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2. Age-related reduction of cerebral ischemic preconditioning: myth or reality?

Author

Della-Morte D, Caciatore F, Salsano E, Pirozzi G, Del Genio MT, D'Antonio I, Gargiulo G, Palmirotta R, Guadagni F, Rundek T, and Abete P

Subjects
ischemic preconditioning, stroke, transitory cerebral ischemic attack, mortality, elderly, Geriatrics, RC952-954.6
Abstract

David Della-Morte,1,2 Francesco Cacciatore,3 Elisa Salsano,4 Gilda Pirozzi,4 Maria Teresa Del Genio,4 Iole D'Antonio,4 Gaetano Gargiulo,5 Raffaele Palmirotta,2 Fiorella Guadagni,2 Tatjana Rundek,1 Pasquale Abete41Department of Neurology, Miller School of Medicine, University of Miami, Miami, FL, USA; 2Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele, Rome, Italy; 3Istituto Scientifico di Campoli/Telese, Fondazione Salvatore Maugeri, IRCCS, Benevento, Italy; 4Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II," Naples, Italy; 5AON, SS Antonio e Biagio e Cesare Arrigo, Struttura Complessa di Geriatria, Alessandria, ItalyAbstract: Stroke is one of the leading causes of death in industrialized countries for people older than 65 years of age. The reasons are still unclear. A reduction of endogenous mechanisms against ischemic insults has been proposed to explain this phenomenon. The “cerebral” ischemic preconditioning mechanism is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. This protective mechanism seems to be reduced with aging both in experimental and clinical studies. Alterations of mediators released and/or intracellular pathways may be responsible for age-related ischemic preconditioning reduction. Agents able to mimic the “cerebral” preconditioning effect may represent a new powerful tool for the treatment of acute ischemic stroke in the elderly. In this article, animal and human cerebral ischemic preconditioning, its age-related difference, and its potential therapeutical applications are discussed.Keywords: ischemic preconditioning, stroke, transient cerebral ischemic attack, mortality, elderly

Published
2013

3. Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆

Author

Frid, P., Xu, H., Mitchell, B.D., Drake, M., Wasselius, J., Gaynor, B., Ryan, K., Giese, A.K., Schirmer, M., Donahue, K.L., Irie, R., Bouts, M.J.R.J., McIntosh, E.C., Mocking, S.J.T., Dalca, A.V., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J.W., McArdle, P.F., Broderick, J.P., Jimenez-Conde, J., Jern, C., Kissela, B.M., Kleindorfer, D.O., Lemmens, R., Meschia, J.F., Rosand, J., Rundek, T., Sacco, R.L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B.B., Kittner, S.J., Petersson, J., Golland, P., Wu, O., Rost, N.S., and Lindgren, A.

Published
2022
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6. “Surviving and Thriving”: Evidence for Cortical GABA Stabilization in Cognitively-Intact Oldest-Old Adults

Author

Britton, MK, primary, Jensen, G, additional, Edden, RA, additional, Puts, NA, additional, Nolin, SA, additional, Merritt, SS, additional, Rezaei, RF, additional, Forbes, M, additional, Johnson, KJ, additional, Bharadwaj, PK, additional, Franchetti, MK, additional, Raichlen, DA, additional, Jessup, CJ, additional, Hishaw, GA, additional, Van Etten, EJ, additional, Gudmundson, AT, additional, Murali-Manohar, S, additional, Cowart, H, additional, Trouard, TP, additional, Geldmacher, DS, additional, Wadley, VG, additional, Alperin, N, additional, Levin, BE, additional, Rundek, T, additional, Visscher, KM, additional, Woods, AJ, additional, Alexander, GE, additional, Cohen, RA, additional, and Porges, EC, additional

Published
2023
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7. The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

Author

Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, AV, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rost, NS, MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium, Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, AV, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Rost, NS, and MRI-GENIE and GISCOME Investigators and the International Stroke Genetics Consortium

Abstract

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Published
2023

8. Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease.

Author

Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, Debette, S, Duperron, M-G, Knol, MJ, Le Grand, Q, Evans, TE, Mishra, A, Tsuchida, A, Roshchupkin, G, Konuma, T, Trégouët, D-A, Romero, JR, Frenzel, S, Luciano, M, Hofer, E, Bourgey, M, Dueker, ND, Delgado, P, Hilal, S, Tankard, RM, Dubost, F, Shin, J, Saba, Y, Armstrong, NJ, Bordes, C, Bastin, ME, Beiser, A, Brodaty, H, Bülow, R, Carrera, C, Chen, C, Cheng, C-Y, Deary, IJ, Gampawar, PG, Himali, JJ, Jiang, J, Kawaguchi, T, Li, S, Macalli, M, Marquis, P, Morris, Z, Muñoz Maniega, S, Miyamoto, S, Okawa, M, Paradise, M, Parva, P, Rundek, T, Sargurupremraj, M, Schilling, S, Setoh, K, Soukarieh, O, Tabara, Y, Teumer, A, Thalamuthu, A, Trollor, JN, Valdés Hernández, MC, Vernooij, MW, Völker, U, Wittfeld, K, Wong, TY, Wright, MJ, Zhang, J, Zhao, W, Zhu, Y-C, Schmidt, H, Sachdev, PS, Wen, W, Yoshida, K, Joutel, A, Satizabal, CL, Sacco, RL, Bourque, G, CHARGE consortium, Lathrop, M, Paus, T, Fernandez-Cadenas, I, Yang, Q, Mazoyer, B, Boutinaud, P, Okada, Y, Grabe, HJ, Mather, KA, Schmidt, R, Joliot, M, Ikram, MA, Matsuda, F, Tzourio, C, Wardlaw, JM, Seshadri, S, Adams, HHH, and Debette, S

Abstract

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.

Published
2023

9. Radiomics-Derived Brain Age Predicts Functional Outcome After Acute Ischemic Stroke.

Author

Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Regenhardt, RW, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, J, Lindgren, AG, Jern, C, Golland, P, Kuchcinski, G, Rost, NS, Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Regenhardt, RW, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, J, Lindgren, AG, Jern, C, Golland, P, Kuchcinski, G, and Rost, NS

Abstract

BACKGROUND AND OBJECTIVES: While chronological age is one of the most influential determinants of post-stroke outcomes, little is known of the impact of neuroimaging-derived biological "brain age". We hypothesized that radiomics analyses of T2-FLAIR images texture would provide brain age estimates and that advanced brain age of stroke patients will be associated with cardiovascular risk factors and worse functional outcomes. METHODS: We extracted radiomics from T2-FLAIR images acquired during acute stroke clinical evaluation. Brain age was determined from brain parenchyma radiomics using an ElasticNet linear regression model. Subsequently, relative brain age (RBA), which expresses brain age in comparison to chronological age-matched peers, was estimated. Finally, we built a linear regression model of RBA using clinical cardiovascular characteristics as inputs, and a logistic regression model of favorable functional outcomes taking RBA as input. RESULTS: We reviewed 4,163 patients from a large multisite ischemic stroke cohort (mean age=62.8 years, 42.0% females). T2-FLAIR radiomics predicted chronological ages (mean absolute error=6.9 years, r=0.81). After adjustment for covariates, RBA was higher and therefore described older-appearing brains in patients with hypertension, diabetes mellitus, a history of smoking, and a history of a prior stroke. In multivariate analyses, age, RBA, NIHSS, and a history of prior stroke were all significantly associated with functional outcome (respective adjusted Odds-Ratios: 0.58, 0.76, 0.48, 0.55; all p-values<0.001). Moreover, the negative effect of RBA on outcome was especially pronounced in minor strokes. DISCUSSION: T2-FLAIR radiomics can be used to predict brain age and derive RBA. Older appearing brains, characterized by a higher RBA, reflect cardiovascular risk factor accumulation and are linked to worse outcomes after stroke.

Published
2023

12. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author

Jaworek, T, Xu, H, Gaynor, BJ, Cole, JW, Rannikmae, K, Stanne, TM, Tomppo, L, Abedi, V, Amouyel, P, Armstrong, ND, Attia, J, Bell, S, Benavente, OR, Boncoraglio, GB, Butterworth, A, Cervical Artery Dissections and Ischemic Stroke Patients (CADSIP) Consortium, Carcel-Marquez, J, Chen, Z, Chong, M, Cruchaga, C, Cushman, M, Danesh, J, Debette, S, Duggan, DJ, Durda, JP, Engstrom, G, Enzinger, C, Faul, JD, Fecteau, NS, Fernandez-Cadenas, I, Gieger, C, Giese, A-K, Grewal, RP, Grittner, U, Havulinna, AS, Heitsch, L, Hochberg, MC, Holliday, E, Hu, J, Ilinca, A, INVENT Consortium, Irvin, MR, Jackson, RD, Jacob, MA, Janssen, RR, Jimenez-Conde, J, Johnson, JA, Kamatani, Y, Kardia, SL, Koido, M, Kubo, M, Lange, L, Lee, J-M, Lemmens, R, Levi, CR, Li, J, Li, L, Lin, K, Lopez, H, Luke, S, Maguire, J, McArdle, PF, McDonough, CW, Meschia, JF, Metso, T, Muller-Nurasyid, M, O'Connor, TD, O'Donnell, M, Peddareddygari, LR, Pera, J, Perry, JA, Peters, A, Putaala, J, Ray, D, Rexrode, K, Ribases, M, Rosand, J, Rothwell, PM, Rundek, T, Ryan, KA, Sacco, RL, Salomaa, V, Sanchez-Mora, C, Schmidt, R, Sharma, P, Slowik, A, Smith, JA, Smith, NL, Wassertheil-Smoller, S, Soederholm, M, Stine, OC, Strbian, D, Sudlow, CL, Tatlisumak, T, Terao, C, Thijs, V, Torres-Aguila, NP, Tregouet, D-A, Tuladhar, AM, Veldink, JH, Walters, RG, Weir, DR, Woo, D, Worrall, BB, Hong, CC, Ross, O, Zand, R, Leeuw, F-ED, Lindgren, AG, Pare, G, Anderson, CD, Markus, HS, Jern, C, Malik, R, Dichgans, M, Mitchell, BD, Kittner, SJ, and Early Onset Stroke Genetics Consortium of the International Stroke Genetics Consortium (ISGC)

Subjects
Neurology & Neurosurgery, 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences
Abstract

BACKGROUND AND OBJECTIVES: Current genome-wide association studies of ischemic stroke have focused primarily on late onset disease. As a complement to these studies, we sought to identifythe contribution of common genetic variants to risk of early onset ischemic stroke. METHODS: We performed a meta-analysis of genome-wide association studies of early onset stroke (EOS), ages 18-59, using individual level data or summary statistics in 16,730 cases and 599,237 non-stroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late onset stroke (LOS) and compared polygenic risk scores for venous thromboembolism between EOS and LOS. RESULTS: We observed genome-wide significant associations of EOS with two variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared to LOS. The odds ratio (OR) for rs529565, tagging O1, 0.88 (95% CI: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with EOS compared to LOS (p=0.008). DISCUSSION: The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.

Published
2022

14. Optimal Management of Asymptomatic Carotid Stenosis in 2021: The Jury is Still Out. An International, Multispecialty, Expert Review and Position Statement

Author

Paraskevas, K.I., Paraskevas, K.I., Mikhailidis, D.P., Antignani, P.L., Baradaran, H., Bokkers, R.P.H., Cambria, R.P., Dardik, A., Davies, A.H., Eckstein, H.H., Faggioli, G., Fernande, J.F.E., Fraedrich, G., Geroulakos, G., Gloviczki, P., Golledge, J., Jezovnik, M.K., Kakkos, S.K., Katsiki, N., Knoflach, M., Kooi, M.E., Lanza, G., Liapis, C.D., Loftus, I.M., Mansilha, A., Millon, A., Nicolaides, A.N., Pini, R., Poredos, P., Ricco, J.B., Riles, T.S., Ringleb, P.A., Rundek, T., Saba, L., Schlachetzki, F., Silvestrini, M., Spinelli, F., Stilo, F., Sultan, S., Suri, J.S., Zeebregts, C.J., Chaturvedi, S., Paraskevas, K.I., Paraskevas, K.I., Mikhailidis, D.P., Antignani, P.L., Baradaran, H., Bokkers, R.P.H., Cambria, R.P., Dardik, A., Davies, A.H., Eckstein, H.H., Faggioli, G., Fernande, J.F.E., Fraedrich, G., Geroulakos, G., Gloviczki, P., Golledge, J., Jezovnik, M.K., Kakkos, S.K., Katsiki, N., Knoflach, M., Kooi, M.E., Lanza, G., Liapis, C.D., Loftus, I.M., Mansilha, A., Millon, A., Nicolaides, A.N., Pini, R., Poredos, P., Ricco, J.B., Riles, T.S., Ringleb, P.A., Rundek, T., Saba, L., Schlachetzki, F., Silvestrini, M., Spinelli, F., Stilo, F., Sultan, S., Suri, J.S., Zeebregts, C.J., and Chaturvedi, S.

Abstract

Objectives: The recommendations of international guidelines for the management of asymptomatic carotid stenosis (ACS) often vary considerably and extend from a conservative approach with risk factor modification and best medical treatment (BMT) alone, to a more aggressive approach with a carotid intervention plus BMT. The aim of the current multispecialty position statement is to reconcile the conflicting views on the topic. Materials and methods: A literature review was performed with a focus on data from recent studies. Results: Several clinical and imaging high-risk features have been identified that are associated with an increased long-term ipsilateral ischemic stroke risk in patients with ACS. Such high-risk clinical/imaging features include intraplaque hemorrhage, impaired cerebrovascular reserve, carotid plaque echolucency/ulceration/ neovascularization, a lipid-rich necrotic core, a thin or ruptured fibrous cap, silent brain infarction, a contralateral transient ischemic attack/stroke episode, male patients < 75 years and microembolic signals on transcranial Doppler. There is growing evidence that 80-99% ACS indicate a higher stroke risk than 50-79% stenoses. Conclusions: Although aggressive risk factor control and BMT should be implemented in all ACS patients, several high-risk features that may increase the risk of a future cerebrovascular event are now documented. Consequently, some guidelines recommend a prophylactic carotid intervention in high-risk patients to prevent future cerebrovascular events. Until the results of the much-anticipated randomized controlled trials emerge, the jury is still out regarding the optimal management of ACS patients. (c) 2021 Elsevier Inc. All rights reserved.

Published
2022

15. Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

Author

Frid, P, Xu, H, Mitchell, BD, Drake, M, Wasselius, J, Gaynor, B, Ryan, K, Giese, AK, Schirmer, M, Donahue, KL, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rosand, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Petersson, J, Golland, P, Wu, O, Rost, NS, Lindgren, A, Frid, P, Xu, H, Mitchell, BD, Drake, M, Wasselius, J, Gaynor, B, Ryan, K, Giese, AK, Schirmer, M, Donahue, KL, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rosand, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Petersson, J, Golland, P, Wu, O, Rost, NS, and Lindgren, A

Abstract

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Published
2022

16. Sex-specific lesion pattern of functional outcomes after stroke

Author

Bonkhoff, AK, Bretzner, M, Hong, S, Schirmer, MD, Cohen, A, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Fox, MD, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Bretzner, M, Hong, S, Schirmer, MD, Cohen, A, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Fox, MD, Bzdok, D, Wu, O, and Rost, NS

Abstract

Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.

Published
2022

17. International stroke genetics consortium recommendations for studies of genetics of stroke outcome and recovery

Author

Lindgren, AG, Braun, RG, Juhl Majersik, J, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, J, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, P, Debette, S, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, Fernandez-Cadenas, I, Lindgren, AG, Braun, RG, Juhl Majersik, J, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, J, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, P, Debette, S, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, and Fernandez-Cadenas, I

Abstract

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Published
2022

18. Association of Stroke Lesion Pattern and White Matter Hyperintensity Burden With Stroke Severity and Outcome.

Author

Bonkhoff, AK, Hong, S, Bretzner, M, Schirmer, MD, Regenhardt, RW, Arsava, EM, Donahue, K, Nardin, M, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, E, Attia, J, Benavente, O, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, S, Lemmens, R, Levi, C, McDonough, CW, Meschia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soederholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, P, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Golland, P, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Hong, S, Bretzner, M, Schirmer, MD, Regenhardt, RW, Arsava, EM, Donahue, K, Nardin, M, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, E, Attia, J, Benavente, O, Cole, JW, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, S, Lemmens, R, Levi, C, McDonough, CW, Meschia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soederholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, P, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Golland, P, Bzdok, D, Wu, O, and Rost, NS

Abstract

BACKGROUND AND OBJECTIVES: To examine whether high white matter hyperintensity (WMH) burden is associated with greater stroke severity and worse functional outcomes in lesion pattern-specific ways. METHODS: MR neuroimaging and NIH Stroke Scale data at index stroke and the modified Rankin Scale (mRS) score at 3-6 months after stroke were obtained from the MRI-Genetics Interface Exploration study of patients with acute ischemic stroke (AIS). Individual WMH volume was automatically derived from fluid-attenuated inversion recovery images. Stroke lesions were automatically segmented from diffusion-weighted imaging (DWI) images, parcellated into atlas-defined brain regions and further condensed to 10 lesion patterns via machine learning-based dimensionality reduction. Stroke lesion effects on AIS severity and unfavorable outcomes (mRS score >2) were modeled within purpose-built Bayesian linear and logistic regression frameworks. Interaction effects between stroke lesions and a high vs low WMH burden were integrated via hierarchical model structures. Models were adjusted for age, age2, sex, total DWI lesion and WMH volumes, and comorbidities. Data were split into derivation and validation cohorts. RESULTS: A total of 928 patients with AIS contributed to acute stroke severity analyses (age: 64.8 [14.5] years, 40% women) and 698 patients to long-term functional outcome analyses (age: 65.9 [14.7] years, 41% women). Stroke severity was mainly explained by lesions focused on bilateral subcortical and left hemispherically pronounced cortical regions across patients with both a high and low WMH burden. Lesions centered on left-hemispheric insular, opercular, and inferior frontal regions and lesions affecting right-hemispheric temporoparietal regions had more pronounced effects on stroke severity in case of high compared with low WMH burden. Unfavorable outcomes were predominantly explained by lesions in bilateral subcortical regions. In difference to the lesion location-specific

Published
2022

19. Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, Gravel, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, HI, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Lee, J-M, Cheng, Y-C, Meschia, JF, Chen, WM, Sale, MM, Zonderman, AB, Evans, MK, Wilson, JG, Correa, A, Traylor, M, Lewis, CM, Reiner, A, Haessler, J, Langefeld, CD, Gottesman, RF, Yaffe, K, Liu, YM, Kooperberg, C, Lange, LA, Furie, KL, Arnett, DK, Benavente, OR, Grewal, RP, Peddareddygari, LR, Hveem, K, Lindstrom, S, Wang, L, Smith, EN, Gordon, W, Vlieg, AVH, de Andrade, M, Brody, JA, Pattee, JW, Brumpton, BM, Suchon, P, Chen, M-H, Frazer, KA, Turman, C, Germain, M, MacDonald, J, Braekkan, SK, Armasu, SM, Pankratz, N, Jackson, RD, Nielsen, JB, Giulianin, F, Puurunen, MK, Ibrahim, M, Heckbert, SR, Bammler, TK, McCauley, BM, Taylor, KD, Pankow, JS, Reiner, AP, Gabrielsen, ME, Deleuze, J-F, O'Donnell, CJ, Kim, J, McKnight, B, Kraft, P, Hansen, J-B, Rosendaal, FR, Heit, JA, Tang, W, Morange, P-E, Johnson, AD, Kabrhel, C, van Dijk, EJ, Koudstaal, PJ, Luijckx, G-J, Nederkoorn, PJ, van Oostenbrugge, RJ, Visser, MC, Wermer, MJH, Kappelle, LJ, Esko, T, Metspalu, A, Magi, R, Nelis, M, Levi, CR, Maguire, J, Jimenez-Conde, J, Sharma, P, Sudlow, CLM, Rannikmae, K, Schmidt, R, Slowik, A, Pera, J, Thijs, VNS, Lindgren, AG, Ilinca, A, Melander, O, Engstrom, G, Rexrode, KM, Rothwell, PM, Stanne, TM, Johnson, JA, Danesh, J, Butterworth, AS, Heitsch, L, Boncoraglio, GB, Kubo, M, Pezzini, A, Rolfs, A, Giese, A-K, Weir, D, Ross, OA, Lemmons, R, Soderholm, M, Cushman, M, Jood, K, McDonough, CW, Bell, S, Linkohr, B, Lee, T-H, Putaala, J, Lopez, OL, Carty, CL, Jian, X, Schminke, U, Cullell, N, Delgado, P, Ibanez, L, Krupinski, J, Lioutas, V, Matsuda, K, Montaner, J, Muino, E, Roquer, J, Sarnowski, C, Sattar, N, Sibolt, G, Teumer, A, Rutten-Jacobs, L, Kanai, M, Gretarsdottir, S, Rost, NS, Yusuf, S, Almgren, P, Ay, H, Bevan, S, Brown, RD, Carrera, C, Buring, JE, Chen, W-M, Cotlarciuc, I, de Bakker, PIW, DeStefano, AL, den Hoed, M, Duan, Q, Engelter, ST, Falcone, GJ, Gustafsson, S, Hassan, A, Holliday, EG, Howard, G, Hsu, F-C, Ingelsson, E, Harris, TB, Kissela, BM, Kleindorfer, DO, Langenberg, C, Leys, D, Lin, W-Y, Lorentzen, E, Magnusson, PK, McArdle, PF, Pulit, SL, Rice, K, Sakaue, S, Sapkota, BR, Tanislav, C, Thorleifsson, G, Thorsteinsdottir, U, Tzourio, C, van Duijn, CM, Walters, M, Wareham, NJ, Amin, N, Aparicio, HJ, Attia, J, Beiser, AS, Berr, C, Bustamante, M, Caso, V, Choi, SH, Chowhan, A, Dartigues, J-F, Delavaran, H, Dorr, M, Ford, I, Gurpreet, WS, Hamsten, A, Hozawa, A, Ingelsson, M, Iwasaki, M, Kaffashian, S, Kalra, L, Kjartansson, O, Kloss, M, Labovitz, DL, Laurie, CC, Lind, L, Lindgren, CM, Makoto, H, Minegishi, N, Morris, AP, Mueller-Nurasyid, M, Norrving, B, Ogishima, S, Parati, EA, Pedersen, NL, Perola, M, Jousilahti, P, Pileggi, S, Rabionet, R, Riba-Llena, I, Ribases, M, Romero, JR, Rudd, AG, Sarin, A-P, Sarju, R, Satoh, M, Sawada, N, Sigurdsson, A, Smith, A, Stine, OC, Stott, DJ, Strauch, K, Takai, T, Tanaka, H, Touze, E, Tsugane, S, Uitterlinden, AG, Valdimarsson, EM, van der Lee, SJ, Wakai, K, Williams, SR, Wolfe, CDA, Wong, Q, Yamaji, T, Sanghera, DK, Stefansson, K, Martinez-Majander, N, Sobue, K, Soriano-Tarraga, C, Volzke, H, Akpa, O, Sarfo, FS, Akpalu, A, Obiako, R, Wahab, K, Osaigbovo, G, Owolabi, L, Komolafe, M, Jenkins, C, Arulogun, O, Ogbole, G, Adeoye, AM, Akinyemi, J, Agunloye, A, Fakunle, AG, Uvere, E, Olalere, A, Adebajo, OJ, Chen, J, Clarke, R, Collins, R, Guo, Y, Wang, C, Lv, J, Peto, R, Chen, Y, Fairhurst-Hunter, Z, Hill, M, Pozarickij, A, Schmidt, D, Stevens, B, Turnbull, I, Yu, C, Nagai, A, Murakami, Y, Shiroma, EJ, Sigurdsson, S, Ghanbari, M, Boerwinkle, E, Fongang, B, Wang, R, Ikram, MK, Volker, U, de Laat, KF, van Norden, AGW, de Kort, PL, Vermeer, SE, Brouwers, PJAM, Gons, RAR, den Heijer, T, van Dijk, GW, van Rooij, FGW, Aamodt, AH, Skogholt, AH, Willer, CJ, Heuch, I, Hagen, K, Fritsche, LG, Pedersen, LM, Ellekjaer, H, Zhou, W, Martinsen, AE, Kristoffersen, ES, Thomas, LF, Kleinschnitz, C, Frantz, S, Ungethum, K, Gallego-Fabrega, C, Lledos, M, Llucia-Carol, L, Sobrino, T, Campos, F, Castillo, J, Freijo, M, Arenillas, JF, Obach, V, Alvarez-Sabin, J, Molina, CA, Ribo, M, Munoz-Narbona, L, Lopez-Cancio, E, Millan, M, Diaz-Navarro, R, Vives-Bauza, C, Serrano-Heras, G, Segura, T, Dhar, R, Delgado-Mederos, R, Prats-Sanchez, L, Camps-Renom, P, Blay, N, Sumoy, L, Marti-Fabregas, J, Schnohr, P, Jensen, GB, Benn, M, Afzal, S, Kamstrup, PR, van Setten, J, van der Laan, SW, Vonk, JMJ, Kim, B-J, Curtze, S, Tiainen, M, Kinnunen, J, Menon, V, Sung, YJ, Saillour-Glenisson, F, and Gravel, S

Abstract

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Published
2022

20. Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics

Author

Bonkhoff, AK, Ullberg, T, Bretzner, M, Hong, S, Schirmer, MD, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Frid, P, Rost, NS, Wasselius, J, Bonkhoff, AK, Ullberg, T, Bretzner, M, Hong, S, Schirmer, MD, Regenhardt, RW, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Wu, O, Frid, P, Rost, NS, and Wasselius, J

Abstract

BACKGROUND PURPOSE: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. MATERIALS AND METHODS: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. RESULTS: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, p FDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, p FDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only

Published
2022

21. Stroke genetics informs drug discovery and risk prediction across ancestries (vol 611, pg 115, 2022)

Author

Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, Debette, S, Mishra, A, Malik, R, Hachiya, T, Jurgenson, T, Namba, S, Posner, DC, Kamanu, FK, Koido, M, Le Grand, Q, Shi, M, He, Y, Georgakis, MK, Caro, I, Krebs, K, Liaw, Y-C, Vaura, FC, Lin, K, Winsvold, BS, Srinivasasainagendra, V, Parodi, L, Bae, H-J, Chauhan, G, Chong, MR, Tomppo, L, Akinyemi, R, Roshchupkin, GV, Habib, N, Jee, YH, Thomassen, JQ, Abedi, V, Carcel-Marquez, J, Nygaard, M, Leonard, HL, Yang, C, Yonova-Doing, E, Knol, MJ, Lewis, AJ, Judy, RL, Ago, T, Amouyel, P, Armstrong, ND, Bakker, MK, Bartz, TM, Bennett, DA, Bis, JC, Bordes, C, Borte, S, Cain, A, Ridker, PM, Cho, K, Chen, Z, Cruchaga, C, Cole, JW, de Jager, PL, de Cid, R, Endres, M, Ferreira, LE, Geerlings, MI, Gasca, NC, Gudnason, V, Hata, J, He, J, Heath, AK, Ho, Y-L, Havulinna, AS, Hopewell, JC, Hyacinth, IH, Inouye, M, Jacob, MA, Jeon, CE, Jern, C, Kamouchi, M, Keene, KL, Kitazono, T, Kittner, SJ, Konuma, T, Kumar, A, Lacaze, P, Launer, LJ, Lee, K-J, Lepik, K, Li, J, Li, L, Manichaikul, A, Markus, HS, Marston, NA, Meitinger, T, Mitchell, BD, Montellano, FA, Morisaki, T, Mosley, TH, Nalls, MA, Nordestgaard, BG, O'Donnell, MJ, Okada, Y, Onland-Moret, NC, Ovbiagele, B, Peters, A, Psaty, BM, Rich, SS, Rosand, J, Sabatine, MS, Sacco, RL, Saleheen, D, Sandset, EC, Salomaa, V, Sargurupremraj, M, Sasaki, M, Satizabal, CL, Schmidt, CO, Shimizu, A, Smith, NL, Sloane, KL, Sutoh, Y, Sun, YV, Tanno, K, Tiedt, S, Tatlisumak, T, Torres-Aguila, NP, Tiwari, HK, Tregouet, D-A, Trompet, S, Tuladhar, AM, Tybjaerg-Hansen, A, van Vugt, M, Vibo, R, Verma, SS, Wiggins, KL, Wennberg, P, Woo, D, Wilson, PWF, Xu, H, Yang, Q, Yoon, K, Millwood, IY, Gieger, C, Ninomiya, T, Grabe, HJ, Jukema, JW, Rissanen, IL, Strbian, D, Kim, YJ, Chen, P-H, Mayerhofer, E, Howson, JMM, Irvin, MR, Adams, H, Wassertheil-Smoller, S, Christensen, K, Ikram, MA, Rundek, T, Worrall, BB, Lathrop, GM, Riaz, M, Simonsick, EM, Korv, J, Franca, PHC, Zand, R, Prasad, K, Frikke-Schmidt, R, de Leeuw, F-E, Liman, T, Haeusler, KG, Ruigrok, YM, Heuschmann, PU, Longstreth, WT, Jung, KJ, Bastarache, L, Pare, G, Damrauer, SM, Chasman, DI, Rotter, JI, Anderson, CD, Zwart, J-A, Niiranen, TJ, Fornage, M, Liaw, Y-P, Seshadri, S, Fernandez-Cadenas, I, Walters, RG, Ruff, CT, Owolabi, MO, Huffman, JE, Milani, L, Kamatani, Y, Dichgans, M, and Debette, S

Published
2022

22. L’âge cérébral radiomique prédit le pronostic fonctionnel après un avc ischémique.

Author

Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, Rost, N, Bretzner, M, Bonkhoff, A, Schirmer, M, Hong, S, Dalca, A, Donahue, K, Giese, A-K, Etherton, M, Rist, P, Nardin, M, Regenhardt, R, Leclerc, X, Lopes, R, Gautherot, M, Wang, C, Benavente, O, Cole, J, Donatti, A, Griessenauer, C, Heitsch, L, Holmegaard, L, Jood, K, Conde, JJ, Kittner, S, Lemmens, R, Levi, C, McArdle, P, McDonough, C, Meshia, J, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, R, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, T, Strbian, D, Tatlisumak, T, Thijs, V, Vagala, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, B, Maguire, J, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, and Rost, N

Published
2022

23. Comparison of Recent Practice Guidelines for the Management of Patients With Asymptomatic Carotid Stenosis

Author

Paraskevas, K.I., Mikhailidis, D.P., Antignani, P.L., Ascher, E., Baradaran, H., Bokkers, R.P.H., Cambria, R.P., Comerota, A.J., Dardik, A., Davies, A.H., Eckstein, H.H., Faggioli, G., Fernandes, J.F.E., Fraedrich, G., Geroulakos, G., Gloviczki, P., Golledge, J., Gupta, A., Jezovnik, M.K., Kakkos, S.K., Katsiki, N., Knoflach, M., Kooi, M.E., Lanza, G., Lavenson, G.S., Liapis, C.D., Loftus, I.M., Mansilha, A., Millon, A., Nicolaides, A.N., Pini, R., Poredos, P., Proczka, R.M., Ricco, J.B., Riles, T.S., Ringleb, P.A., Rundek, T., Saba, L., Schlachetzki, F., Silvestrini, M., Spinelli, F., Stilo, F., Sultan, S., Suri, J.S., Svetlikov, A.V., Zeebregts, C.J., Chaturvedi, S., Paraskevas, K.I., Mikhailidis, D.P., Antignani, P.L., Ascher, E., Baradaran, H., Bokkers, R.P.H., Cambria, R.P., Comerota, A.J., Dardik, A., Davies, A.H., Eckstein, H.H., Faggioli, G., Fernandes, J.F.E., Fraedrich, G., Geroulakos, G., Gloviczki, P., Golledge, J., Gupta, A., Jezovnik, M.K., Kakkos, S.K., Katsiki, N., Knoflach, M., Kooi, M.E., Lanza, G., Lavenson, G.S., Liapis, C.D., Loftus, I.M., Mansilha, A., Millon, A., Nicolaides, A.N., Pini, R., Poredos, P., Proczka, R.M., Ricco, J.B., Riles, T.S., Ringleb, P.A., Rundek, T., Saba, L., Schlachetzki, F., Silvestrini, M., Spinelli, F., Stilo, F., Sultan, S., Suri, J.S., Svetlikov, A.V., Zeebregts, C.J., and Chaturvedi, S.

Abstract

Despite the publication of several national/international guidelines, the optimal management of patients with asymptomatic carotid stenosis (AsxCS) remains controversial. This article compares 3 recently released guidelines (the 2020 German-Austrian, the 2021 European Stroke Organization [ESO], and the 2021 Society for Vascular Surgery [SVS] guidelines) vs the 2017 European Society for Vascular Surgery (ESVS) guidelines regarding the optimal management of AsxCS patients. The 2017 ESVS guidelines defined specific imaging/clinical parameters that may identify patient subgroups at high future stroke risk and recommended that carotid endarterectomy (CEA) should or carotid artery stenting (CAS) may be considered for these individuals. The 2020 German-Austrian guidelines provided similar recommendations with the 2017 ESVS Guidelines. The 2021 ESO Guidelines also recommended CEA for AsxCS patients at high risk for stroke on best medical treatment (BMT), but recommended against routine use of CAS in these patients. Finally, the SVS guidelines provided a strong recommendation for CEA+BMT vs BMT alone for low-surgical risk patients with >70% AsxCS. Thus, the ESVS, German-Austrian, and ESO guidelines concurred that all AsxCS patients should receive risk factor modification and BMT, but CEA should or CAS may also be considered for certain AsxCS patient subgroups at high risk for future ipsilateral ischemic stroke.

Published
2022

24. Benefits and drawbacks of statins and non-statin lipid lowering agents in carotid artery disease

Author

Paraskevas, K.I. Gloviczki, P. Antignani, P.L. Comerota, A.J. Dardik, A. Davies, A.H. Eckstein, H.-H. Faggioli, G. Fernandes e Fernandes, J. Fraedrich, G. Geroulakos, G. Golledge, J. Gupta, A. Gurevich, V.S. Jawien, A. Jezovnik, M.K. Kakkos, S.K. Knoflach, M. Lanza, G. Liapis, C.D. Loftus, I.M. Mansilha, A. Nicolaides, A.N. Pini, R. Poredos, P. Proczka, R.M. Ricco, J.-B. Rundek, T. Saba, L. Schlachetzki, F. Silvestrini, M. Spinelli, F. Stilo, F. Suri, J.S. Svetlikov, A.V. Zeebregts, C.J. Chaturvedi, S. Veith, F.J. Mikhailidis, D.P.

Subjects
lipids (amino acids, peptides, and proteins), cardiovascular diseases
Abstract

International guidelines strongly recommend statins alone or in combination with other lipid-lowering agents to lower low-density lipoprotein cholesterol (LDL-C) levels for patients with asymptomatic/symptomatic carotid stenosis (AsxCS/SCS). Lowering LDL-C levels is associated with significant reductions in transient ischemic attack, stroke, cardiovascular (CV) event and death rates. The aim of this multi-disciplinary overview is to summarize the benefits and risks associated with lowering LDL-C with statins or non-statin medications for Asx/SCS patients. The cerebrovascular and CV beneficial effects associated with statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and other non-statin lipid-lowering agents (e.g. fibrates, ezetimibe) are reviewed. The use of statins and PCSK9 inhibitors is associated with several beneficial effects for Asx/SCS patients, including carotid plaque stabilization and reduction of stroke rates. Ezetimibe and fibrates are associated with smaller reductions in stroke rates. The side-effects resulting from statin and PCSK9 inhibitor use are also highlighted. The benefits associated with lowering LDL-C with statins or non-statin lipid lowering agents (e.g. PCSK9 inhibitors) outweigh the risks and potential side-effects. Irrespective of their LDL-C levels, all Asx/SCS patients should receive high-dose statin treatment±ezetimibe or PCSK9 inhibitors for reduction not only of LDL-C levels, but also of stroke, cardiovascular mortality and coronary event rates. © 2022 Elsevier Inc.

Published
2022

25. Management of patients with asymptomatic carotid stenosis may need to be individualized: A multidisciplinary call for action. Republication of J Stroke 2021;23:202-12

Author

Paraskevas K. I., Mikhailidis D. P., Baradaran H., Davies A. H., Eckstein H. -H., Faggioli G., Fernandes E Fernandes J., Gupta A., Jezovnik M. K., Kakkos S. K., Katsiki N., Kooi M. E., Lanza G., Liapis C. D., Loftus I. M., Millon A., Nicolaides A. N., Poredos P., Pini R., Ricco J. -B., Rundek T., Saba L., Spinelli F., Stilo F., Sultan S., Zeebregts C. J., Chaturvedi S., Paraskevas K.I., Mikhailidis D.P., Baradaran H., Davies A.H., Eckstein H.-H., Faggioli G., Fernandes E Fernandes J., Gupta A., Jezovnik M.K., Kakkos S.K., Katsiki N., Kooi M.E., Lanza G., Liapis C.D., Loftus I.M., Millon A., Nicolaides A.N., Poredos P., Pini R., Ricco J.-B., Rundek T., Saba L., Spinelli F., Stilo F., Sultan S., Zeebregts C.J., and Chaturvedi S.

Subjects
Stroke, Endarterectomy, Carotid, Ischemic Attack, Transient, Risk Factor, Carotid Stenosi, Human
Abstract

The optimal management of patients with asymptomatic carotid stenosis (ACS) is the subject of extensive debate. According to the 2017 European Society for Vascular Surgery Guidelines, carotid endarterectomy should (Class IIa; Level of Evidence: B) or carotid artery stenting may be considered (Class IIb; Level of Evidence: B) in the presence of one or more clinical/imaging characteristics that may be associated with an increased risk of late ipsilateral stroke (e.g. silent embolic infarcts on brain computed tomography/magnetic resonance imaging, progression in the severity of ACS, a history of contralateral transient ischemic attack/stroke, microemboli detection on transcranial Doppler, etc.), provided documented perioperative stroke/death rates are 5 years. Besides these clinical/imaging characteristics, there are additional individual, ethnic/racial or social factors that should probably be evaluated in the decision process regarding the optimal management of these patients, such as individual patient needs/patient choice, patient compliance with best medical treatment, patient sex, culture, race/ethnicity, age and comorbidities, as well as improvements in imaging/operative techniques/outcomes. The present multispecialty position paper will present the rationale why the management of patients with ACS may need to be individualized.

Published
2021

26. Network Segregation Predicts Processing Speed in the Cognitively Healthy Oldest-old

Author

Nolin, SA, primary, Faulkner, ME, additional, Stewart, P, additional, Fleming, L, additional, Merritt, S, additional, Rezaei, RF, additional, Bharadwaj, PK, additional, Franchetti, MK, additional, Raichlen, DA, additional, Jessup, CJ, additional, Edwards, L, additional, Hishaw, GA, additional, Van Etten, EJ, additional, Trouard, TP, additional, Geldmacher, D, additional, Wadley, VG, additional, Alperin, N, additional, Porges, EC, additional, Woods, AJ, additional, Cohen, RA, additional, Levin, BE, additional, Rundek, T, additional, Alexander, GE, additional, and Visscher, KM, additional

Published
2021
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28. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Author

Traylor, M, Persyn, E, Tomppo, L, Klasson, S, Abedi, V, Bakker, MK, Torres, N, Li, LX, Bell, S, Rutten-Jacobs, L, Tozer, DJ, Griessenauer, CJ, Zhang, YF, Pedersen, A, Sharma, P, Jimenez-Conde, J, Rundek, T, Grewal, RP, Lindgren, A, Meschia, JF, Salomaa, V, Havulinna, A, Kourkoulis, C, Crawford, K, Marini, S, Mitchell, BD, Kittner, SJ, Rosand, J, Dichgans, M, Jern, C, Strbian, D, Fernandez-Cadenas, I, Zand, R, Ruigrok, Y, Rost, N, Lemmens, R, Rothwell, PM, Anderson, CD, Wardlaw, J, Lewis, CM, Markus, HS, Helsinki Stroke Study, Dutch Parelsnoer Inst Cerebrovasc, Natl Inst Neurological Disorders, UK DNA Lacunar Stroke Study, Int Stroke Genetics Consortium, University of St Andrews. School of Biology, Bell, Steven [0000-0001-6774-3149], Tozer, Daniel [0000-0002-0404-3214], Markus, Hugh [0000-0002-9794-5996], Apollo - University of Cambridge Repository, HUS Neurocenter, Helsinki University Hospital Area, Neurologian yksikkö, Medicum, Institute for Molecular Medicine Finland, and University of Helsinki

Subjects
Oncology, PATHOGENESIS, LOCI, Genome-wide association study, Disease, VARIANTS, 3124 Neurology and psychiatry, SUBTYPES, 0302 clinical medicine, SMALL VESSEL DISEASE, Stroke, RISK, 0303 health sciences, Magnetic Resonance Imaging, 3. Good health, Europe, ISCHEMIC-STROKE, Meta-analysis, Medical genetics, Life Sciences & Biomedicine, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, medicine.medical_specialty, Lacunar stroke, Clinical Neurology, QH426 Genetics, CLASSIFICATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, QH426, METAANALYSIS, 030304 developmental biology, Genetic association, Science & Technology, business.industry, 3112 Neurosciences, Australia, DAS, medicine.disease, Hyperintensity, United States, ONSET, Stroke, Lacunar, RC0321, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Funding: This work, including collection and genotyping of the UK Young Lacunar Stroke DNA Study 2 (DNA Lacunar 2), was supported by a British Heart Foundation Programme Grant (RG/16/4/32218). 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

Published
2021
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29. EXPRESS: International Stroke Genetics Consortium Recommendations for Studies of Genetics of Stroke Outcome and Recovery

Author

Lindgren, A, Braun, R, Majersik, JJ, Clatworthy, P, Mainali, S, Derdeyn, CP, Maguire, JM, Jern, C, Rosand, J, Cole, JW, Lee, J-M, Khatri, P, Nyquist, PA, Debette, SP, Keat Wei, L, Rundek, T, Leifer, D, Thijs, V, Lemmens, R, Heitsch, L, Prasad, K, Jimenez-Conde, J, Dichgans, M, Rost, NS, Cramer, SC, Bernhardt, J, Worrall, BB, and Cadenas, I

Subjects
Neurology & Neurosurgery, cardiovascular diseases, 1103 Clinical Sciences, 1109 Neurosciences
Abstract

Numerous biological mechanisms contribute to outcome after stroke, including brain injury, inflammation, and repair mechanisms. Clinical genetic studies have the potential to discover biological mechanisms affecting stroke recovery in humans and identify intervention targets. Large sample sizes are needed to detect commonly occurring genetic variations related to stroke brain injury and recovery. However, this usually requires combining data from multiple studies where consistent terminology, methodology, and data collection timelines are essential. Our group of expert stroke and rehabilitation clinicians and researchers with knowledge in genetics of stroke recovery here present recommendations for harmonizing phenotype data with focus on measures suitable for multicenter genetic studies of ischemic stroke brain injury and recovery. Our recommendations have been endorsed by the International Stroke Genetics Consortium.

Published
2021

30. Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative

Author

den Ruijter, H. M., Peters, S. A. E., Groenewegen, K. A., Anderson, T. J., Britton, A. R., Dekker, J. M., Engström, G., Eijkemans, M. J., Evans, G. W., de Graaf, J., Grobbee, D. E., Hedblad, B., Hofman, A., Holewijn, S., Ikeda, A., Kavousi, M., Kitagawa, K., Kitamura, A., Koffijberg, H., Ikram, M. A., Lonn, E. M., Lorenz, M. W., Mathiesen, E. B., Nijpels, G., Okazaki, S., O’Leary, D. H., Polak, J. F., Price, J. F., Robertson, C., Rembold, C. M., Rosvall, M., Rundek, T., Salonen, J. T., Sitzer, M., Stehouwer, C. D. A., Witteman, J. C., Moons, K. G., and Bots, M. L.

Published
2013
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31. Stroke Care during the COVID-19 Pandemic: International Expert Panel Review

Author

Venketasubramanian, N. Anderson, C. Ay, H. Aybek, S. Brinjikji, W. De Freitas, G.R. Del Brutto, O.H. Fassbender, K. Fujimura, M. Goldstein, L.B. Haberl, R.L. Hankey, G.J. Heiss, W.-D. Lestro Henriques, I. Kase, C.S. Kim, J.S. Koga, M. Kokubo, Y. Kuroda, S. Lee, K. Lee, T.-H. Liebeskind, D.S. Lip, G.Y.H. Meairs, S. Medvedev, R. Mehndiratta, M.M. Mohr, J.P. Nagayama, M. Pantoni, L. Papanagiotou, P. Parrilla, G. Pastori, D. Pendlebury, S.T. Pettigrew, L.C. Renjen, P.N. Rundek, T. Schminke, U. Shinohara, Y. Tang, W.K. Toyoda, K. Wartenberg, K.E. Wasay, M. Hennerici, M.G.

Abstract

Background: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. Summary: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced. © 2021 S. Karger AG, Basel. Copyright: All rights reserved.

Published
2021

32. MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes

Author

Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, KL, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Marinescu, R, Wang, C, Regenhardt, RW, Leclerc, X, Lopes, R, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, JM, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, Rost, NS, Bretzner, M, Bonkhoff, AK, Schirmer, MD, Hong, S, Dalca, A, Donahue, KL, Giese, A-K, Etherton, MR, Rist, PM, Nardin, M, Marinescu, R, Wang, C, Regenhardt, RW, Leclerc, X, Lopes, R, Benavente, OR, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McArdle, PF, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Wu, O, Zand, R, Worrall, BB, Maguire, JM, Lindgren, A, Jern, C, Golland, P, Kuchcinski, G, and Rost, NS

Abstract

OBJECTIVE: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes. METHODS: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask-WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA). RESULTS: Radiomic features were predictive of WMH burden (R 2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-values CV 1 - 6 < 0.001, p-value CV 7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes. CONCLUSION: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of

Published
2021

33. Outcome after acute ischemic stroke is linked to sex-specific lesion patterns

Author

Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Brudfors, M, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Bzdok, D, Wu, O, Rost, NS, Bonkhoff, AK, Schirmer, MD, Bretzner, M, Hong, S, Regenhardt, RW, Brudfors, M, Donahue, KL, Nardin, MJ, Dalca, A, Giese, A-K, Etherton, MR, Hancock, BL, Mocking, SJT, McIntosh, EC, Attia, J, Benavente, OR, Bevan, S, Cole, JW, Donatti, A, Griessenauer, CJ, Heitsch, L, Holmegaard, L, Jood, K, Jimenez-Conde, J, Kittner, SJ, Lemmens, R, Levi, CR, McDonough, CW, Meschia, JF, Phuah, C-L, Rolfs, A, Ropele, S, Rosand, J, Roquer, J, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Soderholm, M, Sousa, A, Stanne, TM, Strbian, D, Tatlisumak, T, Thijs, V, Vagal, A, Wasselius, J, Woo, D, Zand, R, McArdle, PF, Worrall, BB, Jern, C, Lindgren, AG, Maguire, J, Bzdok, D, Wu, O, and Rost, NS

Abstract

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

Published
2021

35. Free Communications 5: Epidemiology, genetics, outcomes Inflammatory markers and extent and progression of early atherosclerosis: Pooled analysis of individual participant data from 20 prospective studies of the PROG-IMT collaboration: WSC-1521

Author

Willeit, P, Thompson, S G, Agewall, S, Bergström, G, Bickel, H, Catapano, A L, Chien, K L, de Groot, E, Empana, J P, Etgen, T, Franco, O H, Iglseder, B, Johnsen, S H, Kavousi, M, Lind, L, Liu, J, Mathiesen, E B, Norata, G D, Olsen, M H, Papagianni, A, Poppert, H, Price, J F, Sacco, R L, Yanez, D N, Zhao, D, Schminke, U, Bülbül, A, Polak, J F, Sitzer, M, Hofman, A, Grigore, L, Dörr, M, Su, T C, Ducimetière, P, Xie, W, Ronkainen, K, Kiechl, S, Rundek, T, Robertson, C, Fagerberg, B, Bokemark, L, Steinmetz, H, Ikram, M A, Völzke, H, Lin, H J, Plichart, M, Tuomainen, T P, Desvarieux, M, McLachlan, S, Schmidt, C, Kauhanen, J, Willeit, J, Lorenz, M W, and Sander, D

Published
2014

38. Incidence of Hypertension Among US Hispanics/Latinos: The Hispanic Community Health Study/Study of Latinos, 2008 to 2017

Author

Elfassy, T, Al Hazzouri, AZ, Cai, J, Baldoni, PL, Llabre, MM, Rundek, T, Raij, L, Lash, JP, Talavera, GA, Wassertheil-Smoller, S, Daviglus, M, Booth, JN, Castaneda, SF, Garcia, M, Schneiderman, N, Elfassy, T, Al Hazzouri, AZ, Cai, J, Baldoni, PL, Llabre, MM, Rundek, T, Raij, L, Lash, JP, Talavera, GA, Wassertheil-Smoller, S, Daviglus, M, Booth, JN, Castaneda, SF, Garcia, M, and Schneiderman, N

Abstract

Background Among US Hispanics/Latinos, the largest ethnic minority population in the United States, hypertension incidence has not been thoroughly reported. The goal of this study was to describe the incidence of hypertension among US Hispanic/Latino men and women of diverse Hispanic/Latino background. Methods and Results We studied 6171 participants of the Hispanic Community Health Study/Study of Latinos, a diverse group of self-identified Hispanics/Latinos from 4 US urban communities, aged 18 to 74 years, and free from hypertension in 2008 to 2011 and re-examined in 2014 to 2017. Hypertension was defined as self-reported use of anti-hypertension medication, or measured systolic blood pressure ≥130 mm Hg, or diastolic blood pressure ≥80 mm Hg. Results were weighted given the complex survey design to reflect the target population. Among men, the 6-year age-adjusted probability of developing hypertension was 21.7% (95% CI, 19.5-24.1) and differed by Hispanic/Latino background. Specifically, the probability was significantly higher among men of Cuban (27.1%; 95% CI, 20.2-35.2) and Dominican (28.1%; 95% CI, 19.5-38.8) backgrounds compared with Mexican Americans (17.6%; 95% CI: 14.5-21.2). Among women, the 6-year age-adjusted probability of developing hypertension was 19.7% (95% CI, 18.1-21.5) and also differed by Hispanic/Latino background. Specifically, the probability was significantly higher among women of Cuban (22.6%; 95% CI, 18.3-27.5), Dominican (23.3%; 95% CI, 18.0-29.5), and Puerto Rican (28.2%; 95% CI, 22.7-34.4) backgrounds compared with Mexican Americans (16.0%; 95% CI, 13.9-18.4). Conclusions Hypertension incidence varies by Hispanic/Latino background, with highest incidence among those of Caribbean background.

Published
2020

39. Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Author

Frid, P, Drake, M, Giese, AK, Wasselius, J, Schirmer, MD, Donahue, KL, Cloonan, L, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Sridharan, R, Xu, H, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Mitchell, BD, Petersson, J, Rosand, J, Golland, P, Wu, O, Rost, NS, Lindgren, A, Frid, P, Drake, M, Giese, AK, Wasselius, J, Schirmer, MD, Donahue, KL, Cloonan, L, Irie, R, Bouts, MJRJ, McIntosh, EC, Mocking, SJT, Dalca, AV, Sridharan, R, Xu, H, Giralt-Steinhauer, E, Holmegaard, L, Jood, K, Roquer, J, Cole, JW, McArdle, PF, Broderick, JP, Jimenez-Conde, J, Jern, C, Kissela, BM, Kleindorfer, DO, Lemmens, R, Meschia, JF, Rundek, T, Sacco, RL, Schmidt, R, Sharma, P, Slowik, A, Thijs, V, Woo, D, Worrall, BB, Kittner, SJ, Mitchell, BD, Petersson, J, Rosand, J, Golland, P, Wu, O, Rost, NS, and Lindgren, A

Abstract

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

Published
2020

40. Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium

Author

Bahls, M, Lorenz, MW, Dörr, M, Gao, L, Kitagawa, K, Tuomainen, TP, Agewall, S, Berenson, G, Catapano, AL, Norata, GD, Bots, ML, van Gilst, W, Asselbergs, FW, Brouwers, F, Uthoff, H, Sander, D, Poppert, H, Olsen, M H, Empana, JP, Schminke, U, Baldassarre, D, Veglia, F, Franco Duran, OH, Kavousi, Maryam, de Groot, E, Mathiesen, EB, Grigore, L, Polak, JF, Rundek, T, Stehouwer, CDA, Skilton, M, Hatzitolios, AI, Savopoulos, C, Ntaios, G, Plichart, M, McLachlan, S, Lind, L, Willeit, P, Steinmetz, H, Desvarieux, M, Ikram, Arfan, Johnsen, SH, Schmidt, C, Willeit, J, Ducimetiere, P, Price, JF, Bergström, G, Kauhanen, J, Kiechl, S, Sitzer, M, Bickel, H, Sacco, RL, Hofman, Bert, Völzke, H, Thompson, SG, Bahls, M, Lorenz, MW, Dörr, M, Gao, L, Kitagawa, K, Tuomainen, TP, Agewall, S, Berenson, G, Catapano, AL, Norata, GD, Bots, ML, van Gilst, W, Asselbergs, FW, Brouwers, F, Uthoff, H, Sander, D, Poppert, H, Olsen, M H, Empana, JP, Schminke, U, Baldassarre, D, Veglia, F, Franco Duran, OH, Kavousi, Maryam, de Groot, E, Mathiesen, EB, Grigore, L, Polak, JF, Rundek, T, Stehouwer, CDA, Skilton, M, Hatzitolios, AI, Savopoulos, C, Ntaios, G, Plichart, M, McLachlan, S, Lind, L, Willeit, P, Steinmetz, H, Desvarieux, M, Ikram, Arfan, Johnsen, SH, Schmidt, C, Willeit, J, Ducimetiere, P, Price, JF, Bergström, G, Kauhanen, J, Kiechl, S, Sitzer, M, Bickel, H, Sacco, RL, Hofman, Bert, Völzke, H, and Thompson, SG

Published
2020

41. Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., Lindgren, A., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Frid, Petrea, Drake, Mattias, Giese, A. K., Wasselius, J., Schirmer, Markus, Donahue, K. L., Cloonan, L., Irie, R., Bouts, M. J. R. J., McIntosh, E. C., Mocking, S. J. T., Dalca, Adrian Vasile, Sridharan, Ramesh, Xu, H., Giralt-Steinhauer, E., Holmegaard, L., Jood, K., Roquer, J., Cole, J. W., McArdle, P. F., Broderick, J. P., Jimenez-Conde, J., Jern, C., Kissela, B. M., Kleindorfer, D. O., Lemmens, R., Meschia, J. F., Rundek, T., Sacco, R. L., Schmidt, R., Sharma, P., Slowik, A., Thijs, V., Woo, D., Worrall, B. B., Kittner, S. J., Mitchell, B. D., Petersson, J., Rosand, J., Golland, Polina, Wu, O., Rost, N. S., and Lindgren, A.

Abstract

Objective Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. Methods Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. Results PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. Conclusion Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS., National Institutes of Health NIBIB (Grant P41EB015902)

Published
2020

44. Mannheim Carotid Intima-Media Thickness and Plaque Consensus (2004–2006–2011): An Update on Behalf of the Advisory Board of the 3rd, 4th and 5th Watching the Risk Symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011

Author

Touboul, P.-J., Hennerici, M. G., Meairs, S., Adams, H., Amarenco, P., Bornstein, N., Csiba, L., Desvarieux, M., Ebrahim, S., Hernandez Hernandez, R., Jaff, M., Kownator, S., Naqvi, T., Prati, P., Rundek, T., Sitzer, M., Schminke, U., Tardif, J.-C., Taylor, A., Vicaut, E., and Woo, K. S.

Published
2012
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47. Smoking Impairs Women’s Verbal Learning and Memory Performance More than Men’s: An International Web-Cohort Study of 70,000 Participants

Author

Lewis, C.R., primary, Talboom, J.S., additional, Both, M.D. De, additional, Schmidt, A.M., additional, Naymik, M.A., additional, Håberg, A.K., additional, Rundek, T., additional, Levin, B.E., additional, Hoscheidt, S., additional, Bolla, Y., additional, Brinton, R.D., additional, Hay, M., additional, Barnes, C.A., additional, Glisky, E., additional, Ryan, L., additional, and Huentelman, M.J., additional

Published
2020
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48. Two Separate, Large Cohorts Reveal Potential Modifiers of Age-Associated Variation in Visual Reaction Time Performance

Author

Talboom, J.S., primary, Both, M.D. De, additional, Naymik, M.A., additional, Schmidt, A.M., additional, Lewis, C.R., additional, Jepsen, W.M., additional, Håberg, A.K., additional, Rundek, T., additional, Levin, B.E., additional, Hoscheidt, S., additional, Bolla, Y., additional, Brinton, R.D., additional, Schork, N.J., additional, Hay, M., additional, Barnes, C.A., additional, Glisky, E., additional, Ryan, L., additional, and Huentelman, M.J., additional

Published
2020
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49. P139 Effects of 8-weeks of aerobic exercise intervention on fitness and neuroplasticity in aging adults: Preliminary results of an ongoing trial

Author

Ferreira Cabral, D., primary, Rice, J., additional, Nunez, C., additional, Abel, D., additional, Van Deusen, K., additional, Moustafi, B., additional, Kitaigorodsky, M., additional, Loewenstein, D., additional, Cahalin, L., additional, Rundek, T., additional, Pascual-Leone, A., additional, and Gomes-Osman, J., additional

Published
2020
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