific prevalences of various risk factors. Results-Among 4467 patients (median age, 47 years; interquartile range, 40-51), the most frequent well-documented and modifiable risk factors were smoking (55.5%), physical inactivity (48.2%), arterial hypertension (46.6%), dyslipidemia (34.9%), and obesity (22.3%). Modifiable less well-documented or potentially modifiable risk factors like high-risk alcohol consumption (33.0%) and short sleep duration (20.6%) were more frequent in men, and migraine (26.5%) was more frequent in women. Women were more often physically inactive, most pronouncedly at ages <35 years (18-24: 38.2%; 25-34: 51.7%), and had high proportions of abdominal obesity at age 25 years or older (74%). Physical inactivity, arterial hypertension, dyslipidemia, obesity, and diabetes mellitus increased with age. Conclusions-In this large European cohort of young patients with acute ischemic cerebrovascular events, modifiable risk factors were highly prevalent, particularly in men and older patients. These data emphasize the need for vigorous primary and secondary prevention measures already in young populations targeting modifiable lifestyle vascular risk factors. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00414583. (Stroke. 2013; 44: 119-125.)
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11.
  • Woo, Daniel, et al. (författare)
  • Meta-Analysis of Genome-Wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage.
  • 2014
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:4, s. 511-521
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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12.
  • Ay, Hakan, et al. (författare)
  • Pathogenic Ischemic Stroke Phenotypes in the NINDS-Stroke Genetics Network
  • 2014
  • Ingår i: Stroke. - 0039-2499. ; 45:12, s. 3589-3596
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.
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13.
  • Cheng, Yu-Ching, et al. (författare)
  • Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.
  • 2016
  • Ingår i: Stroke; a journal of cerebral circulation. - 1524-4628. ; 47:2, s. 307-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years.
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14.
  • Cole, John W, et al. (författare)
  • Genetics of the thrombomodulin-endothelial cell protein C receptor system and the risk of early-onset ischemic stroke.
  • 2018
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 13:11
  • Tidskriftsartikel (refereegranskat)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.
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15.
  • Cristovao, Michele, et al. (författare)
  • Single-molecule multiparameter fluorescence spectroscopy reveals directional MutS binding to mismatched bases in DNA
  • 2012
  • Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 40:12, s. 5448-5464
  • Tidskriftsartikel (refereegranskat)abstract
    • Mismatch repair (MMR) corrects replication errors such as mismatched bases and loops in DNA. The evolutionarily conserved dimeric MMR protein MutS recognizes mismatches by stacking a phenylalanine of one subunit against one base of the mismatched pair. In all crystal structures of G:T mismatch-bound MutS, phenylalanine is stacked against thymine. To explore whether these structures reflect directional mismatch recognition by MutS, we monitored the orientation of Escherichia coli MutS binding to mismatches by FRET and anisotropy with steady state, pre-steady state and single-molecule multiparameter fluorescence measurements in a solution. The results confirm that specifically bound MutS bends DNA at the mismatch. We found additional MutS-mismatch complexes with distinct conformations that may have functional relevance in MMR. The analysis of individual binding events reveal significant bias in MutS orientation on asymmetric mismatches (G:T versus T:G, A:C versus C:A), but not on symmetric mismatches (G:G). When MutS is blocked from binding a mismatch in the preferred orientation by positioning asymmetric mismatches near the ends of linear DNA substrates, its ability to authorize subsequent steps of MMR, such as MutH endonuclease activation, is almost abolished. These findings shed light on prerequisites for MutS interactions with other MMR proteins for repairing the appropriate DNA strand.
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16.
  • Feigin, Valery L., et al. (författare)
  • Geomagnetic Storms Can Trigger Stroke Evidence From 6 Large Population-Based Studies in Europe and Australasia
  • 2014
  • Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 45:6, s. 1639-1645
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose-Although the research linking cardiovascular disorders to geomagnetic activity is accumulating, robust evidence for the impact of geomagnetic activity on stroke occurrence is limited and controversial. Methods-We used a time-stratified case-crossover study design to analyze individual participant and daily geomagnetic activity (as measured by Ap Index) data from several large population-based stroke incidence studies (with information on 11 453 patients with stroke collected during 16 031 764 person-years of observation) in New Zealand, Australia, United Kingdom, France, and Sweden conducted between 1981 and 2004. Hazard ratios and corresponding 95% confidence intervals (CIs) were calculated. Results-Overall, geomagnetic storms (Ap Index 60+) were associated with 19% increase in the risk of stroke occurrence (95% CI, 11%-27%). The triggering effect of geomagnetic storms was most evident across the combined group of all strokes in those aged <65 years, increasing stroke risk by >50%: moderate geomagnetic storms (60-99 Ap Index) were associated with a 27% (95% CI, 8%-48%) increased risk of stroke occurrence, strong geomagnetic storms (100-149 Ap Index) with a 52% (95% CI, 19%-92%) increased risk, and severe/extreme geomagnetic storms (Ap Index 150+) with a 52% (95% CI, 19%-94%) increased risk (test for trend, P<2x10(-16)). Conclusions-Geomagnetic storms are associated with increased risk of stroke and should be considered along with other established risk factors. Our findings provide a framework to advance stroke prevention through future investigation of the contribution of geomagnetic factors to the risk of stroke occurrence and pathogenesis.
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17.
  • Hachinski, Vladimir, et al. (författare)
  • Stroke: Working Toward a Prioritized World Agenda
  • 2010
  • Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 41:6, s. 1084-1099
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose-The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods-Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results-Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. Conclusions-To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
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18.
  • Hachinski, Vladimir, et al. (författare)
  • Stroke: Working toward a Prioritized World Agenda
  • 2010
  • Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 30:2, s. 127-147
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e. g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. Conclusions: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress. Copyright (C) 2010 American Heart Association. Inc., S. Karger AG, Basel, and John Wiley & Sons, Inc.
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19.
  • Hachinski, Vladimir, et al. (författare)
  • Stroke: working toward a prioritized world agenda
  • 2010
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4949 .- 1747-4930. ; 5:4, s. 238-256
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background and Purpose The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. Conclusions To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
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20.
  • Hagell, Peter, et al. (författare)
  • Sequential bilateral transplantation in Parkinson's disease: effects of the second graft
  • 1999
  • Ingår i: Brain. - : Oxford University Press (OUP). - 1460-2156. ; 122:6, s. 1121-1132
  • Tidskriftsartikel (refereegranskat)abstract
    • Five parkinsonian patients who had received implants of human embryonic mesencephalic tissue unilaterally in the striatum 10-56 months earlier were grafted with tissue from four to eight donors into the putamen (four patients) or the putamen plus the caudate nucleus (one patient) on the other side, and were followed for 18-24 months. After 12-18 months, PET showed a mean 85% increase in 6-L-[18F]fluorodopa uptake in the putamen with the second graft, whereas there was no significant further change in the previously transplanted putamen. Two patients exhibited marked additional improvements after their second graft: 'on-off' fluctuations virtually disappeared, movement speed increased, and L-dopa could be withdrawn in one patient and reduced by 70% in the other. The improvement in one patient was moderate. Two patients with atypical features, who responded poorly to the first graft, worsened following the second transplantation. These findings indicate that sequential transplantation in patients does not compromise the survival and function of either the first or the second graft. Moreover, putamen grafts that restore fluorodopa uptake to normal levels can give improvements of major therapeutic value.
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21.
  • Helgadottir, Anna, et al. (författare)
  • Apolipoprotein(a) Genetic Sequence Variants Associated With Systemic Atherosclerosis and Coronary Atherosclerotic Burden But Not With Venous Thromboembolism
  • 2012
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 60:8, s. 722-729
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. Background It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. Methods The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (ne = 4,572); venous thromboembolism (ne = 4,607); intracranial aneurysm (ne = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). Results LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 X 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 x 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 x 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 x 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 x 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). Conclusions LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes. (J Am Coll Cardiol 2012; 60: 722-9) (C) 2012 by the American College of Cardiology Foundation
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22.
  • Kilarski, Laura L., et al. (författare)
  • Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12
  • 2014
  • Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 83:8, s. 678-685
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 x 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695). Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
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23.
  • Kim, Joosup, et al. (författare)
  • Global Stroke Statistics 2019
  • 2020
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 15:8, s. 819-838
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning. Aims: To provide the most current incidence, mortality and case–fatality data on stroke and describe current availability of stroke units around the world by country. Methods: We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case–fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population. Results: Since our last report in 2017, there were two countries with new incidence studies, China (n = 1) and India (n = 2) that met the ideal criteria. New data on case–fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries. Conclusion: Up-to-date data on stroke incidence, case–fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low–middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.
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24.
  • Kopczak, Anna, et al. (författare)
  • Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs) : a multicentre, open-label, randomised, crossover trial
  • 2023
  • Ingår i: The Lancet Neurology. - 1474-4422. ; 22:11, s. 991-1004
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. Methods: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. Findings: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10–4%/mm Hg [SE 20·1; 95% CI –37·6 to 41·2] for amlodipine; 16·7 × 10–4%/mm Hg [20·0; –22·3 to 55·8] for losartan; –7·1 × 10–4%/mm Hg [19·6; –45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10–4%/mm Hg [SE 27·5; 95% CI –38·3 to 69·7] for amlodipine; 19·4 × 10–4%/mm Hg [27·9; –35·3 to 74·2] for losartan; –23·9 × 10–4%/mm Hg [27·5; –77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (–39·6 × 10–4%/mm Hg [95% CI –72·5 to –6·6; p=0·019) and with losartan compared with atenolol (–43·3 × 10–4%/mm Hg [–74·3 to –12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. Interpretation: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. Funding: EU Horizon 2020 programme.
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25.
  • Kopczak, Anna, et al. (författare)
  • The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial : Study protocol for a randomised crossover trial
  • 2023
  • Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 8:1, s. 387-397
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union’s Horizon 2020 programme. Trial registration: NCT03082014.
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26.
  • Maguire, Jane M., et al. (författare)
  • GISCOME – Genetics of Ischaemic Stroke Functional Outcome network : A protocol for an international multicentre genetic association study
  • 2017
  • Ingår i: European Stroke Journal. - : SAGE Publications. - 2396-9873 .- 2396-9881. ; 2:3, s. 229-237
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Genome-wide association studies have identified several novel genetic loci associated with stroke risk, but how genetic factors influence stroke outcome is less studied. The Genetics of Ischaemic Stroke Functional outcome network aims at performing genetic studies of stroke outcome. We here describe the study protocol and methods basis of Genetics of Ischaemic Stroke Functional outcome. Methods: The Genetics of Ischaemic Stroke Functional outcome network has assembled patients from 12 ischaemic stroke projects with genome-wide genotypic and outcome data from the International Stroke Genetics Consortium and the National Institute of Neurological Diseases Stroke Genetics Network initiatives. We have assessed the availability of baseline variables, outcome metrics and time-points for collection of outcome data. Results: We have collected 8831 ischaemic stroke cases with genotypic and outcome data. Modified Rankin score was the outcome metric most readily available. We detected heterogeneity between cohorts for age and initial stroke severity (according to the NIH Stroke Scale), and will take this into account in analyses. We intend to conduct a first phase genome-wide association outcome study on ischaemic stroke cases with data on initial stroke severity and modified Rankin score within 60–190 days. To date, we have assembled 5762 such cases and are currently seeking additional cases meeting these criteria for second phase analyses. Conclusion: Genetics of Ischaemic Stroke Functional outcome is a unique collection of ischaemic stroke cases with detailed genetic and outcome data providing an opportunity for discovery of genetic loci influencing functional outcome. Genetics of Ischaemic Stroke Functional outcome will serve as an exploratory study where the results as well as the methodological observations will provide a basis for future studies on functional outcome. Genetics of Ischaemic Stroke Functional outcome can also be used for candidate gene replication or assessing stroke outcome non-genetic association hypotheses.
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27.
  • Mahlknecht, Philipp, et al. (författare)
  • Parkinsonian signs in patients with cervical dystonia treated with pallidal deep brain stimulation
  • 2018
  • Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 141, s. 3023-3034
  • Tidskriftsartikel (refereegranskat)abstract
    • Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, evidence from case series or uncontrolled studies suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia. We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson's Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation and a non-surgical control group of 22 patients, both with predominant cervical dystonia. Additional assessments included MRI-hased models of volume of neural tissue activated to investigate areas of stimulation related to dystonic symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract. Compared with controls, stimulated patients had significantly higher motor scores (median, 25th-75th percentile: 14.0, 8.0-19.5 versus 3.0, 2.0-8.0; P < 0.0001), as well as bradykinesia (8.0, 6.0-14.0 versus 2.0, 0.0-3.0; P < 0.0001) and axial motor subscores (2.0, 1.0-4.0 versus 0.0, 0.0-1.0; P= 0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 min in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs were negatively associated with quality of life. In the descriptive imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping dusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. In conclusion, parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.
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28.
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29.
  • Markus, Hugh S, et al. (författare)
  • Stenting for symptomatic vertebral artery stenosis : The Vertebral Artery Ischaemia Stenting Trial.
  • 2017
  • Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 89:12, s. 1229-1236
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptomatic vertebral artery stenosis.METHODS: VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in 14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis ≥50% were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruitment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was a minimum of ≥1 year for each participant.RESULTS: Three patients did not contribute any follow-up data and were excluded, leaving 91 patients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range 2.1-4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting; 2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95% confidence interval 0.14-1.13, p = 0.08), with an absolute risk reduction of 25 strokes per 1,000 person-years. The hazard ratio for stroke or TIA was 0.50 (p = 0.05).CONCLUSIONS: Stenting in extracranial stenosis appears safe with low complication rates. Large phase 3 trials are required to determine whether stenting reduces stroke risk.ISRCTNCOM IDENTIFIER: ISRCTN95212240.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with symptomatic vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the study lacked the precision to exclude a benefit from stenting.
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30.
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31.
  • Notarnicola, A., et al. (författare)
  • Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis
  • 2023
  • Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 82, s. 574-574
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Autoantibodies are found in up to 80% of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes [1]. Autoantibodies targeting cytosolic 5´-nucleotidase 1A (anti-cN1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM) (2), although detected even in other autoimmune diseases.Objectives To identify new autoimmune targets in IIM by antigen bead array assay.Methods In a first cross-sectional exploratory study, 357 antigens representing 268 proteins were incubated with plasma samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls for screening of IgG reactivity by antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Interesting results obtained for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by western blot. As controls, serum samples from 30 patients with PM and 30 with DM, HLA-matched with the IBM Swedish cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.Results In the exploratory study IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9,7%) than PM (2,8%) and DM samples (2,5%), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 2,3% of SLE and 2,6% of population control samples. In the validation study anti-NDUFA11 autoantibodies were detected in 11/287 IBM patients (3,8%), 0/30 PM and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by western blot (Table 1, Figure 1). The eleven anti-NDUFA11 positive patients showed a trend of lower frequency of wheelchair/walker ever use and higher creatine kinase levels at time of IBM diagnosis compared to the anti-NDUFA11 negative group. Ragged red fibers were significantly more prevalent in anti-NDUFA11 positive than negative patients (p=0.04). Anti-cN1A autoantibodies were detected in 98/287 (34,1%) of IBM, 3/30 (10%) DM and 9/29 (31%) PM patients, p=0.03. Coexistence of anti NDUFA11 and anti-cN1A antibodies was observed in 3 IBM patients.Conclusion Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.References [1]Galindo-Feria AS, Wang G, Lundberg IE. Autoantibodies: Pathogenic or epiphenomenon. Best Pract Res Clin Rheumatol. 2022;36(2):101767.[2]Herbert MK,et al. Disease specificity of autoantibodies to cytosolic 5’-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Ann Rheum Dis. 2016;75(4):696-701.
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32.
  • Rannikmaee, Kristiina, et al. (författare)
  • Common variation in COL4A1/COL4A2 is associated with sporadic cerebral small vessel disease
  • 2015
  • Ingår i: Neurology. - 1526-632X. ; 84:9, s. 918-926
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives:We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease.Methods:We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084).Results:Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r(2) > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes.Conclusions:Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.
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33.
  • Rothwell, Peter M., et al. (författare)
  • Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke : Time-course analysis of randomised trials
  • 2016
  • Ingår i: The Lancet. - 0140-6736. ; 388:10042, s. 365-375
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Aspirin is recommended for secondary prevention after transient ischaemic attack (TIA) or ischaemic stroke on the basis of trials showing a 13% reduction in long-term risk of recurrent stroke. However, the risk of major stroke is very high for only the first few days after TIA and minor ischaemic stroke, and observational studies show substantially greater benefits of early medical treatment in the acute phase than do longer-term trials. We hypothesised that the short-term benefits of early aspirin have been underestimated. Methods: Pooling the individual patient data from all randomised trials of aspirin versus control in secondary prevention after TIA or ischaemic stroke, we studied the effects of aspirin on the risk and severity of recurrent stroke, stratified by the following time periods: less than 6 weeks, 6-12 weeks, and more than 12 weeks after randomisation. We compared the severity of early recurrent strokes between treatment groups with shift analysis of modified Rankin Scale (mRS) score. To understand possible mechanisms of action, we also studied the time course of the interaction between effects of aspirin and dipyridamole in secondary prevention of stroke. In a further analysis we pooled data from trials of aspirin versus control in which patients were randomised less than 48 h after major acute stroke, stratified by severity of baseline neurological deficit, to establish the very early time course of the effect of aspirin on risk of recurrent ischaemic stroke and how this differs by severity at baseline. Findings: We pooled data for 15 778 participants from 12 trials of aspirin versus control in secondary prevention. Aspirin reduced the 6 week risk of recurrent ischaemic stroke by about 60% (84 of 8452 participants in the aspirin group had an ischaemic stroke vs 175 of 7326; hazard ratio [HR] 0·42, 95% CI 0·32-0·55, p
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34.
  • Rothwell, Peter M., et al. (författare)
  • Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials
  • 2010
  • Ingår i: The Lancet. - 1474-547X. ; 376:9754, s. 1741-1750
  • Tidskriftsartikel (refereegranskat)abstract
    • Background High-dose aspirin (>= 500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour. Methods We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. Results In the four trials of aspirin versus control (mean duration of scheduled treatment 6.0 years), 391 (2.8%) of 14 033 patients had colorectal cancer during a median follow-up of 18.3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0.76, 0.60-0.96, p=0.02; mortality HR 0.65, 0.48-0.88, p=0.005), but not rectal cancer (0.90, 0.63-1.30, p=0.58; 0.80, 0.50-1.28, p=0.35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0.45, 0.28-0.74, p=0.001; 0.34, 0.18-0.66, p=0.001), but not the distal colon (1.10, 0.73-1.64, p=0.66; 1.21, 0.66-2.24, p=0.54; for incidence difference p=0.04, for mortality difference p=0.01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0.35, 0.20-0.63; 0.24, 0.11-0.52; both p<0.0001) and also reduced risk of rectal cancer (0.58, 0.36-0.92, p=0.02; 0.47, 0.26-0.87, p=0.01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1.76% (0.61-2.91; p=0.001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2.02, 0.70-6.05, p=0.15). Interpretation Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.
  •  
35.
  • Söderholm, Martin, et al. (författare)
  • Genome-wide association meta-analysis of functional outcome after ischemic stroke
  • 2019
  • Ingår i: Neurology. - 1526-632X. ; 92:12, s. 1271-1283
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study. METHODS: The study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8. RESULTS: We identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1). CONCLUSIONS: In this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.
  •  
36.
  • Thayabaranathan, Tharshanah, et al. (författare)
  • Global stroke statistics 2022
  • 2022
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 17:9, s. 946-956
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Contemporary data on stroke epidemiology and the availability of national stroke clinical registries are important for providing evidence to improve practice and support policy decisions. Aims: To update the most current incidence, case-fatality, and mortality rates on stroke and identify national stroke clinical registries worldwide. Methods: We searched multiple databases (based on our existing search strategy) to identify new original papers, published between 1 November 2018 and 15 December 2021, that met ideal criteria for data on stroke incidence and case-fatality, and added these to the studies reported in our last review. To identify national stroke clinical registries, we updated our last search, using PubMed, from 6 February 2015 until 6 January 2022. We also screened reference lists of review papers, citation history of papers, and the gray literature. Mortality codes for International Classification of Diseases (ICD)-9 and ICD-10 were extracted from the World Health Organization (WHO) for each country providing these data. Population denominators were obtained from the United Nations (UN) or WHO (when data were unavailable in the UN database). Crude and adjusted stroke mortality rates were calculated using country-specific population denominators, and the most recent years of mortality data available for each country. Results: Since our last report in 2020, there were two countries (Chile and France) with new incidence studies meeting criteria for ideal population-based studies. New data on case-fatality were found for Chile and Kenya. The most current mortality data were available for the year 2014 (1 country), 2015 (2 countries), 2016 (11 countries), 2017 (10 countries), 2018 (19 countries), 2019 (36 countries), and 2020 (29 countries). Four countries (Libya, Solomon Islands, United Arab Emirates, and Lebanon) reported mortality data for the first time. Since our last report on registries in 2017, we identified seven more national stroke clinical registries, predominantly in high-income countries. These newly identified registries yielded limited information. Conclusions: Up-to-date data on stroke incidence, case-fatality, and mortality continue to provide evidence of disparities and the scale of burden in low- and middle-income countries. Although more national stroke clinical registries were identified, information from these newly identified registries was limited. Highlighting data scarcity or even where a country is ranked might help facilitate more research or greater policy attention in this field.
  •  
37.
  • Thrift, Amanda G., et al. (författare)
  • Global stroke statistics
  • 2017
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 12:1, s. 13-32
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Up to date data on incidence, mortality, and case-fatality for stroke are important for setting the agenda for prevention and healthcare. Aims and/or hypothesis: We aim to update the most current incidence and mortality data on stroke available by country, and to expand the scope to case-fatality and explore how registry data might be complementary. Methods: Data were compiled using two approaches: (1) an updated literature review building from our previous review and (2) direct acquisition and analysis of stroke events in the World Health Organization (WHO) mortality database for each country providing these data. To assess new and/or updated data on incidence, we searched multiple databases to identify new original papers and review articles that met ideal criteria for stroke incidence studies and were published between 15 May 2013 and 31 May 2016. For data on case-fatality, we searched between 1980 and 31 May 2016. We further screened reference lists and citation history of papers to identify other studies not obtained from these sources. Mortality codes for ICD-8, ICD-9, and ICD-10 were extracted. Using population denominators provided for each country, we calculated both the crude mortality from stroke and mortality adjusted to the WHO world population. We used only the most recent year reported to the WHO for which both population and mortality data were available. Results: Fifty-one countries had data on stroke incidence, some with data over many time periods, and some with data in more than one region. Since our last review, there were new incidence studies from 12 countries, with four meeting pre-determined quality criteria. In these four studies, the incidence of stroke, adjusted to the WHO World standard population, ranged from 76 per 100,000 population per year in Australia (2009–10) up to 119 per 100,000 population per year in New Zealand (2011–12), with the latter being in those aged at least 15 years. Only in Martinique (2011–12) was the incidence of stroke greater in women than men. In countries either lacking or with old data on stroke incidence, eight had national clinical registries of hospital based data. Of the 128 countries reporting mortality data to the WHO, crude mortality was greatest in Kazhakstan (in 2003), Bulgaria, and Greece. Crude mortality and crude incidence of stroke were both positively correlated with the proportion of the population aged ≥ 65 years, but not with time. Data on case-fatality were available in 42 studies in 22 countries, with large variations between regions. Conclusions: In this updated review, we describe the current data on stroke incidence, case-fatality and mortality in different countries, and highlight the growing trend for national clinical registries to provide estimates in lieu of community-based incidence studies.
  •  
38.
  • Thrift, Amanda G., et al. (författare)
  • Global stroke statistics : An update of mortality data from countries using a broad code of “cerebrovascular diseases”
  • 2017
  • Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 12:8, s. 796-801
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Current information on mortality attributed to stroke among different countries is important for policy development and monitoring prevention strategies. Unfortunately, mortality data reported to the World Health Organization by different countries are inconsistent. Aims and/or hypothesis: To update the repository of the most recent country-specific data on mortality from stroke for countries that provide data using a broad code for “cerebrovascular disease.” Methods: Data on mortality from stroke were obtained from the World Health Organization mortality database. We searched for countries that provided data, since 1999, on a combined category of “cerebrovascular disease” (code 1609) that incorporated International Classification of Diseases (10th edition) codes I60–I69. Using population denominators provided by the World Health Organization for the same year when available, or alternatively estimates obtained from the United Nations, we calculated crude mortality from “cerebrovascular disease” and mortality adjusted to the World Health Organization world population. We used the most recent year reported to the World Health Organization, as well as comparing changes over time. Results: Since 1999, seven countries have provided these mortality data. Among these countries, crude mortality was greatest in the Russian Federation (in 2011), Ukraine (2012), and Belarus (2011) and was greater in women than men in these countries. Crude mortality was positively correlated with the proportion of the population aged ≥65 years but not with time. Age-adjusted mortality was greatest in the Russian Federation and Turkmenistan, and greater in men than women. Over time, mortality declined, with the greatest decline per annum evident in Kazakhstan (8.7%) and the Russian Federation (7.0%). Conclusions: Among countries that provided data to the World Health Organization using a broad category of “cerebrovascular disease,” there was a decline in mortality in two of the countries that previously had some of the largest mortality rates for stroke.
  •  
39.
  •  
40.
  • Traylor, Matthew, et al. (författare)
  • A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach.
  • 2014
  • Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10-7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10-8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10-15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
  •  
41.
  • Traylor, Matthew, et al. (författare)
  • Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
  • 2021
  • Ingår i: The Lancet Neurology. - 1474-4422. ; 20:5, s. 351-361
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
  •  
42.
  • Traylor, Matthew, et al. (författare)
  • Genetic Variation at 16q24.2 is associated with small vessel stroke.
  • 2017
  • Ingår i: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 81:3, s. 383-394
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises a quarter of all ischaemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown younger onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger onset SVS population, to identify novel associations with stroke.We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on mRNA expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain.We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (OR(95% CI)=1.16(1.10-1.22); p=3.2x10(-9) ). The lead SNP (rs12445022) was also associated with cerebral white matter hyperintensities (OR(95% CI)=1.10(1.05-1.16); p=5.3x10(-5) ; N=3,670), but not intracerebral haemorrhage (OR(95% CI)=0.97(0.84-1.12); p=0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p=9.4x10(-7) ), and DNA methylation at probe cg16596957 in whole blood (p=5.3x10(-6) ).16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. This article is protected by copyright. All rights reserved.
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43.
  • Viallon, Vivian, et al. (författare)
  • A new pipeline for the normalization and pooling of metabolomics data
  • 2021
  • Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 11:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated, and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through principal component partial R-square (PC-PR2) analysis; (iii) application of linear mixed models to remove unwanted variability, including samples’ originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.
  •  
44.
  • Wenning, Gregor K, et al. (författare)
  • Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease
  • 1997
  • Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 42:1, s. 95-107
  • Tidskriftsartikel (refereegranskat)abstract
    • Six patients with Parkinson's disease were followed for 10 to 72 months after human embryonic mesencephalic tissue from four to seven donors was grafted unilaterally into the putamen (4 patients) or putamen plus caudate (2 patients). After 8 to 12 months, positron emission tomography showed a 68% increase of 6-L-[18F]-fluorodopa uptake in the grafted putamen, no change in the grafted caudate, and minor decreases in nongrafted striatal regions. There was therapeutically valuable improvement in 4 patients, but only modest changes in the other 2, both of whom developed atypical features. Patient 4 was without L-dopa from 32 months and had normal fluorodopa uptake in the grafted putamen at 72 months. Overall, the L-dopa dose was reduced by a mean of 10 and 20%, "off" time was reduced by 34 and 44%, and the "off" phase Unified Parkinson's Disease Rating Scale motor score by 18 and 26%, and the duration of the response to a single L-dopa dose increased by 45 and 58% during the first and second years after surgery, respectively. Rigidity and hypokinesia improved bilaterally, but mainly contralateral to the implant. No consistent changes in dyskinesias were observed. We conclude that transplantation of embryonic mesencephalic tissue leads to highly reproducible survival of dopaminergic neurons, inducing clinically valuable improvements in most recipients.
  •  
45.
  • Zamora-Ros, Raul, et al. (författare)
  • Dietary intakes and food sources of phenolic acids in the European Prospective Investigation into Cancer and Nutrition (EPIC) study
  • 2013
  • Ingår i: British Journal of Nutrition. - : Cambridge University Press. - 1475-2662 .- 0007-1145. ; 110:8, s. 1500-1511
  • Tidskriftsartikel (refereegranskat)abstract
    • Phenolic acids are secondary plant metabolites that may have protective effects against oxidative stress, inflammation and cancer in experimental studies. To date, limited data exist on the quantitative intake of phenolic acids. We estimated the intake of phenolic acids and their food sources and associated lifestyle factors in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Phenolic acid intakes were estimated for 36 037 subjects aged 35-74 years and recruited between 1992 and 2000 in ten European countries using a standardised 24 h recall software (EPIC-Soft), and their food sources were identified. Dietary data were linked to the Phenol-Explorer database, which contains data on forty-five aglycones of phenolic acids in 452 foods. The total phenolic acid intake was highest in Aarhus, Denmark (1265.5 and 980.7 mg/d in men and women, respectively), while the intake was lowest in Greece (213.2 and 158.6 mg/d in men and women, respectively). The hydroxycinnamic acid subclass was the main contributor to the total phenolic acid intake, accounting for 84.6-95.3% of intake depending on the region. Hydroxybenzoic acids accounted for 4.6-14.4%, hydroxyphenylacetic acids 0.1-0.8% and hydroxyphenylpropanoic acids <= 0.1% for all regions. An increasing south-north gradient of consumption was also found. Coffee was the main food source of phenolic acids and accounted for 55.3-80.7% of the total phenolic acid intake, followed by fruits, vegetables and nuts. A high heterogeneity in phenolic acid intake was observed across the European countries in the EPIC cohort, which will allow further exploration of the associations with the risk of diseases.
  •  
46.
  • Niemi, MEK, et al. (författare)
  • 2021
  • swepub:Mat__t
  •  
47.
  • Kanai, M, et al. (författare)
  • 2023
  • swepub:Mat__t
  •  
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