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

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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2. Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries

Author

Mishra, Aniket, Malik, Rainer, Hachiya, Tsuyoshi, Jürgenson, Tuuli, Namba, Shinichi, Posner, Daniel C., Kamanu, Frederick K., Koido, Masaru, Le Grand, Quentin, Shi, Mingyang, He, Yunye, Georgakis, Marios K., Caro, Ilana, Krebs, Kristi, Liaw, Yi-Ching, Vaura, Felix C., Lin, Kuang, Winsvold, Bendik Slagsvold, Srinivasasainagendra, Vinodh, Parodi, Livia, Bae, Hee-Joon, Chauhan, Ganesh, Chong, Michael R., Tomppo, Liisa, Akinyemi, Rufus, Roshchupkin, Gennady V., Habib, Naomi, Jee, Yon Ho, Thomassen, Jesper Qvist, Abedi, Vida, Cárcel-Márquez, Jara, Nygaard, Marianne, Leonard, Hampton L., Yang, Chaojie, Yonova-Doing, Ekaterina, Knol, Maria J., Lewis, Adam J., Judy, Renae L., Ago, Tetsuro, Amouyel, Philippe, Armstrong, Nicole D., Bakker, Mark K., Bartz, Traci M., Bennett, David A., Bis, Joshua C., Bordes, Constance, Børte, Sigrid, Cain, Anael, Ridker, Paul M., Cho, Kelly, Chen, Zhengming, Cruchaga, Carlos, Cole, John W., de Jager, Phil L., de Cid, Rafael, Endres, Matthias, Ferreira, Leslie E., Geerlings, Mirjam I., Gasca, Natalie C., Gudnason, Vilmundur, Hata, Jun, He, Jing, Heath, Alicia K., Ho, Yuk-Lam, Havulinna, Aki S., Hopewell, Jemma C., Hyacinth, Hyacinth I., Inouye, Michael, Jacob, Mina A., Jeon, Christina E., Jern, Christina, Kamouchi, Masahiro, Keene, Keith L., Kitazono, Takanari, Kittner, Steven J., Konuma, Takahiro, Kumar, Amit, Lacaze, Paul, Launer, Lenore J., Lee, Keon-Joo, Lepik, Kaido, Li, Jiang, Li, Liming, Manichaikul, Ani, Markus, Hugh S., Marston, Nicholas A., Meitinger, Thomas, Mitchell, Braxton D., Montellano, Felipe A., Morisaki, Takayuki, Mosley, Thomas H., Nalls, Mike A., Nordestgaard, Børge G., O’Donnell, Martin J., Okada, Yukinori, Onland-Moret, N. Charlotte, Ovbiagele, Bruce, Peters, Annette, Psaty, Bruce M., Rich, Stephen S., Rosand, Jonathan, Sabatine, Marc S., Sacco, Ralph L., Saleheen, Danish, Sandset, Else Charlotte, Salomaa, Veikko, Sargurupremraj, Muralidharan, Sasaki, Makoto, Satizabal, Claudia L., Schmidt, Carsten O., Shimizu, Atsushi, Smith, Nicholas L., Sloane, Kelly L., Sutoh, Yoichi, Sun, Yan V., Tanno, Kozo, Tiedt, Steffen, Tatlisumak, Turgut, Torres-Aguila, Nuria P., Tiwari, Hemant K., Trégouët, David-Alexandre, Trompet, Stella, Tuladhar, Anil Man, Tybjærg-Hansen, Anne, van Vugt, Marion, Vibo, Riina, Verma, Shefali S., Wiggins, Kerri L., Wennberg, Patrik, Woo, Daniel, Wilson, Peter W. F., Xu, Huichun, Yang, Qiong, Yoon, Kyungheon, Millwood, Iona Y., Gieger, Christian, Ninomiya, Toshiharu, Grabe, Hans J., Jukema, J. Wouter, Rissanen, Ina L., Strbian, Daniel, Kim, Young Jin, Chen, Pei-Hsin, Mayerhofer, Ernst, Howson, Joanna M. M., Irvin, Marguerite R., Adams, Hieab, Wassertheil-Smoller, Sylvia, Christensen, Kaare, Ikram, Mohammad A., Rundek, Tatjana, Worrall, Bradford B., Lathrop, G. Mark, Riaz, Moeen, Simonsick, Eleanor M., Kõrv, Janika, França, Paulo H. C., Zand, Ramin, Prasad, Kameshwar, Frikke-Schmidt, Ruth, de Leeuw, Frank-Erik, Liman, Thomas, Haeusler, Karl Georg, Ruigrok, Ynte M., Heuschmann, Peter Ulrich, Longstreth, W. T., Jung, Keum Ji, Bastarache, Lisa, Paré, Guillaume, Damrauer, Scott M., Chasman, Daniel I., Rotter, Jerome I., Anderson, Christopher D., Zwart, John-Anker, Niiranen, Teemu J., Fornage, Myriam, Liaw, Yung-Po, Seshadri, Sudha, Fernández-Cadenas, Israel, Walters, Robin G., Ruff, Christian T., Owolabi, Mayowa O., Huffman, Jennifer E., Milani, Lili, Kamatani, Yoichiro, Dichgans, Martin, and Debette, Stephanie

Published
2022
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3. Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation

Author

Soo, Yannie, Zietz, Annaelle, Yiu, Brian, Mok, Vincent C T, Polymeris, Alexandros A, Seiffge, David, Ambler, Gareth, Wilson, Duncan, Leung, Thomas Wai Hong, Tsang, Suk Fung, Chu, Winnie, Abrigo, Jill, Cheng, Cyrus, Lee, Keon-Joo, Lim, Jae-Sung, Shiozawa, Masayuki, Koga, Masatoshi, Chabriat, Hugues, Hennerici, Michael, Wong, Yuen Kwun, Mak, Henry, Collet, Roger, Inamura, Shigeru, Yoshifuji, Kazuhisa, Arsava, Ethem Murat, Horstmann, Solveig, Purrucker, Jan, Lam, Bonnie Y K, Wong, Adrian, Kim, Young Dae, Song, Tae-Jin, Lemmens, Robin, Eppinger, Sebastian, Gattringer, Thomas, Uysal, Ender, Demirelli, Derya Selçuk, Bornstein, Natan M, Assayag, Einor Ben, Hallevi, Hen, Molad, Jeremy, Nishihara, Masashi, Tanaka, Jun, Coutts, Shelagh B, Kappelle, L Jaap, Salman, Rustam Al-Shahi, Jager, Rolf, Lip, Gregory Y. H., Goeldlin, Martina B, Panos, Leonidas D, Mas, Jean-Louis, Legrand, Laurence, Karayiannis, Chris, Phan, Thanh, Bellut, Maximilian, Chappell, Francesca, Makin, Stephen, Hayden, Derek, Williams, David, van Dam-Nolen, Dianne H K, Nederkoorn, Paul J, Barbato, Carmen, Browning, Simone, Wiegertjes, Kim, Tuladhar, Anil Man, Mendyk, Anne-Marie, Köhler, Sebastian, van Oostenburgge, Robert, Zhou, Ying, Xu, Chao, Hilal, Saima, Gyanwali, Bibek, Chen, Christopher, Lou, Min, Staals, Julie, Bordet, Regis, Kandiah, Nagaendran, de Leeuw, Frank-Erik, Simister, Robert, Hendrikse, Jeroen, Wardlaw, Joanna, Kelly, Peter, Fluri, Felix, Srikanth, Velandai, Calvet, David, Jung, Simon, Kwa, Vincent I H, Smith, Eric E, Hara, Hideo, Yakushiji, Yusuke, Orken, Dilek Necioglu, Fazekas, Franz, Thijs, Vincent, Heo, Ji-Hoe, Veltkamp, Roland, Ay, Hakan, Imaizumi, Toshio, Lau, Kui Kai, Jouvent, Eric, Toyoda, Kazunori, Yoshimura, Sohei, Bae, Hee-Joon, Martí-Fàbregas, Joan, Prats-Sánchez, Luis, Lyrer, Philippe, Best, Jonathan, Werring, David, Engelter, Stefan T, Peters, Nils, Neurology, ACS - Atherosclerosis & ischemic syndromes, and ANS - Neurovascular Disorders

Subjects
All institutes and research themes of the Radboud University Medical Center, Neurology, Neurology (clinical), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract

Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023. Objectives: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet).Methods: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use.Results: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years).Interpretation: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023.

Published
2023
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4. Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED):an open-label, multicentre, randomised controlled trial

Author

van der Steen, Wouter, van de Graaf, Rob A., Chalos, Vicky, Lingsma, Hester F., van Doormaal, Pieter Jan, Coutinho, Jonathan M., Emmer, Bart J., de Ridder, Inger, van Zwam, Wim, van der Worp, H. Bart, van der Schaaf, Irene, Gons, Rob A.R., Yo, Lonneke S.F., Boiten, Jelis, van den Wijngaard, Ido, Hofmeijer, Jeannette, Martens, Jasper, Schonewille, Wouter, Vos, Jan Albert, Tuladhar, Anil Man, de Laat, Karlijn F., van Hasselt, Boudewijn, Remmers, Michel, Vos, Douwe, Rozeman, Anouk, Elgersma, Otto, Uyttenboogaart, Maarten, Bokkers, Reinoud P.H., van Tuijl, Julia, Boukrab, Issam, van den Berg, René, Beenen, Ludo F.M., Roosendaal, Stefan D., Postma, Alida Annechien, Krietemeijer, Menno, Lycklama, Geert, Meijer, Frederick J.A., Hammer, Sebastiaan, van der Hoorn, Anouk, Yoo, Albert J., Gerrits, DIck, Truijman, MTB, Zinkstok, Sanne M., Koudstaal, Peter J., Manschot, Sanne, Kerkhoff, Henk, Nieboer, Daan, Berkhemer, Olvert, Wolff, Lennard, van der Sluijs, Matthijs, van Voorst, Henk, Tolhuisen, ML, Roos, Bwem, Majoie, Charles B.L.M., Staals, Julie, van Oostenbrugge, Robert J., Jenniskens, Sjoerd F.M., van Dijk, Lukas C., den Hertog, Heleen M., van Es, Adriaan C.G.M., van der Lugt, Aad, Dippel, Diederik W.J., Roozenbeek, Bob, van der Steen, Wouter, van de Graaf, Rob A., Chalos, Vicky, Lingsma, Hester F., van Doormaal, Pieter Jan, Coutinho, Jonathan M., Emmer, Bart J., de Ridder, Inger, van Zwam, Wim, van der Worp, H. Bart, van der Schaaf, Irene, Gons, Rob A.R., Yo, Lonneke S.F., Boiten, Jelis, van den Wijngaard, Ido, Hofmeijer, Jeannette, Martens, Jasper, Schonewille, Wouter, Vos, Jan Albert, Tuladhar, Anil Man, de Laat, Karlijn F., van Hasselt, Boudewijn, Remmers, Michel, Vos, Douwe, Rozeman, Anouk, Elgersma, Otto, Uyttenboogaart, Maarten, Bokkers, Reinoud P.H., van Tuijl, Julia, Boukrab, Issam, van den Berg, René, Beenen, Ludo F.M., Roosendaal, Stefan D., Postma, Alida Annechien, Krietemeijer, Menno, Lycklama, Geert, Meijer, Frederick J.A., Hammer, Sebastiaan, van der Hoorn, Anouk, Yoo, Albert J., Gerrits, DIck, Truijman, MTB, Zinkstok, Sanne M., Koudstaal, Peter J., Manschot, Sanne, Kerkhoff, Henk, Nieboer, Daan, Berkhemer, Olvert, Wolff, Lennard, van der Sluijs, Matthijs, van Voorst, Henk, Tolhuisen, ML, Roos, Bwem, Majoie, Charles B.L.M., Staals, Julie, van Oostenbrugge, Robert J., Jenniskens, Sjoerd F.M., van Dijk, Lukas C., den Hertog, Heleen M., van Es, Adriaan C.G.M., van der Lugt, Aad, Dippel, Diederik W.J., and Roozenbeek, Bob

Abstract

Background: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. Methods: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. Findings: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-tre

Published
2022

5. Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial

Author

van der Steen, Wouter, van de Graaf, Rob A, Chalos, Vicky, Lingsma, Hester F, van Doormaal, Pieter Jan, Coutinho, Jonathan M, Emmer, Bart J, de Ridder, Inger, van Zwam, Wim, van der Worp, H Bart, van der Schaaf, Irene, Gons, Rob A R, Yo, Lonneke S F, Boiten, Jelis, van den Wijngaard, Ido, Hofmeijer, Jeannette, Martens, Jasper, Schonewille, Wouter, Vos, Jan Albert, Tuladhar, Anil Man, de Laat, Karlijn F, van Hasselt, Boudewijn, Remmers, Michel, Vos, Douwe, Rozeman, Anouk, Elgersma, Otto, Uyttenboogaart, Maarten, Bokkers, Reinoud P H, van Tuijl, Julia, Boukrab, Issam, van den Berg, René, Beenen, Ludo F M, Roosendaal, Stefan D, Postma, Alida Annechien, Krietemeijer, Menno, Lycklama, Geert, Meijer, Frederick J A, Hammer, Sebastiaan, van der Hoorn, Anouk, Yoo, Albert J, Gerrits, Dick, Truijman, Martine T B, Zinkstok, Sanne, Koudstaal, Peter J, Manschot, Sanne, Kerkhoff, Henk, Nieboer, Daan, Berkhemer, Olvert, Staals, Julie, van Oostenbrugge, Robert J, MR CLEAN-MED investigators, van der Steen, Wouter, van de Graaf, Rob A, Chalos, Vicky, Lingsma, Hester F, van Doormaal, Pieter Jan, Coutinho, Jonathan M, Emmer, Bart J, de Ridder, Inger, van Zwam, Wim, van der Worp, H Bart, van der Schaaf, Irene, Gons, Rob A R, Yo, Lonneke S F, Boiten, Jelis, van den Wijngaard, Ido, Hofmeijer, Jeannette, Martens, Jasper, Schonewille, Wouter, Vos, Jan Albert, Tuladhar, Anil Man, de Laat, Karlijn F, van Hasselt, Boudewijn, Remmers, Michel, Vos, Douwe, Rozeman, Anouk, Elgersma, Otto, Uyttenboogaart, Maarten, Bokkers, Reinoud P H, van Tuijl, Julia, Boukrab, Issam, van den Berg, René, Beenen, Ludo F M, Roosendaal, Stefan D, Postma, Alida Annechien, Krietemeijer, Menno, Lycklama, Geert, Meijer, Frederick J A, Hammer, Sebastiaan, van der Hoorn, Anouk, Yoo, Albert J, Gerrits, Dick, Truijman, Martine T B, Zinkstok, Sanne, Koudstaal, Peter J, Manschot, Sanne, Kerkhoff, Henk, Nieboer, Daan, Berkhemer, Olvert, Staals, Julie, van Oostenbrugge, Robert J, and MR CLEAN-MED investigators

Abstract

BACKGROUND: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke.METHODS: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621.FINDINGS: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified inte

Published
2022

6. Alterations and test–retest reliability of functional connectivity network measures in cerebral small vessel disease

Author

Gesierich, Benno, Tuladhar, Anil Man, Telgte, Annemieke, Wiegertjes, Kim, Konieczny, Marek J., Finsterwalder, Sofia, Hübner, Mathias, Pirpamer, Lukas, Koini, Marisa, Abdulkadir, Ahmed, Franzmeier, Nicolai, Norris, David G., Marques, José P., Zu Eulenburg, Peter, Ewers, Michael, Schmidt, Reinhold, Leeuw, Frank‐Erik, and Duering, Marco

Subjects
610 Medicine & health
Abstract

While structural network analysis consolidated the hypothesis of cerebral small vessel disease (SVD) being a disconnection syndrome, little is known about functional changes on the level of brain networks. In patients with genetically defined SVD (CADASIL, n = 41) and sporadic SVD (n = 46), we independently tested the hypothesis that functional networks change with SVD burden and mediate the effect of disease burden on cognitive performance, in particular slowing of processing speed. We further determined test-retest reliability of functional network measures in sporadic SVD patients participating in a high-frequency (monthly) serial imaging study (RUN DMC-InTENse, median: 8 MRIs per participant). Functional networks for the whole brain and major subsystems (i.e., default mode network, DMN; fronto-parietal task control network, FPCN; visual network, VN; hand somatosensory-motor network, HSMN) were constructed based on resting-state multi-band functional MRI. In CADASIL, global efficiency (a graph metric capturing network integration) of the DMN was lower in patients with high disease burden (standardized beta = -.44; p [corrected] = .035) and mediated the negative effect of disease burden on processing speed (indirect path: std. beta = -.20, p = .047; direct path: std. beta = -.19, p = .25; total effect: std. beta = -.39, p = .02). The corresponding analyses in sporadic SVD showed no effect. Intraclass correlations in the high-frequency serial MRI dataset of the sporadic SVD patients revealed poor test-retest reliability and analysis of individual variability suggested an influence of age, but not disease burden, on global efficiency. In conclusion, our results suggest that changes in functional connectivity networks mediate the effect of SVD-related brain damage on cognitive deficits. However, limited reliability of functional network measures, possibly due to age-related comorbidities, impedes the analysis in elderly SVD patients.

Published
2020
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7. Alterations and test–retest reliability of functional connectivity network measures in cerebral small vessel disease

Author

Gesierich, Benno, primary, Tuladhar, Anil Man, additional, Telgte, Annemieke, additional, Wiegertjes, Kim, additional, Konieczny, Marek J., additional, Finsterwalder, Sofia, additional, Hübner, Mathias, additional, Pirpamer, Lukas, additional, Koini, Marisa, additional, Abdulkadir, Ahmed, additional, Franzmeier, Nicolai, additional, Norris, David G., additional, Marques, José P., additional, zu Eulenburg, Peter, additional, Ewers, Michael, additional, Schmidt, Reinhold, additional, Leeuw, Frank‐Erik, additional, and Duering, Marco, additional

Published
2020
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8. Serum Neurofilament Light Chain Levels Are Related to Small Vessel Disease Burden

Author

Duering, Marco, primary, Konieczny, Marek J., additional, Tiedt, Steffen, additional, Baykara, Ebru, additional, Tuladhar, Anil Man, additional, Leijsen, Esther van, additional, Lyrer, Philippe, additional, Engelter, Stefan T., additional, Gesierich, Benno, additional, Achmüller, Melanie, additional, Barro, Christian, additional, Adam, Ruth, additional, Ewers, Michael, additional, Dichgans, Martin, additional, Kuhle, Jens, additional, de Leeuw, Frank-Erik, additional, and Peters, Nils, additional

Published
2018
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9. Structural Network Connectivity And Hypertension In Cerebral Small Vessel Disease

Author

Tuladhar, Anil Man

Abstract

Background and Aims:Recent studies have shown that white matter disruption, indicated by network efficiency, plays an important role in the development of cognitive impairment in cerebral small vessel disease (SVD). As wide range of network measures now exist, we investigated which network measure is the most biologically informative in explaining the cognitive deficits and we assessed the effect of hypertension on this network measure.Methods:436 non-demented participants with SVD on neuroimaging were included (mean age 65.2 years [SD: 8.8], 46% female). Weighted connectivity matrices from diffusion tensor imaging and graph-theoretical measures were calculated. To identify the most influential network measure, we performed elastic net method. We performed linear regression models and mediation analysis to assess the association between hypertension, SVD markers and network measure, adjusted for age, sex, education and other cardiovascular risk factors.Results:Global efficiency showed the strongest association with psychomotor speed and cognitive index among all network measures in SVD. Hypertension was significantly associated with lower global efficiency (u03b2=-0.15, P=0.01) and higher white matter hypertensities (WMH) volume (u03b2=0.15, P=0.01). Mediation analysis showed that hypertension was directly related to global efficiency (u03b2=-0.19, P=0.03u2009). However the effect of indirect pathway through WMH is stronger (u03b2=-0.24, Pu2009

Published
2017

10. A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms

Author

Baykara, Ebru, Gesierich, Benno, Adam, Ruth, Tuladhar, Anil Man, Biesbroek, J. Matthijs, Koek, Huiberdina L., Ropele, Stefan, Jouvent, Eric, Chabriat, Hugues, Ertl-Wagner, Birgit, Ewers, Michael, Schmidt, Reinhold, de Leeuw, Frank Erik, Biessels, Geert Jan, Dichgans, Martin, Duering, Marco, Baykara, Ebru, Gesierich, Benno, Adam, Ruth, Tuladhar, Anil Man, Biesbroek, J. Matthijs, Koek, Huiberdina L., Ropele, Stefan, Jouvent, Eric, Chabriat, Hugues, Ertl-Wagner, Birgit, Ewers, Michael, Schmidt, Reinhold, de Leeuw, Frank Erik, Biessels, Geert Jan, Dichgans, Martin, and Duering, Marco

Published
2016

11. A Novel Imaging Marker for Small Vessel Disease Based on Skeletonization of White Matter Tracts and Diffusion Histograms

Author

Opleiding Neurologie, Brain, MS Geriatrie, Circulatory Health, ZL Algemene Neurologie Medisch, Baykara, Ebru, Gesierich, Benno, Adam, Ruth, Tuladhar, Anil Man, Biesbroek, J. Matthijs, Koek, Huiberdina L., Ropele, Stefan, Jouvent, Eric, Chabriat, Hugues, Ertl-Wagner, Birgit, Ewers, Michael, Schmidt, Reinhold, de Leeuw, Frank Erik, Biessels, Geert Jan, Dichgans, Martin, Duering, Marco, Opleiding Neurologie, Brain, MS Geriatrie, Circulatory Health, ZL Algemene Neurologie Medisch, Baykara, Ebru, Gesierich, Benno, Adam, Ruth, Tuladhar, Anil Man, Biesbroek, J. Matthijs, Koek, Huiberdina L., Ropele, Stefan, Jouvent, Eric, Chabriat, Hugues, Ertl-Wagner, Birgit, Ewers, Michael, Schmidt, Reinhold, de Leeuw, Frank Erik, Biessels, Geert Jan, Dichgans, Martin, and Duering, Marco

Published
2016

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