TY  - JOUR
AB  - BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (β=-4.82×10-3 per year [95% CI, -6.49×10-3 to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.
AU  - Bakker, M.K.*
AU  - Kanning, J.P.*
AU  - Abraham, G.*
AU  - Martinsen, A.E.*
AU  - Winsvold, B.S.*
AU  - Zwart, J.A.*
AU  - Bourcier, R.*
AU  - Sawada, T.*
AU  - Koido, M.*
AU  - Kamatani, Y.*
AU  - Morel, S.*
AU  - Amouyel, P.*
AU  - Debette, S.*
AU  - Bijlenga, P.*
AU  - Berrandou, T.*
AU  - Ganesh, S.K.*
AU  - Bouatia-Naji, N.*
AU  - Jones, G.*
AU  - Bown, M.*
AU  - Rinkel, G.J.E.*
AU  - Veldink, J.H.*
AU  - Ruigrok, Y.M.*
AU  - HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group (Gieger, C.)
AU  - HUNT All-In Stroke, CADISP group, International Consortium for Blood Pressure, International Headache Genetics Consortium, International Stroke Genetics Consortium (ISGC) Intracranial Aneurysm Working Group (Peters, A.)
C1  - 70157
C2  - 55032
SP  - 810-818
TI  - Genetic risk Score for intracranial aneurysms: Prediction of subarachnoid hemorrhage and role in clinical heterogeneity.
JO  - Stroke
VL  - 54
IS  - 3
PY  - 2023
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND: The soft regions of a thrombus tend to be more susceptible to r-tPA (recombinant tissue-type plasminogen activator)-mediated thrombolysis and are more easily removed by mechanical thrombectomy than the stiff counterpart. This study aimed to understand the molecular pathological differences between the soft and stiff regions of human arterial thrombus. METHODS: We developed a spatial proteomic workflow combining proteomics with laser-captured microdissection to analyze human arterial thrombi with Masson trichrome staining to identify stiff and soft regions from 2 independent cohorts of patients with acute myocardial or cerebral infarction. Dysregulated proteins in a C57BL6/J male mouse model of arterial thrombosis were identified by pathway enrichment and pairwise analyses from the common gene ontology enrichment and dysregulated proteins between carotid and coronary arterial thrombi, and validated by immunohistochemistry. RESULTS: Spatial proteomics of the coronary arterial thrombi collected from 7 patients with myocardial infarct revealed 7 common dysregulated proteins in 2 cohorts of patients, and upregulation of TGF-β1 (transforming growth factor β1) was the most prominent fibrosis-related protein. Inhibition of TGF-β1 resulted in delayed arterial thrombosis and accelerated blood flow restoration in mouse model. We further expanded the spatial proteomic workflow to the carotid artery thrombi collected from 11 patients with cerebral infarction. Pairwise proteomic analysis of stiff and soft regions between carotid and coronary arterial thrombi further revealed 5 common gene ontology clusters including features of platelet activation, and a common dysregulated protein COL1A1 (collagen type 1 alpha 1) that was reported to be influenced by TGF-β1. We also verified the expression in human and mice carotid arterial thrombi. CONCLUSIONS: This study demonstrates the spatially distinct composition of proteins in the stiff and soft regions of human arterial thrombi, and suggests that TGF-β1 is a key therapeutic target for promoting arterial thrombolysis.
AU  - Mai, H.
AU  - Zhang, T.*
AU  - Lu, A.*
AU  - Wu, Z.*
AU  - Yang, B.*
AU  - He, N.*
AU  - Li, X.*
AU  - Tsang, C.K.*
AU  - Xu, A.*
AU  - Lu, D.*
C1  - 67609
C2  - 53916
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 1636-1644
TI  - Spatial proteomics analysis of soft and stiff regions in human acute arterial thrombus.
JO  - Stroke
VL  - 54
IS  - 6
PB  - Lippincott Williams & Wilkins
PY  - 2023
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND: Positive family history and genetic risk scores have been shown to independently capture those individuals with high risk for stroke. The aim of our study was to evaluate the amount of shared information between family history and genetic risk and to investigate their combined effect on the association with prevalent and incident stroke cases. METHODS: We obtained a family risk score (FamRS), weighted for disease onset and family size as well as genome-wide polygenic risk score (PGS) including over 3.2 million single-nucleotide polymorphisms in the population-based prospective KORA F3 (Cooperative Health Research in the Region of Augsburg) study (n=3071) from Southern Germany. FamRS and PGS were evaluated separately and combined. The measures were once treated as continuous variables but also divided in the highest 20%, 10%, 5%, and 1% percentiles. Odds ratios via logistic regression and hazard ratios via Cox regression were estimated. A stroke event was defined as a hospitalization for stroke that was self-reported in a standardized interview by certified and supervised personnel. RESULTS: The FamRS outperformed other simplified family measures such as affected parents or number of affected family members. FamRS and PGS were not correlated, and no individuals were observed with both very high FamRS and very high PGS (top 1% percentile). In a combined model, both FamRS and PGS were independently from each other associated with risk of stroke, also independent of other traditional risk factors (p [FamRS]=0.02, p [PGS]=0.005). Individuals in the top 1% of either FamRS or PGS were found to have >5-fold risk for stroke (odds ratios, 5.82 [95% CI, 2.08-14]; P=0.0002). The results for incident stroke events showed the same trend but were not significant. CONCLUSIONS: Our study shows that a family risk score and PGS capture different information concerning individual stroke risk. Combining the risk measures FamRS and PGS increases predictive power, as demonstrated in a population-based study.
AU  - Hämmerle, M.*
AU  - Forer, L.*
AU  - Schönherr, S.*
AU  - Peters, A.
AU  - Grallert, H.
AU  - Kronenberg, F.*
AU  - Gieger, C.
AU  - Lamina, C.*
C1  - 64806
C2  - 52501
SP  - 2331-2339
TI  - A family and a genome-wide polygenic risk score are independentlyassociated with stroke in a population-based study.
JO  - Stroke
VL  - 53
IS  - 7
PY  - 2022
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - Background and Purpose: Stroke is a common cause of death and a leading cause of disability and morbidity. Stroke risk assessment remains a challenge, but circulating biomarkers may improve risk prediction. Controversial evidence is available on the predictive ability of troponin concentrations and the risk of stroke in the community. Furthermore, reports on the predictive value of troponin concentrations for different stroke subtypes are scarce. Methods: High-sensitivity cardiac troponin I (hsTnI) concentrations were assessed in 82 881 individuals (median age, 50.7 years; 49.7% men) free of stroke or myocardial infarction at baseline from 9 prospective European community cohorts. We used Cox proportional hazards regression to determine relative risks, followed by measures of discrimination and reclassification using 10-fold cross-validation to control for overoptimism. Follow-up was based upon linkage with national hospitalization registries and causes of death registries. Results: Over a median follow-up of 12.7 years, 3033 individuals were diagnosed with incident nonfatal or fatal stroke (n=1654 ischemic strokes, n=612 hemorrhagic strokes, and n=767 indeterminate strokes). In multivariable regression models, hsTnI concentrations were associated with overall stroke (hazard ratio per 1-SD increase, 1.15 [95% CI, 1.10-1.21]), ischemic stroke (hazard ratio, 1.14 [95% CI, 1.09-1.21]), and hemorrhagic stroke (hazard ratio, 1.10 [95% CI, 1.01-1.20]). Adding hsTnI concentrations to classical cardiovascular risk factors (C indices, 0.809, 0.840, and 0.736 for overall, ischemic, and hemorrhagic stroke, respectively) increased the C index significantly but modestly. In individuals with an intermediate 10-year risk (5%-20%), the net reclassification improvement for overall stroke was 0.038 (P=0.021). Conclusions: Elevated hsTnI concentrations are associated with an increased risk of incident stroke in the community, irrespective of stroke subtype. Adding hsTnI concentrations to classical risk factors only modestly improved estimation of 10-year risk of stroke in the overall cohort but might be of some value in individuals at an intermediate risk.
AU  - Camen, S.*
AU  - Palosaari, T.*
AU  - Reinikainen, J.*
AU  - Sprünker, N.A.*
AU  - Niiranen, T.*
AU  - Gianfagna, F.*
AU  - Vishram-Nielsen, J.K.K.*
AU  - Costanzo, S.*
AU  - Söderberg, S.*
AU  - Palmieri, L.*
AU  - Ferrario, M.*
AU  - Peters, A.
AU  - Vartiainen, E.*
AU  - Donati, M.B.*
AU  - Donfrancesco, C.*
AU  - Borchini, R.*
AU  - Börschel, C.S.*
AU  - Giampaoli, S.*
AU  - di Castelnuovo, A.F.*
AU  - Magnussen, C.*
AU  - Kee, F.*
AU  - Koenig, W.*
AU  - Blankenberg, S.*
AU  - de Gaetano, G.*
AU  - Tunstall-Pedoe, H.*
AU  - Rospleszcz, S.
AU  - Jørgensen, T.*
AU  - Zeller, T.*
AU  - Kuulasmaa, K.*
AU  - Linneberg, A.*
AU  - Salomaa, V.*
AU  - Iacoviello, L.*
AU  - Schnabel, R.B.*
C1  - 59926
C2  - 48961
CY  - Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
SP  - 2770-2777
TI  - Cardiac Troponin I and incident stroke in European cohorts: Insights from the BiomarCaRE project,
JO  - Stroke
VL  - 51
IS  - 9
PB  - Lippincott Williams & Wilkins
PY  - 2020
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: In patients receiving direct oral anticoagulants (DOACs), emergency treatment like thrombolysis for acute ischemic stroke is complicated by insufficient availability of DOAC-specific coagulation tests. Conflicting recommendations have been published concerning the use of global coagulation assays for ruling out relevant DOAC-induced anticoagulation. METHODS: Four hundred eighty-one samples from 96 DOAC-treated patients were tested using prothrombin time (PT), activated partial thromboplastin time (aPTT) and thrombin time (TT), DOAC-specific assays (anti-Xa activity, diluted TT), and liquid chromatography-tandem mass spectrometry. Sensitivity and specificity of test results to identify DOAC concentrations <30 ng/mL were calculated. Receiver operating characteristic analyses were used to define reagent-specific cutoff values. RESULTS: Normal PT and aPTT provide insufficient specificity to safely identify DOAC concentrations <30 ng/mL (rivaroxaban/PT: specificity, 77%/sensitivity, 94%; apixaban/PT: specificity, 13%/sensitivity, 94%, dabigatran/aPTT: specificity, 49%/sensitivity, 91%). Normal TT was 100% specific for dabigatran, but sensitivity was 26%. In contrast, reagent-specific PT and aPTT cutoffs provided >95% specificity and a specific TT cutoff enhanced sensitivity for dabigatran to 84%. For apixaban, no cutoffs could be established. CONCLUSIONS: Even if highly DOAC-reactive reagents are used, normal results of global coagulation tests are not suited to guide emergency treatment: whereas normal PT and aPTT lack specificity to rule out DOAC-induced anticoagulation, the low sensitivity of normal TT excludes the majority of eligible patients from treatment. However, reagent-specific cutoffs for global coagulation tests ensure high specificity and optimize sensitivity for safe emergency decision making in rivaroxaban- and dabigatran-treated patients.
AU  - Ebner, M.*
AU  - Birschmann, I.*
AU  - Peter, A.
AU  - Härtig, F.*
AU  - Spencer, C.*
AU  - Kuhn, J.*
AU  - Blumenstock, G.*
AU  - Zuern, C.S.*
AU  - Ziemann, U.*
AU  - Poli, S.*
C1  - 51675
C2  - 43396
SP  - 2457-2463
TI  - Emergency coagulation assessment during treatment with direct oral anticoagulants: Limitations and solutions.
JO  - Stroke
VL  - 48
IS  - 9
PY  - 2017
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: Ischemic stroke of undetermined cause is a major health issue because of its high frequency and clinical relevance. Histopathologic analysis of human thrombi, retrieved from stroke patients with large-vessel occlusion during mechanical thrombectomy, may provide information about underlying pathologies. This study examines the relationship between stroke causes and histological clot composition to identify specific patterns that might help to distinguish causes of cryptogenic stroke. METHODS: Thrombi of 145 consecutive stroke patients with large-vessel occlusion were collected during intracranial mechanical recanalization. The hematoxylin and eosin-stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria. RESULTS: The composition of thrombi from cardioembolic and noncardioembolic stroke patients differed significantly for all main thrombus components. Cardioembolic thrombi had higher proportions of fibrin/platelets (P=0.009), less erythrocytes (P=0.003), and more leucocytes (P=0.035) than noncardioembolic thrombi. Cryptogenic strokes showed strong overlap with cardioembolic strokes but not with noncardioembolic strokes, in terms of both thrombus histology and interventional and clinical outcome parameters. CONCLUSIONS: Quantitative evaluation of thrombus composition may help to distinguish between different stroke causes. Our findings support the notion that the majority of cryptogenic strokes are cardioembolic.
AU  - Boeckh-Behrens, T.*
AU  - Kleine, J.F.*
AU  - Zimmer, C.*
AU  - Neff, F.
AU  - Scheipl, F.*
AU  - Pelisek, J.*
AU  - Schirmer, L.*
AU  - Nguyen, K.H.*
AU  - Karatas, D.*
AU  - Poppert, H.*
C1  - 48757
C2  - 41328
SP  - 1864-1871
TI  - Thrombus histology suggests cardioembolic cause in cryptogenic stroke.
JO  - Stroke
VL  - 47
IS  - 7
PY  - 2016
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset <60 years. METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls. RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.
AU  - Cheng, Y.C.*
AU  - Stanne, T.M.*
AU  - Giese, A.K.*
AU  - Ho, W.K.*
AU  - Traylor, M.*
AU  - Amouyel, P.*
AU  - Holliday, E.G.*
AU  - Malik, R.*
AU  - Xu, H.*
AU  - Kittner, S.J.*
AU  - Cole, J.W.*
AU  - O'Connell, J.R.*
AU  - Danesh, J.*
AU  - Rasheed, A.*
AU  - Zhao, W.*
AU  - Engelter, S.T.*
AU  - Grond-Ginsbach, C.*
AU  - Kamatani, Y.*
AU  - Lathrop, M*
AU  - Leys, D.*
AU  - Thijs, V.*
AU  - Metso, T.M.*
AU  - Tatlisumak, T.*
AU  - Pezzini, A.*
AU  - Parati, E.A.*
AU  - Norrving, B.*
AU  - Bevan, S.*
AU  - Rothwell, P.M.*
AU  - Sudlow, C.*
AU  - Slowik, A.*
AU  - Lindgren, A.*
AU  - Walters, M.R.*
AU  - Jannes, J.*
AU  - Shen, J.*
AU  - Crosslin, D.R.*
AU  - Doheny, K.F.*
AU  - Laurie, C.C.*
AU  - Kanse, S.M.*
AU  - Bis, J.C.*
AU  - Fornage, M.*
AU  - Mosley, T.H.*
AU  - Hopewell, J.C.*
AU  - Strauch, K.
AU  - Müller-Nurasyid, M.
AU  - Gieger, C.
AU  - Waldenberger, M.
AU  - Peters, A.
AU  - Meisinger, C.
AU  - Ikram, M.A.*
AU  - Longstreth, W.T. Jr.*
AU  - Meschia, J.F.*
AU  - Seshadri, S*
AU  - Sharma, P.*
AU  - Worrall, B.B.*
AU  - Jern, C.*
AU  - Levi, C.*
AU  - Dichgans, M.*
AU  - Boncoraglio, G.B.*
AU  - Markus, H.S.*
AU  - Debette, S.*
AU  - Rolfs, A.*
AU  - Saleheen, D.*
AU  - Mitchell, B.D.*
C1  - 47648
C2  - 40677
CY  - Philadelphia
SP  - 307-316
TI  - Genome-wide association analysis of young onset stroke identifies a locus on chromosome 10q25 near HABP2.
JO  - Stroke
VL  - 47
IS  - 2
PB  - Lippincott Williams & Wilkins
PY  - 2016
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. METHODS: Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype. RESULTS: Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10-8) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10-7) and ABO (PIS=2.6×10-4), as well as at HDAC9 (PLAS=2.32×10-12), 9p21 (PLAS=3.70×10-6), RAI1-PEMT-RASD1 (PLAS=2.69×10-5), EDNRA (PLAS=7.29×10-4), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10-4). CONCLUSIONS: Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.  
AU  - Dichgans, M.*
AU  - Malik, R.*
AU  - König, I.R.*
AU  - Rosand, J.*
AU  - Clarke, R.*
AU  - Gretarsdottir, S.*
AU  - Thorleifsson, G.*
AU  - Mitchell, B.D.*
AU  - Assimes, T.L.*
AU  - Levi, C.*
AU  - O'Donnell, C.J.*
AU  - Fornage, M.*
AU  - Thorsteinsdottir, U.*
AU  - Psaty, B.M.*
AU  - Hengstenberg, C.*
AU  - Seshadri, S*
AU  - Erdmann, J.*
AU  - Bis, J.C.*
AU  - Peters, A.
AU  - Boncoraglio, G.B.*
AU  - Marz, W.*
AU  - Meschia, J.F.*
AU  - Kathiresan, S.*
AU  - Ikram, M.A.*
AU  - McPherson, R.*
AU  - Stefansson, K.*
AU  - Sudlow, C.*
AU  - Reilly, M.P.*
AU  - Thompson, J.R.*
AU  - Sharma, P.*
AU  - Hopewell, J.C.*
AU  - Chambers, J.C.*
AU  - Watkins, H.*
AU  - Rothwell, P.M.*
AU  - Roberts, R.*
AU  - Markus, H.S.*
AU  - Samani, N.J.*
AU  - Farrall, M.*
AU  - Schunkert, H.*
AU  - METASTROKE Consortium (*)
AU  - CARDIoGRAM Consortium (Döring, A.
AU  - Wichmann, H.-E.
AU  - Illig, T.
AU  - Klopp, N.
AU  - Meisinger, C.
AU  - Peters, A.
AU  - Meitinger, T.)
AU  - C4D Consortium (*)
AU  - International Stroke Genetics Consortium (*)
C1  - 28433
C2  - 33373
SP  - 24-36
TI  - Shared genetic susceptibility to ischemic stroke and coronary artery disease: A genome-wide analysis of common variants.
JO  - Stroke
VL  - 45
IS  - 1
PB  - Lippincott Williams & Wilkins
PY  - 2014
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: White matter hyperintensities (WMH) on MRI are a quantitative marker for sporadic cerebral small vessel disease and are highly heritable. To date, large-scale genetic studies have identified only a single locus influencing WMH burden. This might in part relate to biological heterogeneity of sporadic WMH. The current study searched for genetic modifiers of WMH volume in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease. METHODS: We performed a genome-wide association study to identify quantitative trait loci for WMH volume by combining data from 517 CADASIL patients collected through 7 centers across Europe. WMH volumes were centrally analyzed and quantified on fluid attenuated inversion recovery images. Genotyping was performed using the Affymetrix 6.0 platform. Individuals were assigned to 2 distinct genetic clusters (cluster 1 and cluster 2) based on their genetic background. RESULTS: Four hundred sixty-six patients entered the final genome-wide association study analysis. The phenotypic variance of WMH burden in CADASIL explained by all single nucleotide polymorphisms in cluster 1 was 0.85 (SE=0.21), suggesting a substantial genetic contribution. Using cluster 1 as derivation and cluster 2 as a validation sample, a polygenic score was significantly associated with WMH burden (P=0.001) after correction for age, sex, and vascular risk factors. No single nucleotide polymorphism reached genome-wide significance. CONCLUSIONS: We found a polygenic score to be associated with WMH volume in CADASIL subjects. Our findings suggest that multiple variants with small effects influence WMH burden in CADASIL. The identification of these variants and the biological pathways involved will provide insights into the pathophysiology of white matter disease in CADASIL and possibly small vessel disease in general.
AU  - Opherk, C.*
AU  - Gonik, M.*
AU  - Duering, M.*
AU  - Malik, R.*
AU  - Jouvent, E.*
AU  - Hervé, D.*
AU  - Adib-Samii, P.*
AU  - Bevan, S.*
AU  - Pianese, L.*
AU  - Silvestri, S.*
AU  - Dotti, M.T.*
AU  - De Stefano, N.*
AU  - Liem, M.*
AU  - Boon, E.M.*
AU  - Pescini, F.*
AU  - Pachai, C.*
AU  - Bracoud, L.*
AU  - Müller-Myhsok, B.*
AU  - Meitinger, T.
AU  - Rost, N.*
AU  - Pantoni, L.*
AU  - Oberstein, S.L.*
AU  - Federico, A.*
AU  - Ragno, M.*
AU  - Markus, H.S.*
AU  - Tournier-Lasserve, E.*
AU  - Rosand, J.*
AU  - Chabriat, H.*
AU  - Dichgans, M.*
C1  - 30675
C2  - 33855
SP  - 968-972
TI  - Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL.
JO  - Stroke
VL  - 45
IS  - 4
PY  - 2014
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - Background and Purpose-Adult neurogenesis in the dentate gyrus is a unique form of brain plasticity that is strongly stimulated after stroke. We investigate the morphological properties of new granule cells, which are born and develop after the ischemic insult, and query whether these adult-born neurons properly integrate into the pre-existing hippocampal circuitries. Methods-Two well-established models were used to induce either small cortical infarcts (photothrombosis model) or large territorial infarcts (transient middle cerebral artery occlusion model). New granule cells were labeled 4 days after the initial insult by intrahippocampal injection of a retroviral vector encoding green fluorescent protein and newborn neurons were morphologically analyzed using a semiautomatic Neurolucida system and confocal laser scanning microscopy at 6 weeks. Results-Approximately 5% to 10% of newborn granule cells displayed significant morphological abnormalities comprising additional basal dendrites and, after middle cerebral artery occlusion, also ectopic cell position. The extent of morphological abnormalities was higher after large territorial infarcts and seems to depend on the severity of ischemic damage. An increased portion of mushroom spines in aberrant neurons suggests stable synaptic integration. However, poststroke generated granule cells with regular appearance also demonstrate alterations in dendritic complexity and spine morphology. Conclusions-The remarkable stimulation of dentate neurogenesis after stroke coincides with an increased rate of aberrantly integrated neurons, which may contribute to functional impairments and, hypothetically, favor pathogenesis of adjustment disorders, cognitive deficits, or epilepsy often seen in stroke patients. (Stroke. 2012;43:2468-2475.)
AU  - Niv, F.*
AU  - Keiner, S.*
AU  - Krishna-K, .*
AU  - Witte, O.W.*
AU  - Lie, D.C.
AU  - Redecker, C.*
C1  - 10636
C2  - 30448
SP  - 2468-2475
TI  - Aberrant neurogenesis after stroke: A retroviral cell labeling study.
JO  - Stroke
VL  - 43
IS  - 9
PB  - Lippincott Williams & Wilkins
PY  - 2012
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - BACKGROUND AND PURPOSE: Although in vitro studies suggest that non-neurogenic regions of the adult central nervous system potentially contain multipotent parenchymal progenitors, neurons are clearly not replaced in most brain regions after injury. Here, in a well-established model of mild transient brain ischemia, we explored Olig2 antagonism and Pax6 overexpression as potential avenues to redirect endogenous progenitors proliferating in situ toward a neuronal fate. METHODS: Retroviral vectors containing either Pax6 or a strong activator form of the repressor Olig2 (Olig2VP16), ie, a functionally dominant negative form of Olig2, were stereotaxically injected into the lateral striatum at 48 hours after 30 minutes middle cerebral artery occlusion (MCAo)/reperfusion. RESULTS: Retroviral modulation of fate determinants resulted in a significant number of infected cells differentiating into Doublecortin (DCX)-expressing immature neurons that were not observed after injection of a control virus. Whole-cell patch-clamp recordings in acute brain slices showed that the percentage of virus-infected cells with Na(+) currents was increased by inhibition of the repressor function of Olig2 and by overexpression of Pax6. Furthermore, on retroviral transduction of fate determinants, we detected newly generated cells within the ischemic lesion that were capable of generating single action potentials and that received synaptic input. CONCLUSIONS: Taken together, these data show that resident glia in the striatum can be reprogrammed toward functional neuronal differentiation following brain injury.
AU  - Kronenberg, G.*
AU  - Gertz, K.*
AU  - Cheung, G.*
AU  - Buffo, A.
AU  - Kettenmann, H.*
AU  - Götz, M.
AU  - Endres, M.*
C1  - 5154
C2  - 27649
SP  - 2944-2999
TI  - Modulation of fate determinants Olig2 and Pax6 in resident glia evokes spiking neuroblasts in a model of mild brain ischemia.
JO  - Stroke
VL  - 41
IS  - 12
PB  - American Heart Assoc.
PY  - 2010
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - Several genes involved in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) have been linked with the risk of myocardial infarction. Here, we present a comprehensive analysis of these genes in patients with ischemic stroke (IS). METHODS: Twenty-three single nucleotide polymorphisms (SNPs) from LTA, LGALS2, and PSMA6 were genotyped in 601 German IS patients and 736 matched controls. SNPs and haplotypes were tested for association with overall IS, large vessel stroke, and cardioembolic stroke. Significant associations were replicated in an independent sample of 843 IS cases and 933 controls from the UK. RESULTS: Only one SNP (rs1048990 in PSMA6) showed association with overall IS, but this was not replicated in the UK sample. Three SNPs showed significant associations with stroke subtypes (P<0.05), but none of these associations could be replicated in the UK population. CONCLUSIONS: Genetic variation in the lymphotoxin-alpha cascade (LTA, LGALS2, and PSMA6) is not a major risk factor for IS.
AU  - Freilinger, T.*
AU  - Bevan, S.*
AU  - Ripke, S.*
AU  - Gschwendtner, A.*
AU  - Lichtner, P.
AU  - Müller-Myhsok, B.*
AU  - Wichmann, H.-E.
AU  - Markus, H.S.*
AU  - Meitinger, T.*
AU  - Dichgans, M.*
C1  - 1947
C2  - 26600
CY  - United States
SP  - 970-972
TI  - Genetic variation in the lymphotoxin-alpha pathway and the risk of ischemic stroke in European populations.
JO  - Stroke
VL  - 40
IS  - 3
PB  - American Heart Assoc.
PY  - 2009
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - Background and Purpose - The recent finding that genetic variants in 5-lipoxygenase activating protein and leukotriene A4 hydrolase may confer an increased risk of ischemic stroke has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a case control replication methodology, all members of the leukotriene synthesis pathway and their receptors were examined for genetic variants, which may act as risk factors for all ischemic stroke and stroke subtypes. Methods - A case control methodology using a UK stroke cohort (872 cases, 933 controls) was adopted, with additional 5-lipoxygenase activating protein genotyping and replication of positive findings undertaken in an independent stroke population from Germany (601 cases, 736 controls). Results - Association was identified with variants in 5-lipoxygenase activating protein, leukotriene C4 synthase (leukotriene A4 hydrolase), and the leukotriene B4 receptor complex. Differing risks were identified for ischemic stroke subtypes. A variant in leukotriene C4 synthase was found to confer a 1.5-fold increase in risk of small vessel disease (RR, 1.515; 1.041 to 2.262; P = 0.043) with replication in an independent cohort showing a similar risk (RR, 1.687; 1.065 to 2.675; P = 0.026). A haplotype in the leukotriene B4 receptor complex was found to confer a 2.3-fold increase in risk of cardioembolic stroke (RR, 2.118; 1.194 to 3.760; P = 0.01) and replication in a German cohort revealed a similar risk with a second distinct haplotype (RR, 2.060; 1.162 to 3.665; P = 0.013). Conclusions - Genetic variation in leukotriene pathway members and their receptors confer an increased risk of ischemic stroke in 2 independent populations. These risks show different magnitudes depending on ischemic stroke subtype.
AU  - Bevan, S.*
AU  - Dichgans, M.*
AU  - Wichmann, H.-E.
AU  - Gschwendtner, A.*
AU  - Meitinger, T.
AU  - Markus, H.S.*
C1  - 3653
C2  - 34679
SP  - 1109-1114
TI  - Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke - A replication study in two independent populations.
JO  - Stroke
VL  - 39
IS  - 4
PB  - Lippincott Williams & Wilkins
PY  - 2008
SN  - 0039-2499
ER  - 

TY  - JOUR
AB  - Genetic variation in the EPHX2 gene region has been reported to influence susceptibility to ischemic stroke in blacks. We assessed the role of this gene region in white Europeans and performed analyses with regard to stroke subtypes. METHODS: Twenty-six single nucleotide polymorphisms in the EPHX2 gene region were genotyped in 601 patients with ischemic stroke and 736 matched controls. Cases were subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system. Analyses were done on single markers and haplotypes using a sliding-window approach. RESULTS: Three single nucleotide polymorphisms showed associations with an increased risk for ischemic stroke (allelic models; all P
AU  - Gschwendtner, A.*
AU  - Ripke, S.*
AU  - Freilinger, T.*
AU  - Lichtner, P.
AU  - Müller-Myhsok, B.*
AU  - Wichmann, H.-E.
AU  - Meitinger, T.
AU  - Dichgans, M.*
C1  - 3151
C2  - 25558
SP  - 1593-1596
TI  - Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans.
JO  - Stroke
VL  - 39
IS  - 5
PB  - Lippincott Williams & Wilkins
PY  - 2008
SN  - 0039-2499
ER  - 

TY  - JOUR
AU  - Löhmussaar, E.*
AU  - Gschwendtner, A.*
AU  - Mueller, J.C.
AU  - Org, T.*
AU  - Wichmann, H.-E.
AU  - Hamann, G.*
AU  - Meitinger, T.
AU  - Dichgans, M.*
C1  - 3130
C2  - 23132
SP  - 731-736
TI  - ALOX5AP gene and the PDE4D gene in a central European population of stroke patients.
JO  - Stroke
VL  - 36
PY  - 2005
SN  - 0039-2499
ER  -