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3. Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial

Author

Phan, Timmy, Selmes, Christine, Lees, Kennedy, Kaste, Markku, MacIsaac, Rachael, Wellings, Tom, Loiselle, Andre, Pepper, Elizabeth, Miteff, Ferdi, Krishnamurthy, Venkatesh, Ang, Timothy, Alanati, Khaled, Gangadharan, Shyam, Zareie, Hossein, Starling, Rita, Dunkerton, Sophie, He, Jiacheng, Datta, Raka, Royan, Angela, Kerr, Erin, Kaauwai, Lara, Belevski, Linda, Ormond, Sally, Johnson, Annalese, Evans, Malcolm, Lachapelle, Nicole, Ombelet, Fouke, Bladin, Chris, Dewey, Helen, Wong, Joseph, Park, Peter, Cody, Ross, Tan, Peter, Callaly, Edward, Senanayake, Channa, Thomas, Grace, Liu, Jennifer, Busch, Tessa, Stuart, Narelle, Chung, Malcohm, Yassi, Nawaf, Valente, Michael, Sharobeam, Angelos, Cooley, Regan, Zhao, Henry, Alemseged, Fana, Williams, Cameron, Ng, Jo Lyn, Balabanski, Anna, dos Santos, Angela, Williamson, John, Pavlin-Premrl, Davor, Beharry, James, Ma, Margaret, Park, Ashley, Yan, Bernard, Hand, Peter, Jackson, David, McDonald, Amy, Fisicchia, Laura, Parsons, Nicola, Olenko, Liudmyla, Johns, Hannah, Guha, Prodipta, Rokaha, Birendra, Dhimal, Niruta, Harvey, Jackson, Cagi, Lavenia, Chia, Nicholas, Goh, Rudy, Palanikumar, Log, El-Masri, Shaddy, Mahadevan, Joshua, Kuranawai, Craig, Waters, Michael, Vallat, Wilson, Cheong, Eddie, Drew, Roy, Cordato, Dennis, McDougall, Alan, Cappelen-Smith, Cecilia, Venkat, Abhay, Edwards, Leon, Blair, Christopher, Thomas, James, Helou, Jacob, Green, Daniel, Nguyen, Tram, Pham, Timmy, Khan, Jasmeen, Miller, Megan, Loubiere, Laurence, Buck, Brian, Butcher, Ken, Fairall, Paige, Butt, Asif, Kalashyan, Hayrapet, Nomani, Ali, Lloret, Mar, Mishra, Sachin, Thirunavukkarasu, Sibi, Sivakumar, Leka, D'Souza, Atlantic, Tsai, Chon-Haw, Tseng, Billy, Tai, Iris, Chiang, I-Husan, Kuan, Angela, Tsai, Vivian, Hsu, Alice, Hsu, Sammi, Alchin, Deborah, Sanjuan, Estela, Fink, John, Wilson, Duncan, Mason, Deborah, Berry-Norohna, Alexander, Winders, Joel, Eagle, Jane, Green, Rosemary, Bremner, Kathleen, Celestino, Sherisse, Lee, Jiunn-Tay, Chou, Chung-Hsing, Tsai, Chia-Kuang, Sung, Yueh-Feng, Tsai, Chia-Lin, Lin, Yu-Kai, Kao, Hung-Wen, Vuong, Jason, Thirugnanachandran, Tharani, Hervet, Marie Veronic, Simmons, Karen, Sabet, Arman, Bailey, Peter, Urbi, Berzenn, Kurakose, Sumole, Martinez-Majander, Nicolas, Räty, Silja, Tiainen, Marjaana, Sibolt, Gerli, Ivanoff, Terhi, Sanz, Ana Calleja, García, Elisa Cortijo, De Lera Alfonso, Mercedes C., Araque, Maria Ester Ramos, Gómez, Alicia Sierra, Peñacoba, Gonzalo Valle, Vicente, Beatriz Gómez, Muñoz, Javier Reyes, Muñoz Rubio, Pedro Luis, Shah, Darshan, Harrison, Emma, Bendall, Carol, Subramanian, Ganesh, Jeng, Jiann-Shing, Tang, Sung-Chun, Tsai, Li-Kai, Yeh, Shin-Joe, Chen, Chih-Hao, Chung, Tai-Chun, Wong, Andrew, Muller, Claire, Skinner, Genevieve, Gunathilagan, Gunaratnam, Natarajan, Indira, Coutts, Shelagh, Menon, Bijoy, Kenney, Carol, Clarke, Brian, Ghatala, Rita, Mudd, Paul, Chen, Chih-Hung, Lemmens, Robin, Demeestere, Jelle, Mahant, Neil, Sun, Mu-Chien, Parsons, Mark W, Yogendrakumar, Vignan, Churilov, Leonid, Garcia-Esperon, Carlos, Campbell, Bruce C V, Russell, Michelle L, Sharma, Gagan, Chen, Chushuang, Lin, Longting, Chew, Beng Lim, Ng, Felix C, Deepak, Akshay, Choi, Philip M C, Kleinig, Timothy J, Cordato, Dennis J, Wu, Teddy Y, Fink, John N, Ma, Henry, Phan, Thanh G, Markus, Hugh S, Molina, Carlos A, Strbian, Daniel, Meretoja, Atte, Arenillas, Juan F, Buck, Brian H, Devlin, Michael J, Brown, Helen, Butcher, Ken S, O'Brien, Billy, Wijeratne, Tissa, Bivard, Andrew, Grimley, Rohan S, Agarwal, Smriti, Munshi, Sunil K, Donnan, Geoffrey A, Davis, Stephen M, Miteff, Ferdinand, Spratt, Neil J, and Levi, Christopher R

Published
2024
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7. Pragmatic solutions to reduce the global burden of stroke: a World Stroke Organization–Lancet Neurology Commission

Author

Feigin, Valery L, Abd-Allah, Foad, Akinyemi, Rufus O, Bhattacharjee, Natalia V, Brainin, Michael, Cao, Jackie, Caso, Valeria, Dalton, Bronte, Davis, Alan, Dempsey, Robert, Duprey, Joseph, Feng, Wuwei, Ford, Gary A, Gall, Seana, Gandhi, Dorcas, Good, David C, Hachinski, Vladimir, Hacke, Werner, Hankey, Graeme J, Ishida, Marie, Johnson, Walter, Kim, Julie, Lavados, Pablo, Lindsay, Patrice, Mahal, Ajay, Martins, Sheila, Murray, Christopher, Nguyen, Thuy Phuong, Norrving, Bo, Olaiya, Muideen T, Olalusi, Oladotun V, Pandian, Jeyaraj, Phan, Hoang, Platz, Thomas, Ranta, Anna, Rehman, Sabah, Roth, Greg, Sebastian, Ivy Anne, Smith, Amanda E, Suwanwela, Nijasri C, Sylaja, P N, Thapa, Rajshree, Thrift, Amanda G, Uvere, Ezinne, Vollset, Stein Emil, Yavagal, Dileep, Yaria, Joseph, Owolabi, Mayowa O, Abera, Semaw Ferede, Akinyemi, Rufus, Dempsey, Robert J, Ibrahim, Norlinah Mohamed, Liu, Liping, Ovbiagele, Bruce, Piradov, Michael, Suwanwela, Nijasri, Abanto, Carlos, Addissie, Adamu, Adeleye, Amos O, Adilbekov, Yerzhan, Adilbekova, Bibigul, Adoukonou, Thierry A, Aguiar de Sousa, Diana, Akhmetzhanova, Zauresh, Akpalu, Albert, El Alaoui-Faris, Mustapha, Ameriso, Sebastian F, Andonova, Silva, Arsovska, Anita, Awoniyi, Folorunso E, Bakhiet, Moiz, Barboza, Miguel A, Basri, Hamidon, Bath, Philip M, Bereczki, Daniel, Beretta, Simone, Berkowitz, Aaron L, Bernhardt, Julie, Berzina, Guna, Bhavsar, Bhavan, Bisharyan, Mher S, Bohara, Manoj, Bovet, Pascal, Budincevic, Hrvoje, Cadilhac, Dominique A, Čerimagić, Denis, Charway-Felli, Augustina, Chen, Christopher, Chin, Jerome H, Christensen, Hanne, Chwojnicki, Kamil, Conforto, Adriana B, Correia, Manuel, Mora Cuervo, Daissy L, Członkowska, Anna, D'Amelio, Marco, Danielyan, Kristine E, Davis, Stephen, Demarin, Vida, Demchuk, Andrew M, Dichgans, Martin, Dokova, Klara, Donnan, Geoffrey, Duran, Juan Carlos, Ekeng, Gloria, Elkind, Mitchell S, Endres, Matthias, Fischer, Urs, Flomin, Yuriy, Gankpe, Fortuné, Gavidia, Martin, Gaye Saavedra, Andrés, Gebreyohanns, Mehari, George, Mary, Gierlotka, Marek, Giroud, Maurice, Gnedovskaya, Elena V, Gonçalves, Ivete Pillo, Gongora-Rivera, Fernando, Gunaratne, Padma S, Hamadeh, Randah R, Hamzat, Tal-hatu K, Heldner, Mirjam R, Ibrahim, Etedal, Ihle-Hansen, Hanne, Jee, Sungju, Jiann-Shing, Jeng, Johnston, S Clay, Jovanovic, Dejana, Jurjāns, Kristaps, Kalani, Rizwan, Kalkonde, Yogeshwar, Kamenova, Saltanat, Karaszewski, Bartosz, Kelly, Peter, Kiechl, Stefan, Kondybayeva, Aida, Kõrv, Janika, Kozera, Grzegorz, Kravchenko, Michael, Krespi, Yakup, Krishnamurthi, Rita, Kruja, Jera, Kutluk, Kursad, Langhorne, Peter, Law, Zhe K, Lebedynets, Dmytro, Lee, Tsong-Hai, Leung, Thomas W, Liebeskind, David S, López-Jaramillo, Patricio, Lotufo, Paulo A, Machline-Carrion, M Julia, Maia, Luis F, Malojcic, Branko, Markus, Hugh S, Marquez-Romero, Juan M, Medina, Marco T, Medukhanova, Sabina, Mehndiratta, Man Mohan, Miglāne, Evija, Mihejeva, Illa, Mikulik, Robert, Mirrakhimov, Erkin, Mohl, Stephanie, Munakomi, Sunil, Murphy, Sean, Musa, Kamarul I, Nasreldein, Ahmed, Nogueira, Raul G, Nolte, Christian H, Noubiap, Jean Jacques, Novarro-Escudero, Nelson, Ocampo, Cassandra, O'Donnell, Martin, Ogun, Yomi, Ogunniyi, Adesola, Oraby, Mohammed I, Ōrken, Dilek N, Ōzdemir, Atilla O, Ozturk, Serefnur, Paccot, Mélanie, Pereira, Telmo, Peeters, André, Potpara, Tatjana, Proios, Hariklia, Rathore, Farooq A, Sacco, Ralph L, Sahathevan, Ramesh, Sandset, Else S, Renato Santos, Irving, Saposnik, Gustavo, Sarfo, Fred S, Sargento-Freitas, João, Sharma, Mukul, Shaw, Louise, Sheth, Kevin N, Shin, Yong-Il, Shobhana, A, Silva, S Nishan, Tedim Cruz, Vitor, Thakur, Kiran, Thapa, Lekh Jung, Toni, Danilo, Topcuoglu, Mehmetakif A, Torales, Julio, Towfighi, Amytis, Truelsen, Thomas, Tsiskaridze, Alexander, Tulloch-Reid, Marshall, Useche, Juan N, Vanacker, Peter, Vassilopoulou, Sophia, Vukorepa, Gorana, Vuletic, Vladimira, Wahab, Kolawole W, Wang, Wenzhi, Wijeratne, Tissa, Wojtyniak, Bogdan, Wolfe, Charles, Yacouba, Mapoure N, Yang, Jie, Yifru, Yared M, Yock-Corrales, Adriana, Yonemoto, Naohiro, Yperzeele, Laetitia, and Zagożdżon, Pawel

Published
2023
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9. Neuroimaging standards for research into small vessel disease—advances since 2013

Author

Duering, Marco, Biessels, Geert Jan, Brodtmann, Amy, Chen, Christopher, Cordonnier, Charlotte, de Leeuw, Frank-Erik, Debette, Stéphanie, Frayne, Richard, Jouvent, Eric, Rost, Natalia S, ter Telgte, Annemieke, Al-Shahi Salman, Rustam, Backes, Walter H, Bae, Hee-Joon, Brown, Rosalind, Chabriat, Hugues, De Luca, Alberto, deCarli, Charles, Dewenter, Anna, Doubal, Fergus N, Ewers, Michael, Field, Thalia S, Ganesh, Aravind, Greenberg, Steven, Helmer, Karl G, Hilal, Saima, Jochems, Angela C C, Jokinen, Hanna, Kuijf, Hugo, Lam, Bonnie Y K, Lebenberg, Jessica, MacIntosh, Bradley J, Maillard, Pauline, Mok, Vincent C T, Pantoni, Leonardo, Rudilosso, Salvatore, Satizabal, Claudia L, Schirmer, Markus D, Schmidt, Reinhold, Smith, Colin, Staals, Julie, Thrippleton, Michael J, van Veluw, Susanne J, Vemuri, Prashanthi, Wang, Yilong, Werring, David, Zedde, Marialuisa, Akinyemi, Rufus O, Del Brutto, Oscar H, Markus, Hugh S, Zhu, Yi-Cheng, Smith, Eric E, Dichgans, Martin, and Wardlaw, Joanna M

Published
2023
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10. Association of common genetic variants with brain microbleeds: A Genome-wide Association Study

Author

Knol, Maria J, Lu, Dongwei, Traylor, Matthew, Adams, Hieab HH, Romero, José Rafael J, Smith, Albert V, Fornage, Myriam, Hofer, Edith, Liu, Junfeng, Hostettler, Isabel C, Luciano, Michelle, Trompet, Stella, Giese, Anne-Katrin, Hilal, Saima, van den Akker, Erik B, Vojinovic, Dina, Li, Shuo, Sigurdsson, Sigurdur, van der Lee, Sven J, Jack, Clifford R, Wilson, Duncan, Yilmaz, Pinar, Satizabal, Claudia L, Liewald, David CM, van der Grond, Jeroen, Chen, Christopher, Saba, Yasaman, van der Lugt, Aad, Bastin, Mark E, Windham, B Gwen, Cheng, Ching Yu, Pirpamer, Lukas, Kantarci, Kejal, Himali, Jayandra J, Yang, Qiong, Morris, Zoe, Beiser, Alexa S, Tozer, Daniel J, Vernooij, Meike W, Amin, Najaf, Beekman, Marian, Koh, Jia Yu, Stott, David J, Houlden, Henry, Schmidt, Reinhold, Gottesman, Rebecca F, MacKinnon, Andrew D, DeCarli, Charles, Gudnason, Vilmundur, Deary, Ian J, van Duijn, Cornelia M, Slagboom, P Eline, Wong, Tien Yin, Rost, Natalia S, Jukema, J Wouter, Mosley, Thomas H, Werring, David J, Schmidt, Helena, Wardlaw, Joanna M, Ikram, M Arfan, Seshadri, Sudha, Launer, Lenore J, Markus, Hugh S, and Initiative, for the Alzheimer’s Disease Neuroimaging

Subjects
Stroke, Human Genome, Neurosciences, Brain Disorders, Genetics, Prevention, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Alleles, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, Case-Control Studies, Cerebral Hemorrhage, Cerebral Small Vessel Diseases, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk, White Matter, Alzheimer's Disease Neuroimaging Initiative, Clinical Sciences, Cognitive Sciences, Neurology & Neurosurgery
Abstract

ObjectiveTo identify common genetic variants associated with the presence of brain microbleeds (BMBs).MethodsWe performed genome-wide association studies in 11 population-based cohort studies and 3 case-control or case-only stroke cohorts. Genotypes were imputed to the Haplotype Reference Consortium or 1000 Genomes reference panel. BMBs were rated on susceptibility-weighted or T2*-weighted gradient echo MRI sequences, and further classified as lobar or mixed (including strictly deep and infratentorial, possibly with lobar BMB). In a subset, we assessed the effects of APOE ε2 and ε4 alleles on BMB counts. We also related previously identified cerebral small vessel disease variants to BMBs.ResultsBMBs were detected in 3,556 of the 25,862 participants, of which 2,179 were strictly lobar and 1,293 mixed. One locus in the APOE region reached genome-wide significance for its association with BMB (lead single nucleotide polymorphism rs769449; odds ratio [OR]any BMB [95% confidence interval (CI)] 1.33 [1.21-1.45]; p = 2.5 × 10-10). APOE ε4 alleles were associated with strictly lobar (OR [95% CI] 1.34 [1.19-1.50]; p = 1.0 × 10-6) but not with mixed BMB counts (OR [95% CI] 1.04 [0.86-1.25]; p = 0.68). APOE ε2 alleles did not show associations with BMB counts. Variants previously related to deep intracerebral hemorrhage and lacunar stroke, and a risk score of cerebral white matter hyperintensity variants, were associated with BMB.ConclusionsGenetic variants in the APOE region are associated with the presence of BMB, most likely due to the APOE ε4 allele count related to a higher number of strictly lobar BMBs. Genetic predisposition to small vessel disease confers risk of BMB, indicating genetic overlap with other cerebral small vessel disease markers.

Published
2020

11. 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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12. Complement genes contribute sex-biased vulnerability in diverse disorders

Author

Arranz, Maria J, Bakker, Steven, Bender, Stephan, Bramon, Elvira, Collier, David A, Crespo-Facorro, Benedicto, Hall, Jeremy, Iyegbe, Conrad, Jablensky, Assen V, Kahn, René S, Kalaydjieva, Luba, Lawrie, Stephen, Lewis, Cathryn M, Lin, Kuang, Linszen, Don H, Mata, Ignacio, McIntosh, Andrew M, Murray, Robin M, Ophoff, Roel A, Van Os, Jim, Powell, John, Rujescu, Dan, Walshe, Muriel, Weisbrod, Matthias, Wiersma, Durk, Donnelly, Peter, Barroso, Ines, Blackwell, Jenefer M, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Giannoulatou, Eleni, Hellenthal, Garrett, Pearson, Richard, Pirinen, Matti, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Edkins, Sarah, Gillman, Matthew, Gray, Emma, Gwilliam, Rhian, Hammond, Naomi, Hunt, Sarah E, Jayakumar, Alagurevathi, Liddle, Jennifer, McCann, Owen T, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Tashakkori-Ghanbaria, Avazeh, Waller, Matthew, Weston, Paul, Whittaker, Pamela, Widaa, Sara, and McCarthy, Mark I

Subjects
Autoimmune Disease, Schizophrenia, Mental Health, Lupus, Genetics, Brain Disorders, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Adult, Alleles, Complement C3, Complement C4, Female, Genetic Predisposition to Disease, HLA Antigens, Haplotypes, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Male, Middle Aged, Sex Characteristics, Sjogren's Syndrome, Young Adult, Schizophrenia Working Group of the Psychiatric Genomics Consortium, General Science & Technology
Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Published
2020

13. Proceedings from the Albert Charitable Trust Inaugural Workshop on white matter and cognition in aging

Author

Sorond, Farzaneh A, Whitehead, Shawn, Arai, Ken, Arnold, Douglas, Carmichael, S Thomas, De Carli, Charles, Duering, Marco, Fornage, Myriam, Flores-Obando, Rafael E, Graff-Radford, Jonathan, Hamel, Edith, Hess, David C, Ihara, Massafumi, Jensen, Majken K, Markus, Hugh S, Montagne, Axel, Rosenberg, Gary, Shih, Andy Y, Smith, Eric E, Thiel, Alex, Tse, Kai Hei, Wilcock, Donna, and Barone, Frank

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Neurosciences, Aging, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Behavioral and Social Science, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Cognition, Cognitive Dysfunction, Dementia, Vascular, Humans, White Matter, Blood-brain barrier, Brain white matter, Myelin, Neurovascular, Oligovascular, Vascular cognitive impairment, Genetics, Clinical sciences
Abstract

This third in a series of vascular cognitive impairment (VCI) workshops, supported by "The Leo and Anne Albert Charitable Trust," was held from February 8 to 12 at the Omni Resort in Carlsbad, CA. This workshop followed the information gathered from the earlier two workshops suggesting that we focus more specifically on brain white matter in age-related cognitive impairment. The Scientific Program Committee (Frank Barone, Shawn Whitehead, Eric Smith, and Rod Corriveau) assembled translational, clinical, and basic scientists with unique expertise in acute and chronic white matter injury at the intersection of cerebrovascular and neurodegenerative etiologies. As in previous Albert Trust workshops, invited participants addressed key topics related to mechanisms of white matter injury, biomarkers of white matter injury, and interventions to prevent white matter injury and age-related cognitive decline. This report provides a synopsis of the presentations and discussions by the participants, including the existing knowledge gaps and the delineation of the next steps towards advancing our understanding of white matter injury and age-related cognitive decline. Workshop discussions and consensus resulted in action by The Albert Trust to (1) increase support from biannual to annual "White Matter and Cognition" workshops; (2) provide funding for two collaborative, novel research grants annually submitted by meeting participants; and (3) coordinate the formation of the "Albert Research Institute for White Matter and Cognition." This institute will fill a gap in white matter science, providing white matter and cognition communications, including annual updates from workshops and the literature and interconnecting with other Albert Trust scientific endeavors in cognition and dementia, and providing support for newly established collaborations between seasoned investigators and to the development of talented young investigators in the VCI-dementia (VCID) and white matter cognition arena.

Published
2020

15. A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia

Author

Sri, Sarmi, Greenstein, Adam, Granata, Alessandra, Collcutt, Alex, Jochems, Angela C C, McColl, Barry W, Castro, Blanca Díaz, Webber, Caleb, Reyes, Carmen Arteaga, Hall, Catherine, Lawrence, Catherine B, Hawkes, Cheryl, Pegasiou-Davies, Chrysia-Maria, Gibson, Claire, Crawford, Colin L, Smith, Colin, Vivien, Denis, McLean, Fiona H, Wiseman, Frances, Brezzo, Gaia, Lalli, Giovanna, Pritchard, Harry A T, Markus, Hugh S, Bravo-Ferrer, Isabel, Taylor, Jade, Leiper, James, Berwick, Jason, Gan, Jian, Gallacher, John, Moss, Jonathan, Goense, Jozien, McMullan, Letitia, Work, Lorraine, Evans, Lowri, Stringer, Michael S, Ashford, MLJ, Abulfadl, Mohamed, Conlon, Nina, Malhotra, Paresh, Bath, Philip, Canter, Rebecca, Brown, Rosalind, Ince, Selvi, Anderle, Silvia, Young, Simon, Quick, Sophie, Szymkowiak, Stefan, Hill, Steve, Allan, Stuart, Wang, Tao, Quinn, Terry, Procter, Tessa, Farr, Tracy D, Zhao, Xiangjun, Yang, Zhiyuan, Hainsworth, Atticus H, and Wardlaw, Joanna M

Published
2023
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19. MINocyclinE to Reduce inflammation and blood‐brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double‐blind, placebo‐controlled experimental medicine trial

Author

Brown, Robin B., primary, Tozer, Daniel J., additional, Loubière, Laurence, additional, Harshfield, Eric L., additional, Hong, Young T., additional, Fryer, Tim D., additional, Williams, Guy B., additional, Graves, Martin J., additional, Aigbirhio, Franklin I., additional, O'Brien, John T., additional, and Markus, Hugh S., additional

Published
2024
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21. Population‐based identity‐by‐descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia

Author

Harold, Denise, Connolly, Siobhan, Riley, Brien P, Kendler, Kenneth S, McCarthy, Shane E, McCombie, William R, Richards, Alex, Owen, Michael J, O'Donovan, Michael C, Walters, James, Donnelly, Peter, Bates, Lesley, Barroso, Ines, Blackwell, Jenefer M, Bramon, Elvira, Brown, Matthew A, Casas, Juan P, Corvin, Aiden, Deloukas, Panos, Duncanson, Audrey, Jankowski, Janusz, Markus, Hugh S, Mathew, Christopher G, Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Sawcer, Stephen J, Trembath, Richard C, Viswanathan, Ananth C, Wood, Nicholas W, Spencer, Chris CA, Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Giannoulatou, Eleni, Hopkins, Lucinda, Pirinen, Matti, Pearson, Richard, Strange, Amy, Su, Zhan, Vukcevic, Damjan, Langford, Cordelia, Hunt, Sarah E, Edkins, Sarah, Gwilliam, Rhian, Blackburn, Hannah, Bumpstead, Suzannah J, Dronov, Serge, Gillman, Matthew, Gray, Emma, Hammond, Naomi, Jayakumar, Alagurevathi, McCann, Owen T, Liddle, Jennifer, Potter, Simon C, Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, Whittaker, Pamela, Ripke, Stephan, Neale, Benjamin M, Walters, James TR, Farh, Kai‐How, Holmans, Peter A, Lee, Phil, Bulik‐Sullivan, Brendan, Collier, David A, Huang, Hailiang, Pers, Tune H, Agartz, Ingrid, Agerbo, Esben, Albus, Margot, Alexander, Madeline, Amin, Farooq, Bacanu, Silviu A, Begemann, Martin, Belliveau, Richard A, Bene, Judit, Bergen, Sarah E, Bevilacqua, Elizabeth, Bigdeli, Tim B, Black, Donald W, Bruggeman, Richard, Buccola, Nancy G, Buckner, Randy L, Byerley, William, Cahn, Wiepke, Cai, Guiqing, Campion, Dominique, Cantor, Rita M, Carr, Vaughan J, Carrera, Noa, Catts, Stanley V, Chambert, Kimberley D, Chan, Raymond CK, and Chan, Ronald YL

Subjects
Biological Sciences, Genetics, Clinical Research, Schizophrenia, Brain Disorders, Human Genome, Prevention, Serious Mental Illness, Mental Health, Aetiology, 2.1 Biological and endogenous factors, Adult, Case-Control Studies, Chromosome Mapping, DNA Copy Number Variations, Databases, Genetic, Exome, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Male, Middle Aged, Risk Factors, Sequence Analysis, DNA, Exome Sequencing, GWAS, IBD mapping, rare variants, Wellcome Trust Case Control Consortium 2, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Clinical Sciences, Neurosciences, Clinical sciences
Abstract

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re-analyze an Irish schizophrenia GWAS dataset (n = 3,473) by performing identity-by-descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNT but did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow-up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Published
2019

22. Vascular dysfunction-The disregarded partner of Alzheimer's disease.

Author

Sweeney, Melanie D, Montagne, Axel, Sagare, Abhay P, Nation, Daniel A, Schneider, Lon S, Chui, Helena C, Harrington, Michael G, Pa, Judy, Law, Meng, Wang, Danny JJ, Jacobs, Russell E, Doubal, Fergus N, Ramirez, Joel, Black, Sandra E, Nedergaard, Maiken, Benveniste, Helene, Dichgans, Martin, Iadecola, Costantino, Love, Seth, Bath, Philip M, Markus, Hugh S, Salman, Rustam A, Allan, Stuart M, Quinn, Terence J, Kalaria, Rajesh N, Werring, David J, Carare, Roxana O, Touyz, Rhian M, Williams, Steve CR, Moskowitz, Michael A, Katusic, Zvonimir S, Lutz, Sarah E, Lazarov, Orly, Minshall, Richard D, Rehman, Jalees, Davis, Thomas P, Wellington, Cheryl L, González, Hector M, Yuan, Chun, Lockhart, Samuel N, Hughes, Timothy M, Chen, Christopher LH, Sachdev, Perminder, O'Brien, John T, Skoog, Ingmar, Pantoni, Leonardo, Gustafson, Deborah R, Biessels, Geert Jan, Wallin, Anders, Smith, Eric E, Mok, Vincent, Wong, Adrian, Passmore, Peter, Barkof, Frederick, Muller, Majon, Breteler, Monique MB, Román, Gustavo C, Hamel, Edith, Seshadri, Sudha, Gottesman, Rebecca F, van Buchem, Mark A, Arvanitakis, Zoe, Schneider, Julie A, Drewes, Lester R, Hachinski, Vladimir, Finch, Caleb E, Toga, Arthur W, Wardlaw, Joanna M, and Zlokovic, Berislav V

Subjects
Blood-Brain Barrier, Brain, Humans, Alzheimer Disease, Vascular Diseases, Cerebrovascular Circulation, United States, National Institute on Aging (U.S.), Amyloid beta-Peptides, White Matter, Biomarkers, Alzheimer's disease, Blood-brain barrier, Cerebral blood flow, MRI, Vascular, National Institute on Aging, Neurosciences, Clinical Sciences, Geriatrics
Abstract

Increasing evidence recognizes Alzheimer's disease (AD) as a multifactorial and heterogeneous disease with multiple contributors to its pathophysiology, including vascular dysfunction. The recently updated AD Research Framework put forth by the National Institute on Aging-Alzheimer's Association describes a biomarker-based pathologic definition of AD focused on amyloid, tau, and neuronal injury. In response to this article, here we first discussed evidence that vascular dysfunction is an important early event in AD pathophysiology. Next, we examined various imaging sequences that could be easily implemented to evaluate different types of vascular dysfunction associated with, and/or contributing to, AD pathophysiology, including changes in blood-brain barrier integrity and cerebral blood flow. Vascular imaging biomarkers of small vessel disease of the brain, which is responsible for >50% of dementia worldwide, including AD, are already established, well characterized, and easy to recognize. We suggest that these vascular biomarkers should be incorporated into the AD Research Framework to gain a better understanding of AD pathophysiology and aid in treatment efforts.

Published
2019

23. GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Author

Franceschini, Nora, Giambartolomei, Claudia, de Vries, Paul S, Finan, Chris, Bis, Joshua C, Huntley, Rachael P, Lovering, Ruth C, Tajuddin, Salman M, Winkler, Thomas W, Graff, Misa, Kavousi, Maryam, Dale, Caroline, Smith, Albert V, Hofer, Edith, van Leeuwen, Elisabeth M, Nolte, Ilja M, Lu, Lingyi, Scholz, Markus, Sargurupremraj, Muralidharan, Pitkänen, Niina, Franzén, Oscar, Joshi, Peter K, Noordam, Raymond, Marioni, Riccardo E, Hwang, Shih-Jen, Musani, Solomon K, Schminke, Ulf, Palmas, Walter, Isaacs, Aaron, Correa, Adolfo, Zonderman, Alan B, Hofman, Albert, Teumer, Alexander, Cox, Amanda J, Uitterlinden, André G, Wong, Andrew, Smit, Andries J, Newman, Anne B, Britton, Annie, Ruusalepp, Arno, Sennblad, Bengt, Hedblad, Bo, Pasaniuc, Bogdan, Penninx, Brenda W, Langefeld, Carl D, Wassel, Christina L, Tzourio, Christophe, Fava, Cristiano, Baldassarre, Damiano, O'Leary, Daniel H, Teupser, Daniel, Kuh, Diana, Tremoli, Elena, Mannarino, Elmo, Grossi, Enzo, Boerwinkle, Eric, Schadt, Eric E, Ingelsson, Erik, Veglia, Fabrizio, Rivadeneira, Fernando, Beutner, Frank, Chauhan, Ganesh, Heiss, Gerardo, Snieder, Harold, Campbell, Harry, Völzke, Henry, Markus, Hugh S, Deary, Ian J, Jukema, J Wouter, de Graaf, Jacqueline, Price, Jacqueline, Pott, Janne, Hopewell, Jemma C, Liang, Jingjing, Thiery, Joachim, Engmann, Jorgen, Gertow, Karl, Rice, Kenneth, Taylor, Kent D, Dhana, Klodian, Kiemeney, Lambertus ALM, Lind, Lars, Raffield, Laura M, Launer, Lenore J, Holdt, Lesca M, Dörr, Marcus, Dichgans, Martin, Traylor, Matthew, Sitzer, Matthias, Kumari, Meena, Kivimaki, Mika, Nalls, Mike A, Melander, Olle, Raitakari, Olli, Franco, Oscar H, Rueda-Ochoa, Oscar L, Roussos, Panos, Whincup, Peter H, Amouyel, Philippe, and Giral, Philippe

Subjects
MEGASTROKE Consortium, Humans, Coronary Disease, Genetic Predisposition to Disease, Amino Acid Oxidoreductases, Protein-Lysine 6-Oxidase, Risk Factors, Lod Score, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Plaque, Atherosclerotic, Carotid Intima-Media Thickness, ADAMTS9 Protein, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide
Abstract

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

Published
2018

24. Multi‐phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author

Temprano‐Sagrera, Gerard, Sitlani, Colleen M., Bone, William P., Martin‐Bornez, Miguel, Voight, Benjamin F., Morrison, Alanna C., Damrauer, Scott M., de Vries, Paul S., Smith, Nicholas L., Sabater‐Lleal, Maria, Dehghan, Abbas, Heath, Adam S, Morrison, Alanna C, Reiner, Alex P, Johnson, Andrew, Richmond, Anne, Peters, Annette, van Hylckama Vlieg, Astrid, McKnight, Barbara, Psaty, Bruce M, Hayward, Caroline, Ward‐Caviness, Cavin, O’Donnell, Christopher, Chasman, Daniel, Strachan, David P, Tregouet, David A, Mook‐Kanamori, Dennis, Gill, Dipender, Thibord, Florian, Asselbergs, Folkert W, Leebeek, Frank W.G., Rosendaal, Frits R, Davies, Gail, Homuth, Georg, Temprano, Gerard, Campbell, Harry, Taylor, Herman A, Bressler, Jan, Huffman, Jennifer E, Rotter, Jerome I, Yao, Jie, Wilson, James F, Bis, Joshua C, Hahn, Julie M, Desch, Karl C, Wiggins, Kerri L, Raffield, Laura M, Bielak, Lawrence F, Yanek, Lisa R, Kleber, Marcus E, Mueller, Martina, Kavousi, Maryam, Mangino, Massimo, Liu, Melissa, Brown, Michael R, Conomos, Matthew P, Jhun, Min‐A, Chen, Ming‐Huei, de Maat, Moniek P.M., Pankratz, Nathan, Smith, Nicholas L, Peyser, Patricia A, Elliot, Paul, de Vries, Paul S, Wei, Peng, Wild, Philipp S, Morange, Pierre E, van der Harst, Pim, Yang, Qiong, Le, Ngoc‐Quynh, Marioni, Riccardo, Li, Ruifang, Damrauer, Scott M, Cox, Simon R, Trompet, Stella, Felix, Stephan B, Völker, Uwe, Tang, Weihong, Koenig, Wolfgang, Jukema, J. Wouter, Guo, Xiuqing, Lindstrom, Sara, Wang, Lu, Smith, Erin N, Gordon, William, de Andrade, Mariza, Brody, Jennifer A, Pattee, Jack W, Haessler, Jeffrey, Brumpton, Ben M, Chasman, Daniel I, Suchon, Pierre, Turman, Constance, Germain, Marine, MacDonald, James, Braekkan, Sigrid K, Armasu, Sebastian M, Jackson, Rabecca D, Nielsen, Jonas B, Giulianini, Franco, Puurunen, Marja K, Ibrahim, Manal, Heckbert, Susan R, Bammler, Theo K, Frazer, Kelly A, McCauley, Bryan M, Taylor, Kent, Pankow, James S, Reiner, Alexander P, Gabrielsen, Maiken E, Deleuze, Jean‐François, O’Donnell, Chris J, Kim, Jihye, Kraft, Peter, Hansen, John‐Bjarne, Heit, John A, Kooperberg, Charles, Hveem, Kristian, Ridker, Paul M, Morange, Pierre‐Emmanuel, Johnson, Andrew D, Kabrhel, Christopher, Trégouët, David‐Alexandre, Malik, Rainer, Chauhan, Ganesh, Traylor, Matthew, Sargurupremraj, Muralidharan, Okada, Yukinori, Mishra, Aniket, Rutten‐Jacobs, Loes, Giese, Anne‐Katrin, van der Laan, Sander W, Gretarsdottir, Solveig, Anderson, Christopher D, Chong, Michael, Adams, Hieab HH, Ago, Tetsuro, Almgren, Peter, Amouyel, Philippe, Ay, Hakan, Bartz, Traci M, Benavente, Oscar R, Bevan, Steve, Boncoraglio, Giorgio B, Brown, Robert D, Butterworth, Adam S, Carrera, Caty, Carty, Cara L, Chen, Wei‐Min, Cole, John W, Correa, Adolfo, Cotlarciuc, Ioana, Cruchaga, Carlos, Danesh, John, de Bakker, Paul IW, DeStefano, Anita L, den Hoed, Marcel, Duan, Qing, Engelter, Stefan T, Falcone, Guido J, Gottesman, Rebecca F, Grewal, Raji P, Gudnason, Vilmundur, Gustafsson, Stefan, Harris, Tamara B, Hassan, Ahamad, Havulinna, Aki S, Holliday, Elizabeth G, Howard, George, Hsu, Fang‐Chi, Hyacinth, Hyacinth I, Arfan Ikram, M, Ingelsson, Erik, Irvin, Marguerite R, Jian, Xueqiu, Jiménez‐Conde, Jordi, Johnson, Julie A, Jukema, J Wouter, Kanai, Masahiro, Keene, Keith L, Kissela, Brett M, Kleindorfer, Dawn O, Kubo, Michiaki, Lange, Leslie A, Langefeld, Carl D, Langenberg, Claudia, Launer, Lenore J, Lee, Jin‐Moo, Lemmens, Robin, Leys, Didier, Lewis, Cathryn M, Lin, Wei‐Yu, Lindgren, Arne G, Lorentzen, Erik, Magnusson, Patrik K, Maguire, Jane, Manichaikul, Ani, McArdle, Patrick F, Meschia, James F, Mitchell, Braxton D, Mosley, Thomas H, Nalls, Michael A, Ninomiya, Toshiharu, O’Donnell, Martin J, Pulit, Sara L, Rannikmäe, Kristiina, Rexrode, Kathryn M, Rice, Kenneth, Rich, Stephen S, Rost, Natalia S, Rothwell, Peter M, Rundek, Tatjana, Sacco, Ralph L, Sakaue, Saori, Sale, Michele M, Salomaa, Veikko, Sapkota, Bishwa R, Schmidt, Reinhold, Schmidt, Carsten O, Schminke, Ulf, Sharma, Pankaj, Slowik, Agnieszka, Sudlow, Cathie LM, Tanislav, Christian, Tatlisumak, Turgut, Taylor, Kent D, Thijs, Vincent NS, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tiedt, Steffen, Tzourio, Christophe, van Duijn, Cornelia M, Walters, Matthew, Wareham, Nicholas J, Wassertheil‐Smoller, Sylvia, Wilson, James G, Yusuf, Salim, Amin, Najaf, Aparicio, Hugo S, Arnett, Donna K, Attia, John, Beiser, Alexa S, Berr, Claudine, Buring, Julie E, Bustamante, Mariana, Caso, Valeria, Cheng, Yu‐Ching, Hoan Choi, Seung, Chowhan, Ayesha, Cullell, Natalia, Dartigues, Jean‐François, Delavaran, Hossein, Delgado, Pilar, Dörr, Marcus, Engström, Gunnar, Ford, Ian, Gurpreet, Wander S, Hamsten, Anders, Heitsch, Laura, Hozawa, Atsushi, Ibanez, Laura, Ilinca, Andreea, Ingelsson, Martin, Iwasaki, Motoki, Jackson, Rebecca D, Jood, Katarina, Jousilahti, Pekka, Kaffashian, Sara, Kalra, Lalit, Kamouchi, Masahiro, Kitazono, Takanari, Kjartansson, Olafur, Kloss, Manja, Koudstaal, Peter J, Krupinski, Jerzy, Labovitz, Daniel L, Laurie, Cathy C, Levi, Christopher R, Li, Linxin, Lind, Lars, Lindgren, Cecilia M, Lioutas, Vasileios, Mei Liu, Yong, Lopez, Oscar L, Makoto, Hirata, Martinez‐Majander, Nicolas, Matsuda, Koichi, Minegishi, Naoko, Montaner, Joan, Morris, Andrew P, Muiño, Elena, Müller‐Nurasyid, Martina, Norrving, Bo, Ogishima, Soichi, Parati, Eugenio A, Reddy Peddareddygari, Leema, Pedersen, Nancy L, Pera, Joanna, Perola, Markus, Pezzini, Alessandro, Pileggi, Silvana, Rabionet, Raquel, Riba‐Llena, Iolanda, Ribasés, Marta, Romero, Jose R, Roquer, Jaume, Rudd, Anthony G, Sarin, Antti‐Pekka, Sarju, Ralhan, Sarnowski, Chloe, Sasaki, Makoto, Satizabal, Claudia L, Satoh, Mamoru, Sattar, Naveed, Sawada, Norie, Sibolt, Gerli, Sigurdsson, Ásgeir, Smith, Albert, Sobue, Kenji, Soriano‐Tárraga, Carolina, Stanne, Tara, Colin Stine, O, Stott, David J, Strauch, Konstantin, Takai, Takako, Tanaka, Hideo, Tanno, Kozo, Teumer, Alexander, Tomppo, Liisa, Torres‐Aguila, Nuria P, Touze, Emmanuel, Tsugane, Shoichiro, Uitterlinden, Andre G, Valdimarsson, Einar M, van der Lee, Sven J, Völzke, Henry, Wakai, Kenji, Weir, David, Williams, Stephen R, Wolfe, Charles DA, Wong, Quenna, Xu, Huichun, Yamaji, Taiki, Sanghera, Dharambir K, Melander, Olle, Jern, Christina, Strbian, Daniel, Fernandez‐Cadenas, Israel, Longstreth, W T, Rolfs, Arndt, Hata, Jun, Woo, Daniel, Rosand, Jonathan, Pare, Guillaume, Hopewell, Jemma C, Saleheen, Danish, Stefansson, Kari, Worrall, Bradford B, Kittner, Steven J, Seshadri, Sudha, Fornage, Myriam, Markus, Hugh S, Howson, Joanna MM, Kamatani, Yoichiro, Debette, Stephanie, and Dichgans, Martin

Published
2022
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25. Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke

Author

Chen, Lingyan, Peters, James E., Prins, Bram, Persyn, Elodie, Traylor, Matthew, Surendran, Praveen, Karthikeyan, Savita, Yonova-Doing, Ekaterina, Di Angelantonio, Emanuele, Roberts, David J., Watkins, Nicholas A., Ouwehand, Willem H., Danesh, John, Lewis, Cathryn M., Bronson, Paola G., Markus, Hugh S., Burgess, Stephen, Butterworth, Adam S., and Howson, Joanna M. M.

Published
2022
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26. Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study

Author

Low, Audrey, Prats-Sedano, Maria A., McKiernan, Elizabeth, Carter, Stephen F., Stefaniak, James D., Nannoni, Stefania, Su, Li, Dounavi, Maria-Eleni, Muniz-Terrera, Graciela, Ritchie, Karen, Lawlor, Brian, Naci, Lorina, Malhotra, Paresh, Mackay, Clare, Koychev, Ivan, Ritchie, Craig W., Markus, Hugh S., and O’Brien, John T.

Published
2022
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32. Cerebrospinal fluid-based spatial statistics: towards quantitative analysis of cerebrospinal fluid pseudodiffusivity.

Author

Chen, Yutong, Hong, Hui, Nazeri, Arash, Markus, Hugh S., and Luo, Xiao

Subjects
CEREBROSPINAL fluid examination, QUANTITATIVE research, MAGNETIC resonance imaging, CEREBROSPINAL fluid, LONG-term memory
Abstract

Background: Cerebrospinal fluid (CSF) circulation is essential in removing metabolic wastes from the brain and is an integral component of the glymphatic system. Abnormal CSF circulation is implicated in neurodegenerative diseases. Low b-value magnetic resonance imaging quantifies the variance of CSF motion, or pseudodiffusivity. However, few studies have investigated the relationship between the spatial patterns of CSF pseudodiffusivity and cognition. Methods: We introduced a novel technique, CSF-based spatial statistics (CBSS), to automatically quantify CSF pseudodiffusivity in each sulcus, cistern and ventricle. Using cortical regions as landmarks, we segmented each CSF region. We retrospectively analyzed a cohort of 93 participants with varying degrees of cognitive impairment. Results: We identified two groups of CSF regions whose pseudodiffusivity profiles were correlated with each other: one group displaying higher pseudodiffusivity and near large arteries and the other group displaying lower pseudodiffusivity and away from the large arteries. The pseudodiffusivity in the third ventricle positively correlated with short-term memory (standardized slope of linear regression = 0.38, adjusted p < 0.001) and long-term memory (slope = 0.37, adjusted p = 0.005). Fine mapping along the ventricles revealed that the pseudodiffusivity in the region closest to the start of the third ventricle demonstrated the highest correlation with cognitive performance. Conclusions: CBSS enabled quantitative spatial analysis of CSF pseudodiffusivity and suggested the third ventricle pseudodiffusivity as a potential biomarker of cognitive impairment. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Author

Jolly, Amy A, Brown, Robin B, Tozer, Daniel J, Hong, Young T, Fryer, Tim D, Aigbirhio, Franklin I, O'Brien, John T, and Markus, Hugh S

Abstract

Background: Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Methods: Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET–MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Results: Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. Conclusion: In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data access statement: Data for this study are available from the corresponding author upon reasonable request. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Contribution of Common Genetic Variants to Risk of Early Onset Ischemic Stroke

Author

Jaworek, Thomas, Xu, Huichun, Gaynor, Brady J, Cole, John W., Rannikmae, Kristiina, Stanne, Tara M, Tomppo, Liisa, Abedi, Vida, Amouyel, Philippe, Armstrong, Nicole D, Attia, John, Bell, Steven, Benavente, Oscar R, Boncoraglio, Giorgio B, Butterworth, Adam, Carcel-Marquez, Jara, Chen, Zhengming, Chong, Michael, Cruchaga, Carlos, Cushman, Mary, Danesh, John, Debette, Stephanie, Duggan, David J, Durda, Jon Peter, Engstrom, Gunnar, Enzinger, Chris, Faul, Jessica D, Fecteau, Natalie S, Fernandez-Cadenas, Israel, Gieger, Christian, Giese, Anne-Katrin, Grewal, Raji P, Grittner, Ulrike, Havulinna, Aki S, Heitsch, Laura, Hochberg, Marc C, Holliday, Elizabeth, Hu, Jie, Ilinca, Andreea, Irvin, Marguerite R, Jackson, Rebecca D, Jacob, Mina A., Janssen, Raquel Rabionet, Jimenez-Conde, Jordi, Johnson, Julie A, Kamatani, Yoichiro, Kardia, Sharon L, Koido, Masaru, Kubo, Michiaki, Lange, Leslie, Lee, Jin-Moo, Lemmens, Robin, Levi, Christopher R, Li, Jiang, Li, Liming, Lin, Kuang, Lopez, Haley, Luke, Sothear, Maguire, Jane, McArdle, Patrick F, McDonough, Caitrin W., Meschia, James F, Metso, Tiina, Muller-Nurasyid, Martina, OʼConnor, Timothy D, OʼDonnell, Martin, Peddareddygari, Leema R, Pera, Joanna, Perry, James A, Peters, Annette, Putaala, Jukka, Ray, Debashree, Rexrode, Kathryn, Ribases, Marta, Rosand, Jonathan, Rothwell, Peter M, Rundek, Tatjana, Ryan, Kathleen A, Sacco, Ralph L., Salomaa, Veikko, Sanchez-Mora, Cristina, Schmidt, Reinhold, Sharma, Pankaj, Slowik, Agnieszka, Smith, Jennifer A, Smith, Nicholas L, Wassertheil-Smoller, Sylvia, Soederholm, Martin, Stine, O. C, Strbian, Daniel, Sudlow, Cathie L, Tatlisumak, Turgut, Terao, Chikashi, Thijs, Vincent, Torres-Aguila, Nuria P, Tregouet, David-Alexandre, Tuladhar, Anil M., Veldink, Jan H, Walters, Robin G, Weir, David R, Woo, Daniel, Worrall, Bradford B, Hong, Charles C, Ross, Owen, Zand, Ramin, Leeuw, Frank-Erik de, Lindgren, Arne G, Pare, Guillaume, Anderson, Christopher D., Markus, Hugh S, Jern, Christina, Malik, Rainer, Dichgans, Martin, Mitchell, Braxton D, and Kittner, Steven J

Published
2022
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37. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies

Author

Traylor, Matthew, Persyn, Elodie, Tomppo, Liisa, Klasson, Sofia, Abedi, Vida, Bakker, Mark K, Torres, Nuria, Li, Linxin, Bell, Steven, Rutten-Jacobs, Loes, Tozer, Daniel J, Griessenauer, Christoph J, Zhang, Yanfei, Pedersen, Annie, Sharma, Pankaj, Jimenez-Conde, Jordi, Rundek, Tatjana, Grewal, Raji P, Lindgren, Arne, Meschia, James F, Salomaa, Veikko, Havulinna, Aki, Kourkoulis, Christina, Crawford, Katherine, Marini, Sandro, Mitchell, Braxton D, Kittner, Steven J, Rosand, Jonathan, Dichgans, Martin, Jern, Christina, Strbian, Daniel, Fernandez-Cadenas, Israel, Zand, Ramin, Ruigrok, Ynte, Rost, Natalia, Lemmens, Robin, Rothwell, Peter M, Anderson, Christopher D, Wardlaw, Joanna, Lewis, Cathryn M, and Markus, Hugh S

Published
2021
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39. Anticoagulation Versus Antiplatelets in Spontaneous Cervical Artery Dissection: A Systematic Review and Meta-Analysis

Author

Yaghi, Shadi, Shu, Liqi, Fletcher, Lauren, Fayad, Fayez H., Shah, Asghar, Herning, Ana, Isho, Noail, Mansour, Perla, Joudi, Kareem, Zaidat, Bashar, Mahmoud, Noor A., Abdul Khalek, Feras, Xiao, Han, Goldstein, Eric, Ghannam, Malik, Siegler, James E., Salehi Omran, Setareh, Bakradze, Ekaterina, Nguyen, Thanh N., Keser, Zafer, Khan, Muhib, Bavarsad Shahripour, Reza, de Havenon, Adam, Henninger, Nils, Heldner, Mirjam R., Field, Thalia S., Aziz, Yasmin, Mistry, Eva A., Furie, Karen, Engelter, Stefan, and Markus, Hugh S.

Published
2024
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43. Antithrombotic Treatment for Cervical Artery Dissection: A Systematic Review and Individual Patient Data Meta-Analysis.

Author

Kaufmann, Josefin E., Harshfield, Eric L., Gensicke, Henrik, Wegener, Susanne, Michel, Patrik, Kägi, Georg, Nedeltchev, Krassen, Kellert, Lars, Rosenbaum, Sverre, Nolte, Christian H., Christensen, Hanne, Arnold, Marcel, Lyrer, Philippe, Levi, Christopher, Bath, Philip M., Engelter, Stefan T., Traenka, Christopher, and Markus, Hugh S.

Published
2024
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44. 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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45. Consensus statement for diagnosis of subcortical small vessel disease

Author

Rosenberg, Gary A, Wallin, Anders, Wardlaw, Joanna M, Markus, Hugh S, Montaner, Joan, Wolfson, Leslie, Iadecola, Costantino, Zlokovic, Berislav V, Joutel, Anne, Dichgans, Martin, Duering, Marco, Schmidt, Reinhold, Korczyn, Amos D, Grinberg, Lea T, Chui, Helena C, and Hachinski, Vladimir

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Dementia, Vascular Cognitive Impairment/Dementia, Biomedical Imaging, Rare Diseases, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Aging, Blood-Brain Barrier, Capillary Permeability, Dementia, Vascular, Humans, Leukoaraiosis, Microvessels, Binswanger's disease, blood-brain barrier permeability, cerebrospinal fluid, inflammation, leukoaraiosis
Abstract

Vascular cognitive impairment (VCI) is the diagnostic term used to describe a heterogeneous group of sporadic and hereditary diseases of the large and small blood vessels. Subcortical small vessel disease (SVD) leads to lacunar infarcts and progressive damage to the white matter. Patients with progressive damage to the white matter, referred to as Binswanger's disease (BD), constitute a spectrum from pure vascular disease to a mixture with neurodegenerative changes. Binswanger's disease patients are a relatively homogeneous subgroup with hypoxic hypoperfusion, lacunar infarcts, and inflammation that act synergistically to disrupt the blood-brain barrier (BBB) and break down myelin. Identification of this subgroup can be facilitated by multimodal disease markers obtained from clinical, cerebrospinal fluid, neuropsychological, and imaging studies. This consensus statement identifies a potential set of biomarkers based on underlying pathologic changes that could facilitate diagnosis and aid patient selection for future collaborative treatment trials.

Published
2016

49. Do Regions of Increased Inflammation Progress to New White Matter Hyperintensities?: A Longitudinal Positron Emission Tomography-Magnetic Resonance Imaging Study

Author

Tozer, Daniel J, Brown, Robin B, Walsh, Jessica, Hong, Young T, Williams, Guy B, O'Brien, John T, Aigbirhio, Franklin I, Fryer, Tim D, Markus, Hugh S, Tozer, Daniel J [0000-0002-0404-3214], Brown, Robin B [0000-0003-0431-7841], Walsh, Jessica [0000-0001-9723-3043], Williams, Guy B [0000-0001-5223-6654], O'Brien, John T [0000-0002-0837-5080], Markus, Hugh S [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
Inflammation, Advanced and Specialized Nursing, positron emission tomography, cerebral small vessel disease, Brain, CADASIL, Cerebral Infarction, White Matter, Magnetic Resonance Imaging, Diffusion Tensor Imaging, Leukoencephalopathies, Positron-Emission Tomography, Neuroinflammatory Diseases, Humans, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Background: Recent studies have demonstrated increased microglial activation using 11 C-PK11195 positron emission tomography imaging, indicating central nervous system inflammation, in cerebral small vessel disease. However, whether such areas of neuroinflammation progress to tissue damage is uncertain. We determined whether white matter destined to become white matter hyperintensities (WMH) at 1 year had evidence of altered inflammation at baseline. Methods: Forty subjects with small vessel disease (20 sporadic and 20 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) and 20 controls were recruited to this case-control observational study from in- and out-patient clinics at Addenbrooke’s Hospital, Cambridge, UK and imaged at baseline with both 11 C-PK11195 positron emission tomography and magnetic resonance imaging; and magnetic resonance imaging including diffusion tensor imaging was repeated at 1 year. WMH were segmented at baseline and 1 year, and areas of new lesion identified. Baseline 11 C-PK11195 binding potential and diffusion tensor imaging parameters in these voxels, and normal appearing white matter, was measured. Results: Complete positron emission tomography-magnetic resonance imaging data was available for 17 controls, 16 sporadic small vessel disease, and 14 cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy participants. 11 C-PK11195 binding in voxels destined to become new WMH was lower than in normal appearing white matter, which did not progress to WMH (−0.133[±0.081] versus −0.045 [±0.044]; P −6 versus 1045 [±149]×10 −6 mm 2 /s and 0.37±0.05 versus 0.29±0.06, both P Conclusions: White matter tissue destined to develop into new WMH over the subsequent year is associated with both lower neuroinflammation, and white matter ultrastructural damage at baseline. Our results suggest that this tissue is already damaged 1 year prior to lesion formation. This may reflect that the role of neuroinflammation in the lesion development process occurs at an early stage, although more studies over a longer period would be needed to investigate this further.

Published
2023

50. Contribution of Conventional Cardiovascular Risk Factors to Brain White Matter Hyperintensities

Author

Koohi, Fatemeh, Harshfield, Eric L, Markus, Hugh S, Koohi, Fatemeh [0000-0003-1326-8594], Harshfield, Eric L [0000-0001-8767-0928], Markus, Hugh S [0000-0002-9794-5996], and Apollo - University of Cambridge Repository

Subjects
cardiovascular risk factors, magnetic resonance imaging, white matter hyperintensities, structural equation modeling
Abstract

Background White matter hyperintensities (WMHs) are a major risk factor for stroke and dementia, but their pathogenesis is incompletely understood. It has been debated how much risk is accounted for by conventional cardiovascular risk factors (CVRFs), and this has major implications as to how effective a preventative strategy targeting these risk factors will be. Methods and Results We included 41 626 UK Biobank participants (47.2% men), with a mean age of 55 years (SD, 7.5 years), who underwent brain magnetic resonance imaging at the first imaging assessment beginning in 2014. The relationships among CVRFs, cardiovascular conditions, and WMH volume as a percentage of total brain volume were examined using correlations and structural equation models. Only 32% of the variance in WMH volume was explained by measures of CVRFs, sex, and age, of which age accounted for 16%. CVRFs combined accounted for ≈15% of the variance. However, a large portion of the variance (well over 60%) remains unexplained. Of the individual CVRFs, blood pressure parameters together accounted for ≈10.5% of the total variance (diagnosis of hypertension, 4.4%; systolic blood pressure, 4.4%; and diastolic blood pressure, 1.7%). The variance explained by most individual CVRFs declined with age. Conclusions Our findings suggest the presence of other vascular and nonvascular factors underlying the development of WMHs. Although they emphasize the importance of modification of conventional CVRFs, particularly hypertension, they highlight the need to better understand risk factors underlying the considerable unexplained variance in WMHs if we are to develop better preventative approaches.

Published
2023

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