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Escott-Price, Valentina ; Bellenguez, Céline ; Wang, Li-San ; Choi, Seung-Hoan ; Harold, Denise ; Jones, Lesley ; Holmans, Peter ; Gerrish, Amy ; Vedernikov, Alexey ; Richards, Alexander ; DeStefano, Anita L. ; Lambert, Jean-Charles ; Ibrahim-Verbaas, Carla A. ; Naj, Adam C. ; Sims, Rebecca ; Jun, Gyungah ; Bis, Joshua C. ; Beecham, Gary W. ; Grenier-Boley, Benjamin ; Russo, Giancarlo ; Thornton-Wells, Tricia A. ; Denning, Nicola ; Smith, Albert V. ; Chouraki, Vincent ; Thomas, Charlene ; Ikram, M. Arfan ; Zelenika, Diana ; Vardarajan, Badri N. ; Kamatani, Yoichiro ; Lin, Chiao-Feng ; Schmidt, Helena ; Kunkle, Brian ; Dunstan, Melanie L. ; Vronskaya, Maria ; Johnson, Andrew D. ; Ruiz, Agustin ; Bihoreau, Marie-Thérèse ; Reitz, Christiane ; Pasquier, Florence ; Hollingworth, Paul ; Hanon, Olivier ; Fitzpatrick, Annette L. ; Buxbaum, Joseph D. ; Campion, Dominique ; Crane, Paul K. ; Baldwin, Clinton ; Becker, Tim ; Gudnason, Vilmundur ; Cruchaga, Carlos ; Craig, David ; Amin, Najaf ; Berr, Claudine ; Lopez, Oscar L. ; Jager, Philip L. De ; Deramecourt, Vincent ; Johnston, Janet A. ; Evans, Denis ; Lovestone, Simon ; Letenneur, Luc ; Hernández, Isabel ; Rubinsztein, David C. ; Eiriksdottir, Gudny ; Sleegers, Kristel ; Goate, Alison M. ; Fiévet, Nathalie ; Huentelman, Matthew J. ; Gill, Michael ; Brown, Kristelle ; Kamboh, M. Ilyas ; Keller, Lina ; Barberger-Gateau, Pascale ; McGuinness, Bernadette ; Larson, Eric B. ; Myers, Amanda J. ; Dufouil, Carole ; Todd, Stephen ; Wallon, David ; Love, Seth ; Rogaeva, Ekaterina ; Gallacher, John ; St George-Hyslop, Peter ; Clarimon, Jordi ; Lleo, Alberto ; Bayer, Anthony ; Tsuang, Debby W. ; Yu, Lei ; Tsolaki, Magda ; Bossù, Paola ; Spalletta, Gianfranco ; Proitsi, Petra ; Collinge, John ; Sorbi, Sandro ; Sanchez Garcia, Florentino ; Fox, Nick C. ; Hardy, John ; Deniz Naranjo, Maria Candida ; Bosco, Paolo ; Clarke, Robert ; Brayne, Carol ; Galimberti, Daniela ; Scarpini, Elio ; Bonuccelli, Ubaldo ; Mancuso, Michelangelo ; Siciliano, Gabriele ; Moebus, Susanne ; Mecocci, Patrizia ; Del Zompo, Maria ; Maier, Wolfgang ; Hampel, Harald ; Pilotto, Alberto ; Frank-García, Ana ; Panza, Francesco ; Solfrizzi, Vincenzo ; Caffarra, Paolo ; Nacmias, Benedetta ; Perry, William ; Mayhaus, Manuel ; Lannfelt, Lars ; Hakonarson, Hakon ; Pichler, Sabrina ; Carrasquillo, Minerva M. ; Ingelsson, Martin ; Beekly, Duane ; Alvarez, Victoria ; Zou, Fanggeng ; Valladares, Otto ; Younkin, Steven G. ; Coto, Eliecer ; Hamilton-Nelson, Kara L. ; Gu, Wei ; Razquin, Cristina ; Pastor, Pau ; Mateo, Ignacio ; Owen, Michael J. ; Faber, Kelley M. ; Jonsson, Palmi V. ; Combarros, Onofre ; O'Donovan, Michael C. ; Cantwell, Laura B. ; Soininen, Hilkka ; Blacker, Deborah ; Mead, Simon ; Mosley, Thomas H. ; Bennett, David A. ; Harris, Tamara B. ; Fratiglioni, Laura ; Holmes, Clive ; Bruijn, Renee F. A. G. de ; Passmore, Peter ; Montine, Thomas J. ; Bettens, Karolien ; Rotter, Jerome I. ; Brice, Alexis ; Morgan, Kevin ; Foroud, Tatiana M. ; Kukull, Walter A. ; Hannequin, Didier ; Powell, John F. ; Nalls, Michael A. ; Ritchie, Karen ; Lunetta, Kathryn L. ; Kauwe, John S. K. ; Boerwinkle, Eric ; Riemenschneider, Matthias ; Boada, Mercè ; Hiltunen, Mikko ; Martin, Eden R. ; Schmidt, Reinhold ; Rujescu, Dan ; Dartigues, Jean-François ; Mayeux, Richard ; Tzourio, Christophe ; Hofman, Albert ; Nöthen, Markus Maria ; Graff, Caroline ; Psaty, Bruce M. ; Haines, Jonathan L. ; Lathrop, Mark ; Pericak-Vance, Margaret Ann ; Launer, Lenore J. ; Broeckhoven, Christine Van ; Farrer, Lindsay A. ; Duijn, Cornelia M. van ; Ramirez, Alfredo ; Seshadri, Sudha ; Schellenberg, Gerard D. ; Amouyel, Philippe ; Williams, Julie
Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.
Principal findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci.
Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
Théry, Clotilde ; Witwer, Kenneth W. ; Aikawa, Elena ; Alcaraz, Maria Jose ; Anderson, Johnathon D. ; Andriantsitohaina, Ramaroson ; Antoniou, Anna ; Arab, Tanina ; Archer, Fabienne ; Atkin-Smith, Georgia K. ; Ayre, D. Craig ; Bach, Jean-Marie ; Bachurski, Daniel ; Baharvand, Hossein ; Balaj, Leonora ; Baldacchino, Shawn ; Bauer, Natalie N. ; Baxter, Amy A. ; Bebawy, Mary ; Beckham, Carla ; Zavec, Apolonija Bedina ; Benmoussa, Abderrahim ; Berardi, Anna C. ; Bergese, Paolo ; Bielska, Ewa ; Blenkiron, Cherie ; Bobis-Wozowicz, Sylwia ; Boilard, Eric ; Boireau, Wilfrid ; Bongiovanni, Antonella ; Borràs, Francesc E. ; Bosch, Steffi ; Boulanger, Chantal M. ; Breakefield, Xandra ; Breglio, Andrew M. ; Brennan, Meadhbh Aín ; Brigstock, David R. ; Brisson, Alain ; Broekman, Marike L. D. ; Bromberg, Jacqueline F. ; Bryl-Gorecka, Paulina ; Buch, Shilpa ; Buck, Amy H. ; Burger, Dylan ; Busatto, Sara ; Buschmann, Dominik ; Bussolati, Benedetta ; Buzás, Edit I. ; Byrd, James Bryan ; Camussi, Giovanni ; Carter, David R. F. ; Caruso, Sarah ; Chamley, Lawrence W. ; Chang, Yu-Ting ; Chen, Chihchen ; Chen, Shuai ; Cheng, Lesley ; Chin, Andrew R. ; Clayton, Aled ; Clerici, Stefano P. ; Cocks, Alex ; Cocucci, Emanuele ; Coffey, Robert J. ; Cordeiro-da-Silva, Anabela ; Couch, Yvonne ; Coumans, Frank A. W. ; Coyle, Beth ; Crescitelli, Rossella ; Criado, Miria Ferreira ; D’Souza-Schorey, Crislyn ; Das, Saumya ; Chaudhuri, Amrita Datta ; de-Candia, Paola ; De Santana, Eliezer F. ; De Wever, Olivier ; del Portillo, Hernando A. ; Demaret, Tanguy ; Deville, Sarah ; Devitt, Andrew ; Dhondt, Bert ; Di Vizio, Dolores ; Dieterich, Lothar C. ; Dolo, Vincenza ; Dominguez Rubio, Ana Paula ; Dominici, Massimo ; Dourado, Mauricio R. ; Driedonks, Tom A. P. ; Duarte, Filipe V. ; Duncan, Heather M. ; Eichenberger, Ramon Marc ; Ekström, Karin ; El Andaloussi, Samir ; Elie-Caille, Celine ; Erdbrügger, Uta ; Falcón-Pérez, Juan M. ; Fatima, Farah ; Fish, Jason E. ; Flores-Bellver, Miguel ; Försönits, András ; Frelet-Barrand, Annie ; Fricke, Fabia ; Fuhrmann, Gregor ; Gabrielsson, Susanne ; Gámez-Valero, Ana ; Gardiner, Chris ; Gärtner, Kathrin ; Gaudin, Raphael ; Gho, Yong Song ; Giebel, Bernd ; Gilbert, Caroline ; Gimona, Mario ; Giusti, Ilaria ; Goberdhan, Deborah C. I. ; Görgens, André ; Gorski, Sharon M. ; Greening, David W. ; Groß, Julia Christina ; Gualerzi, Alice ; Gupta, Gopal N. ; Gustafson, Dakota ; Handberg, Aase ; Haraszti, Réka Ágnes ; Harrison, Paul ; Hegyesi, Hargita ; Hendrix, An ; Hill, Andrew F. ; Hochberg, Fred H. ; Hoffmann, Karl F. ; Holder, Beth ; Holthofer, Harry ; Hosseinkhani, Baharak ; Hu, Guoku ; Huang, Yiyao ; Huber, Veronica ; Hunt, Stuart ; Ibrahim, Ahmed Gamal-Eldin ; Ikezu, Tsuneya ; Inal, Jameel M. ; Isin, Mustafa ; Ivanova, Alena ; Jackson, Hannah K. ; Jacobsen, Soren ; Jay, Steven M. ; Jayachandran, Muthuvel ; Jenster, Guido ; Jiang, Lanzhou ; Johnson, Suzanne M. ; Jones, Jennifer C. ; Jong, Ambrose ; Jovanovic-Talisman, Tijana ; Jung, Stephanie ; Kalluri, Raghu ; Kano, Shin-ichi ; Kaur, Sukhbir ; Kawamura, Yumi ; Keller, Evan T. ; Khamari, Delaram ; Khomyakova, Elena ; Khvorova, Anastasia ; Kierulf, Peter ; Kim, Kwang Pyo ; Kislinger, Thomas ; Klingeborn, Mikael ; Klinke, David J. ; Kornek, Miroslaw ; Kosanović, Maja M. ; Kovács, Árpád Ferenc ; Krämer-Albers, Eva-Maria ; Krasemann, Susanne ; Krause, Mirja ; Kurochkin, Igor V. ; Kusuma, Gina D. ; Kuypers, Sören ; Laitinen, Saara ; Langevin, Scott M. ; Languino, Lucia R. ; Lannigan, Joanne ; Lässer, Cecilia ; Laurent, Louise C. ; Lavieu, Gregory ; Lázaro-Ibáñez, Elisa ; Le Lay, Soazig ; Lee, Myung-Shin ; Lee, Yi Xin Fiona ; Lemos, Debora S. ; Lenassi, Metka ; Leszczynska, Aleksandra ; Li, Isaac T. S. ; Liao, Ke ; Libregts, Sten F. ; Ligeti, Erzsebet ; Lim, Rebecca ; Lim, Sai Kiang ; Linē, Aija ; Linnemannstöns, Karen ; Llorente, Alicia ; Lombard, Catherine Ann ; Lorenowicz, Magdalena J. ; Lörincz, Ákos M. ; Lötvall, Jan ; Lovett, Jason ; Lowry, Michelle C. ; Loyer, Xavier ; Lu, Quan ; Lukomska, Barbara ; Lunavat, Taral Rameshchand ; Maas, Sybren L. N. ; Malhi, Harmeet ; Marcilla, Antonio ; Mariani, Jacopo ; Mariscal, Javier ; Martens-Uzunova, Elena S. ; Martin-Jaular, Lorena ; Martinez, M. Carmen ; Martins, Vilma Regina ; Mathieu, Mathilde ; Mathivanan, Suresh ; Maugeri, Marco ; McGinnis, Lynda K. ; McVey, Mark J. ; Meckes, David G. ; Meehan, Katie ; Mertens, Inge ; Minciacchi, Valentina R. ; Möller, Andreas ; Møller Jørgensen, Malene ; Morales-Kastresana, Aizea ; Morhayim, Jess ; Mullier, François ; Muraca, Maurizio ; Musante, Luca ; Mussack, Veronika ; Muth, Dillon C. ; Myburgh, Kathryn H. ; Najrana, Tanbir ; Nawaz, Muhammad ; Nazarenko, Irina ; Nejsum, Peter ; Neri, Christian ; Neri, Tommaso ; Nieuwland, Rienk ; Nimrichter, Leonardo ; Nolan, John P. ; Nolte-’t Hoen, Esther N. M. ; Hooten, Nicole Noren ; O’Driscoll, Lorraine ; O’Grady, Tina ; O’Loghlen, Ana ; Ochiya, Takahiro ; Olivier, Martin ; Ortiz, Alberto ; Ortiz, Luis A. ; Osteikoetxea, Xabier ; Østergaard, Ole ; Ostrowski, Matias ; Park, Jaesung ; Pegtel, Dirk Michiel ; Peinado, Hector ; Perut, Francesca ; Pfaffl, Michael ; Phinney, Donald G. ; Pieters, Bartijn C. H. ; Pink, Ryan Charles ; Pisetsky, David S. ; Pogge von Strandmann, Elke ; Polakovicova, Iva ; Poon, Ivan K. H. ; Powell, Bonita H. ; Prada, Ilaria ; Pulliam, Lynn ; Quesenberry, Peter ; Radeghieri, Annalisa ; Raffai, Robert L. ; Raimondo, Stefania ; Rak, Janusz ; Ramirez, Marcel I. ; Raposo, Graça ; Rayyan, Morsi S. ; Regev-Rudzki, Neta ; Ricklefs, Franz Lennard ; Robbins, Paul D. ; Roberts, David D. ; Rodrigues, Silvia C. ; Rohde, Eva ; Rome, Sophie ; Rouschop, Kasper M. ; Rughetti, Aurelia ; Russell, Ashley E. ; Saá, Paula ; Sahoo, Susmita ; Salas-Huenuleo, Edison ; Sánchez, Catherine ; Saugstad, Julie A. ; Saul, Meike J. ; Schiffelers, Raymond M. ; Schneider, Raphael ; Schøyen, Tine Hiorth ; Scott, Aaron ; Shahaj, Eriomina ; Sharma, Shivani ; Shatnyeva, Olga ; Shekari, Faezeh ; Shelke, Ganesh Vilas ; Shetty, Ashok K. ; Shiba, Kiyotaka ; Siljander, Pia R.-M. ; Silva, Andreia M. ; Skowronek, Agata ; Snyder, Orman L. ; Soares, Rodrigo Pedro ; Sódar, Barbara W. ; Soekmadji, Carolina ; Sotillo, Javier ; Stahl, Philip D. ; Stoorvogel, Willem ; Stott, Shannon L. ; Strasser, Erwin F. ; Swift, Simon ; Tahara, Hidetoshi ; Tewari, Muneesh ; Timms, Kate ; Tiwari, Swasti ; Tixeira, Rochelle ; Tkach, Mercedes ; Toh, Wei Seong ; Tomasini, Richard ; Torrecilhas, Ana Claudia ; Tosar, Juan Pablo ; Toxavidis, Vasilis ; Urbanelli, Lorena ; Vader, Pieter ; Balkom, Bastiaan Wilhelmus Maria van ; Grein, Susanne G. van der ; Van Deun, Jan ; Herwijnen, Martijn J. C. van ; Van Keuren-Jensen, Kendall R. ; Niel, Guillaume van ; Royen, Martin E. van ; Wijnen, Andre J. van ; Vasconcelos, M. Helena ; Vechetti, Ivan J. ; Veit, Tiago D. ; Vella, Laura J. ; Velot, Émilie ; Verweij, Frederik ; Vestad, Beate ; Viñas, Jose Luis ; Visnovitz, Tamás ; Vukman, Krisztina V. ; Wahlgren, Jessica ; Watson, Dionysios C. ; Wauben, Marca H. M. ; Weaver, Alissa ; Webber, Jason P. ; Weber, Viktoria ; Wehman, Ann M. ; Weiss, Daniel J. ; Welsh, Joshua A. ; Wendt, Sebastian ; Wheelock, Åsa M. ; Wiener, Zoltán ; Witte, Leonie ; Wolfram, Joy ; Xagorari, Angeliki ; Xander, Patricia ; Xu, Jing ; Yan, Xiaomei ; Yáñez-Mó, María ; Yin, Hang ; Yuana, Yuana ; Zappulli, Valentina ; Zarubova, Jana ; Žėkas, Vytautas ; Zhang, Jian-ye ; Zhao, Zezhou ; Zheng, Lei ; Zheutlin, Alexander R. ; Zickler, Antje Maria ; Zimmermann, Pascale ; Zivkovic, Angela M. ; Zocco, Davide ; Zuba-Surma, Ewa K.
The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study
(2019)
Hatton, Sean N. ; Huynh, Khoa H. ; Bonilha, Leonardo ; Abela, Eugenio Cecilio ; Alhusaini, Saud ; Altmann, André ; Alvim, Marina K. M. ; Balachandra, Akshara R. ; Bartolini, Emanuele ; Bender, Benjamin ; Bernasconi, Neda ; Bernasconi, Andrea ; Bernhardt, Boris ; Bargallo, Núria ; Caldairou, Benoit ; Caligiuri, Maria Eugenia ; Carr, Sarah J. A. ; Cavalleri, Gianpiero L. ; Cendes, Fernando ; Concha, Luis ; Davoodi-Bojd, Esmaeil ; Desmond, Patricia M. ; Devinsky, Orrin ; Doherty, Colin P. ; Domin, Martin ; Duncan, John S. ; Focke, Niels K. ; Foley, Sonya F. ; Gambardella, Antonio ; Gleichgerrcht, Ezequiel ; Guerrini, Renzo ; Hamandi, Khalid ; Ishikawa, Akari ; Keller, Simon S. ; Kochunov, Peter V. ; Kotikalapudi, Raviteja ; Kreilkamp, Barbara A. K. ; Kwan, Patrick ; Labate, Angelo ; Langner, Sönke ; Lenge, Matteo ; Liu, Min ; Lui, Elaine ; Martin, Pascal ; Mascalchi, Mario ; Moreira, José Carlos Vasques ; Morita-Sherman, Marcia Elisabete ; O’Brien, Terence J. ; Pardoe, Heath R. ; Pariente Zorrilla, José Carlos ; Ribeiro, Letı́cia F. ; Richardson, Mark Philip ; Rocha, Cristiane S. ; Rodrı́guez-Cruces, Raúl ; Rosenow, Felix ; Severino, Mariasavina ; Sinclair, Benjamin ; Soltanian-Zadeh, Hamid ; Striano, Pasquale ; Taylor, Peter N. ; Thomas, Rhys H. ; Tortora, Domenico ; Velakoulis, Dennis ; Vezzani, Annamaria ; Vivash, Lucy ; Podewils, Felix von ; Vos, Sjoerd B. ; Weber, Bernd ; Winston, Gavin P. ; Yasuda, Clarissa L. ; Thompson, Paul M. ; Jahanshad, Neda ; Sisodiya, Sanjay M. ; McDonald, Carrie R.
The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across “all epilepsies” lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.
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