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101. Elektrische Aufladung und Hybridisierung mit 12 V

Author: Simon Mead, John Martin, Stefan Hoffmann, and Simon Gellineck
Subjects: Engineering, business.industry, Automotive Engineering, business, Engineering physics
Published: 2018
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102. Electric Supercharging and Hybridization with 12 V

Author: Simon Mead, Simon Gellineck, John Martin, and Stefan Hoffmann
Subjects: Materials science, 020209 energy, 0202 electrical engineering, electronic engineering, information engineering, 02 engineering and technology, Automotive engineering
Published: 2018
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103. Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

Author: Zane Jaunmuktane, Sebastian Brandner, Annelies Quaegebeur, Miguel Viana-Baptista, Carolin Koriath, Ricardo Taipa, Simon Mead, Raf Sciot, and Raquel Barbosa
Subjects: 0301 basic medicine, Male, Pathology, Dura mater, Disease, Neurosurgical Procedures, 0302 clinical medicine, Traumatic brain injury, Fatal Outcome, Postoperative Complications, TBI, Medicine, CAA, Decontamination, Aβ, Aged, 80 and over, Transmission (medicine), Brain, Middle Aged, medicine.anatomical_structure, Female, Neurosurgery, Cerebral amyloid angiopathy, Adult, medicine.medical_specialty, Prion diseases, Context (language use), Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, mental disorders, Parenchyma, Transmission, Humans, Amyloid-β, Aged, Retrospective Studies, Original Paper, business.industry, Proteopathic seeding, medicine.disease, Head trauma, Transplantation, 030104 developmental biology, Intracerebral haemorrhage, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early Aβ pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that Aβ pathology may be transmissible, as prion disease is, through neurosurgical procedures. Electronic supplementary material The online version of this article (10.1007/s00401-018-1822-2) contains supplementary material, which is available to authorized users.
Published: 2018

104. A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features

Author: Tammaryn Lashley, Catherine J. Mummery, Carolin Koriath, Olaf Ansorge, Lucía Chávez-Gutiérrez, Martin N. Rossor, Nick C. Fox, Emily Abel, James M. Polke, Natalie S. Ryan, M.R. Fraser, Simon Mead, Daniel Jiménez, and Antoinette O'Connor
Subjects: Male, Myoclonus, 0301 basic medicine, Aging, medicine.disease_cause, Presenilin, 03 medical and health sciences, 0302 clinical medicine, INDEL Mutation, Alzheimer Disease, Seizures, Gene duplication, Presenilin-1, medicine, PSEN1, Humans, Dementia, Early-onset Alzheimer's disease, Cognitive decline, Genetics, Mutation, business.industry, General Neuroscience, medicine.disease, Mutagenesis, Insertional, 030104 developmental biology, Female, Neurology (clinical), Geriatrics and Gerontology, medicine.symptom, business, 030217 neurology & neurosurgery, Developmental Biology
Abstract: Mutations in the Presenilin 1 (PSEN1) gene are the most common cause of autosomal dominant familial Alzheimer's disease. We report the clinical, imaging and postmortem findings of kindred carrying a novel duplication mutation (Ile168dup) in the PSEN1 gene. We interpret the pathogenicity of this novel variant and discuss the additional neurological features (pyramidal dysfunction, myoclonus and seizures) that accompanied cognitive decline. This report broadens the clinical phenotype of PSEN1 insertion mutations while also highlighting the importance of considering duplication, insertion and deletion mutations in cases of young onset dementia.
Published: 2021
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105. Imaging and CSF analyses effectively distinguish CJD from its mimics

Author: Harpreet Hyare, Alison Green, John Collinge, Peter Rudge, and Simon Mead
Subjects: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Pediatrics, Encephalopathy, Cell Count, S100 Calcium Binding Protein beta Subunit, Creutzfeldt-Jakob Syndrome, Prion Proteins, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Humans, Dementia, Neurodegeneration, Hepatic encephalopathy, Aged, Aged, 80 and over, Dementia with Lewy bodies, business.industry, Progressive multifocal leukoencephalopathy, Case-control study, Middle Aged, medicine.disease, nervous system diseases, Psychiatry and Mental health, Diffusion Magnetic Resonance Imaging, 030104 developmental biology, 14-3-3 Proteins, Case-Control Studies, Female, Surgery, Neurology (clinical), medicine.symptom, business, Myoclonus, Biomarkers, 030217 neurology & neurosurgery, Cohort study
Abstract: ObjectiveTo review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis.MethodsReview the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics).ResultsPatients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer’s disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics.ConclusionThe combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study.
Published: 2017
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106. Prion diseases

Author: Tze How Mok and Simon Mead
Subjects: 0301 basic medicine, Ataxia, business.industry, Bovine spongiform encephalopathy, General Medicine, Neuropathology, Disease, 030105 genetics & heredity, medicine.disease, Bioinformatics, nervous system diseases, PRNP, 03 medical and health sciences, 0302 clinical medicine, Genotype, Kuru, Medicine, Dementia, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Prion diseases are transmissible and fatal neurodegenerative diseases affecting humans and animals, in which the infectious agent is composed of misfolded and multimeric forms of cellular prion protein. These conditions can be sporadic, inherited or acquired. Rapidly progressive dementia and ataxia are the common themes in the clinical presentation, but these can be accompanied by a wide variety of neurological or psychiatric syndromes. Neuropathological examination of brain tissue remains the only way of making a definite diagnosis, but major advances in magnetic resonance brain imaging, such as diffusion-weighted sequences, and cerebrospinal fluid prion amplification assays have proved to be reliable ante mortem diagnostic tools. Prion protein gene (PRNP) analysis is also recommended, to rule out Mendelian forms and provide the codon 129 genotype, which has profound effects on incubation period, susceptibility, duration of illness, clinical phenotype and neuropathology. At present, there is no effective treatment for prion disease.
Published: 2017
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107. Identification of genetic variants associated with Huntington's disease progression

Author: Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. Gørvell, Eirin Lorentzen, Lars Retterstøl, Bodil Stokke, Inga Bjørnevoll, Sigrid Botne Sando, Artur Dziadkiewicz, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Magdalena Blaszcyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Gregorz Opala, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Bocwinska, Kamila Bojakowska-Jaremek, Malgorzata Dec, Malgorzata Krawczyk, Monika Rudzinska, Elzbieta Szczygiel, Andrzej Szczudlik, Anna Wasielewska, Magdalena Wójcik, Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempolowicz, Anna Gogol, Piotr Janik, Hubert Kwiecinski, Zygmunt Jamrozik, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stepniak, Anna Sulek, Elzbieta Zdzienicka, Karolina Zieora-Jakutowicz, Joaquim J Ferreira, Miguel Coelho, Tiago Mendes, Anabela Valadas, Carlos Andrade, Miguel Gago, Carolina Garrett, Maria Rosália Guerra, Carmen Durán Herrera, Patrocinio Moreno Garcia, Miquel Aguilar Barbera, Dolors Badenes Guia, Laura Casas Hernanz, Judit López Catena, Pilar Quiléz Ferrer, Ana Rojo Sebastián, Gemma Tome Carruesco, Jordi Bas, Núria Busquets, Matilde Calopa, Misericordia Floriach Robert, Celia Mareca Viladrich, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Esther Cubo, Cecilia Gil Polo, Natividad Mariscal, Perez Jessica Rivadeneyra, Francisco Barrero, Blas Morales, María Fenollar, Rocío García-Ramos García, Paloma Ortega, Clara Villanueva, Javier Alegre, Mónica Bascuñana, Juan Garcia Caldentey, Marta Fatás Ventura, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Fernando Alonso Frech, Pedro J García Ruíz, Asunción Martínez-Descals, Rosa Guerrero, María José Saiz Artiga, Vicenta Sánchez, María Fuensanta Noguera Perea, Lorenza Fortuna, Salvadora Manzanares, Gema Reinante, María Martirio Antequera Torres, Laura Vivancos Moreau, Sonia González González, Luis Menéndez Guisasola, Carlos Salvador, Esther Suaréz San Martín, Inés Legarda Ramirez, Aranzazú Gorospe, Mónica Rodriguez Lopera, Penelope Navas Arques, María José Torres Rodríguez, Barbara Vives Pastor, Itziar Gaston, Maria Dolores Martinez-Jaurrieta, Jose Manuel Garcia Moreno, Carolina Mendez Lucena, Fatima Damas, Hermoso Eva Pacheco Cortegana, José Chacón Peña, Luis Redondo, Fátima Carrillo, María Teresa Cáceres, Pablo Mir, María José Lama Suarez, Laura Vargas-González, Maria E. Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. Barker, Deidre O'Keefe, Anna Di Pietro, Kate Fisher, Anna Goodman, Susan Hill, Ann Kershaw, Sarah Mason, Nicole Paterson, Lucy Raymond, Rachel Swain, Natalie Valle Guzman, Monica Busse, Cynthia Butcher, Catherine Clenaghan, Sarah Hunt, Una Jones, Hanan Khalil, Michael Owen, Kathleen Price, Anne Rosser, Maureen Edwards, Carrie Ho, Teresa Hughes, Marie McGill, Pauline Pearson, Mary Porteous, Paul Smith, Peter Brockie, Jillian Foster, Nicola Johns, Sue McKenzie, Jean Rothery, Gareth Thomas, Shona Yates, Liz Burrows, Carol Chu, Amy Fletcher, Deena Gallantrae, Stephanie Hamer, Alison Harding, Stefan Klöppel, Alison Kraus, Fiona Laver, Monica Lewis, Mandy Longthorpe, Ivana Markova, Ashok Raman, Nicola Robertson, Mark Silva, Aileen Thomson, Sue Wild, Pam Yardumian, Carole Evans, Deena Gallentrae, Emma Hobson, Stuart Jamieson, Hannah Musgrave, Liz Rowett, Jean Toscano, Colin Bourne, Jackie Clapton, Carole Clayton, Heather Dipple, Dawn Freire-Patino, Janet Grant, Diana Gross, Caroline Hallam, Julia Middleton, Ann Murch, Catherine Thompson, Sundus Alusi, Rhys Davies, Kevin Foy, Emily Gerrans, Louise Pate, Thomasin Andrews, Andrew Dougherty, Charlotte Golding, Fred Kavalier, Hana Laing, Alison Lashwood, Dene Robertson, Deborah Ruddy, Alastair Santhouse, Anna Whaite, Stefania Bruno, Karen Doherty, Salman Haider, Davina Hensman, Nayana Lahiri, Marianne Novak, Aakta Patel, Elisabeth Rosser, Rachel Taylor, Thomas Warner, Edward Wild, Natalie Arran, Judith Bek, David Craufurd, Marianne Hare, Liz Howard, Susan Huson, Liz Johnson, Mary Jones, Helen Murphy, Emma Oughton, Lucy Partington-Jones, Dawn Rogers, Andrea Sollom, Julie Snowden, Cheryl Stopford, Jennifer Thompson, Iris Trender-Gerhard, Nichola Verstraelen, Leann Westmoreland, Richard Armstrong, Kathryn Dixon, Andrea H Nemeth, Gill Siuda, Ruth Valentine, David Harrison, Max Hughes, Andrew Parkinson, Beverley Soltysiak, Oliver Bandmann, Alyson Bradbury, Paul Gill, Helen Fairtlough, Kay Fillingham, Isabella Foustanos, Mbombe Kazoka, Kirsty O'Donovan, Cat Taylor, Katherine Tidswell, Oliver Quarrell, Puay Ngoh Lau, Emmanul Pica, Louis Tan, Univ Angers, Okina, Moss, Davina J. Hensman, Tabrizi, Sarah J, Mead, Simon, Kitty, Lo, Pardiã±as, Antonio F, Holmans, Peter, Jones, Lesley, Langbehn, Dougla, Coleman, A., Santos, R. Dar, Decolongon, J., Sturrock, A., Bardinet, E., Ret, C. Jauff, Justo, D., Lehericy, S., Marelli, C., Nigaud, K., Valabrãgue, R., van den Bogaard, S. J. A., Dumas, E. M., van der Grond, J., T'Hart, E. P., Jurgens, C., Witjes-Ane, M. -. N., Arran, N., Callaghan, J., Stopford, C., Frost, C., Jones, R., Hobbs, N., Lahiri, N., Ordidge, R., Owen, G., Pepple, T., Read, J., Say, M., Wild, E., Patel, A., Fox, N. C., Gibbard, C., Malone, I., Crawford, H., Whitehead, D., Keenan, S., Cash, D. M., Berna, C., Bechtel, N., Bohlen, S., Man, A. Hoff, Kraus, P., Axelson, E., Wang, C., Acharya, T., Lee, S., Monaco, W., Campbell, C., Queller, S., Whitlock, K., Campbell, M., Frajman, E., Milchman, C., O'Regan, A., Labuschagne, I., Stout, J., Landwehrmeyer, B., Craufurd, D., Scahill, R., Hicks, S., Kennard, C., Johnson, H., Tobin, A., Rosas, H. D., Reilmann, R., Borowsky, B., Pourchot, C., Andrews, S. C., Bachoud-LÃ©vi, Anne-Catherine, Bentivoglio, Anna Rita, Biunno, Ida, Bonelli, Raphael, Burgunder, Jean-Marc, Dunnett, Stephen, Ferreira, Joaquim, Handley, Olivia, Heiberg, Arvid, Illmann, Torsten, Landwehrmeyer, G. Bernhard, Levey, Jamie, Ramos-Arroyo, Maria A., Nielsen, Jã¸rgen, Koivisto, Susana Pro, Pã¤ivã¤rinta, Markku, Roos, Raymund A. C., Sebastiã¡n, A. Rojo, Tabrizi, Sarah, Vandenberghe, Wim, Verellen-Dumoulin, Christine, Uhrova, Tereza, Wahlstrã¶m, Jan, Zaremba, Jacek, Baake, Verena, Barth, Katrin, Garde, Monica BascuÃ±ana, Betz, Sabrina, Bos, Reineke, Callaghan, Jenny, Come, Adrien, Guedes, Leonor Correia, Ecker, Daniel, Finisterra, Ana Maria, Fullam, Ruth, Gilling, Mette, Gustafsson, Lena, Handley, Olivia J, Hvalstedt, Carina, Held, Christine, Koppers, Kerstin, Lamanna, Claudia, Laurã , Matilde, Descals, AsunciÃ³n MartÃnez, Martinez-Horta, Saã¼l, Mestre, Tiago, Minster, Sara, Monza, Daniela, Mã¼tze, Lisanne, Oehmen, Martin, Orth, Michael, Padieu, Hã©lãne, Paterski, Laurent, Peppa, Nadia, Di Renzo, Martina, Rialland, Amandine, Rã¸ren, Niini, Å aå¡inkovã¡, Pavla, Timewell, Erika, Townhill, Jenny, Cubillo, Patricia Trigo, da Silva, Wildson Vieira, van Walsem, Marleen R, Whalstedt, Carina, Witjes-AnÃ©, Marie-Noelle, Witkowski, Grzegorz, Wright, Abigail, Zielonka, Daniel, Zielonka, Eugeniusz, Zinzi, Paola, Bonelli, Raphael M., Lilek, Sabine, Hecht, Karen, Herranhof, Brigitte, Holl, Anna, Kapfhammer, Hans-Peter, Koppitz, Michael, Magnet, Marku, Mã¼ller, Nicole, Otti, Daniela, Painold, Annamaria, Reisinger, Karin, Scheibl, Monika, Schã¶ggl, Helmut, Ullah, Jasmin, Braunwarth, Eva-Maria, Brugger, Florian, Buratti, Lisa, Hametner, Eva-Maria, Hepperger, Caroline, Holas, Christiane, Hotter, Anna, Hussl, Anna, Mã¼ller, Christoph, Poewe, Werner, Seppi, Klau, Sprenger, Fabienne, Wenning, Gregor, Boogaerts, Andrea, Calmeyn, Godelinde, Delvaux, Isabelle, Liessens, Dirk, Somers, Nele, Dupuit, Michel, Minet, Cã©cile, van Paemel, Dominique, Ribaã¯, Pascale, van Reijen, Dimphna, Klempãr, Jirã, Majerovã¡, Veronika, Roth, Jan, Stã¡rkovã¡, Irena, Hjermind, Lena E., Jacobsen, Oda, Nielsen, JÃ¸rgen E., Larsen, Ida Unmack, Vinther-Jensen, Tua, Hiivola, Heli, Hyppã¶nen, Hannele, Martikainen, Kirsti, Tuuha, Katri, Allain, Philippe, Bonneau, Dominique, Bost, Marie, Gohier, Bã©nã©dicte, Guã©rid, Marie-Anne, Olivier, Audrey, Prundean, Adriana, Scherer-Gagou, Clarisse, Verny, Christophe, Babiloni, Blandine, Debruxelles, Sabrina, Duchã©, Charlotte, Goizet, Cyril, Jameau, Laetitia, Lafoucriãre, Danielle, Spampinato, Umberto, Barthã©lã©my, Rekha, De Bruycker, Christelle, Carette, Maryline Cabaret Anne-Sophie, Defebvre, Eric Decorte Luc, Delliaux, Marie, Delval, Arnaud, Destee, Alain, Dujardin, Kathy, Lemaire, Marie-HÃ©lÃne, Manouvrier, Sylvie, Peter, Mireille, Plomhouse, Lucie, Sablonniãre, Bernard, Simonin, Clã©mence, Thibault-Tanchou, Stã©phanie, Vuillaume, Isabelle, Bellonet, Marcellin, Berrissoul, Hassan, Blin, Stã©phanie, Courtin, Franã§oise, Duru, Cã©cile, Fasquel, Vã©ronique, Godefroy, Olivier, Krystkowiak, Pierre, Mantaux, Bã©atrice, Roussel, Martine, Wannepain, Sandrine, Azulay, Jean-Philippe, Delfini, Marie, Eusebio, Alexandre, Fluchere, Frã©dã©rique, Mundler, Laura, Anheim, Mathieu, Juliã©, Celine, Boukbiza, Ouhaid Lagha, Longato, Nadine, Rudolf, Gabrielle, Tranchant, Christine, Zimmermann, Marie-Agathe, Kosinski, Christoph Michael, Milkereit, Eva, Probst, Daniela, Reetz, Kathrin, Sass, Christian, Schiefer, Johanne, Schlangen, Christiane, Werner, Cornelius J., Gelderblom, Harald, Priller, Josef, Prã¼ã , Harald, Spruth, Eike Jakob, Ellrichmann, Gisa, Herrmann, Lennard, Hoffmann, Rainer, Kaminski, Barbara, Kotz, Peter, Prehn, Christian, Saft, Carsten, Lange, Herwig, Maiwald, Robert, Lã¶hle, Matthia, Maass, Antonia, Schmidt, Simone, Bosredon, Cecile, Storch, Alexander, Wolz, Annett, Wolz, Martin, Capetian, Philipp, Lambeck, Johann, Zucker, Birgit, Boelmans, Kai, Ganos, Christo, Heinicke, Walburgi, Hidding, Ute, Lewerenz, Jan, Mã¼nchau, Alexander, Schmalfeld, Jenny, Stubbe, Lar, Zittel, Simone, Diercks, Gabriele, Dressler, Dirk, Gorzolla, Heike, Schrader, Christoph, Tacik, Pawel, Ribbat, Michael, Longinus, Bernhard, Bã¼rk, Katrin, Mã¶ller, Jens Carsten, Rissling, Ida, Mã¼hlau, Mark, Peinemann, Alexander, Stã¤dtler, Michael, Weindl, Adolf, Winkelmann, Juliane, Ziegler, Cornelia, Bechtel, Natalie, Beckmann, Heike, Bohlen, Stefan, Hã¶lzner, Eva, Reilmann, Ralf, Rohm, Stefanie, Rumpf, Silke, Schepers, Sigrun, Weber, Natalia, Dose, Matthia, Leythã¤user, Gabriele, Marquard, Ralf, Raab, Tina, Wiedemann, Alexandra, Buck, Andrea, Connemann, Julia, Geitner, Carolin, Kesse, Andrea, Landwehrmeyer, Bernhard, Lang, Christina, Lezius, Franziska, Nepper, Solveig, Niess, Anke, Schneider, Ariane, Schwenk, Daniela, Sã¼ã muth, Sigurd, Trautmann, Sonja, Weydt, Patrick, Cormio, Claudia, Sciruicchio, Vittorio, Serpino, Claudia, de Tommaso, Marina, Capellari, Sabina, Cortelli, Pietro, Galassi, Roberto, Rizzo, Giovanni, Poda, Roberto, Scaglione, Cesa, Bertini, Elisabetta, Ghelli, Elena, Ginestroni, Andrea, Massaro, Francesca, Mechi, Claudia, Paganini, Marco, Piacentini, Silvia, Pradella, Silvia, Romoli, Anna Maria, Sorbi, Sandro, Abbruzzese, Giovanni, di Poggio, Monica Bandettini, Ferrandes, Giovanna, Mandich, Paola, Roberta, Marchese, Albanese, Alberto, Di Bella, Daniela, Castaldo, Anna, Di Donato, Stefano, Gellera, Cinzia, Genitrini, Silvia, Mariotti, Caterina, Nanetti, Lorenzo, Paridi, Dominga, Soliveri, Paola, Tomasello, Chiara, De Michele, Giuseppe, Di Maio, Luigi, Massarelli, Marco, Peluso, Silvio, Roca, Alessandro, Russo, Cinzia Valeria, Salvatore, Elena, Sorrentino, Pierpaolo, Amico, Enrico, Favellato, Mariagrazia, Griguoli, Annamaria, Mazzante, Irene, Petrollini, Martina, Squitieri, Ferdinando, D'Alessio, Barbara, Esposito, Chiara, Bentivoglio, Rita, Frontali, Marina, Guidubaldi, Arianna, Ialongo, Tamara, Jacopini, Gioia, Piano, Carla, Romano, Silvia, Soleti, Francesco, Spadaro, Maria, van Hout, Monique S. E., Verhoeven, Marloes E., van Vugt, Jeroen P. P., de Weert, A. Marit, Bolwijn, J. J. W., Dekker, M., Kremer, B., Leenders, K. L., van Oostrom, J. C. H., van den Bogaard, Simon J. A., Dumas, Eve M., â t Hart, Ellen P., Kremer, Berry, Verstappen, C. C. P., Aaserud, Olaf, Jan Frich, C., Wehus, Ragnhild, Bjã¸rgo, Kathrine, Fannemel, Madeleine, Gã¸rvell, Per F., Lorentzen, Eirin, Retterstã¸l, Lar, Stokke, Bodil, Bjã¸rnevoll, Inga, Sando, Sigrid Botne, Dziadkiewicz, Artur, Nowak, Malgorzata, Robowski, Piotr, Sitek, Emilia, Slawek, Jaroslaw, Soltan, Witold, Szinwelski, Michal, Blaszcyk, Magdalena, Boczarska-Jedynak, Magdalena, Ciach-Wysocka, Ewelina, Gorzkowska, Agnieszka, Jasinska-Myga, Barbara, Klodowska-Duda, Gabriela, Opala, Gregorz, Stompel, Daniel, Banaszkiewicz, Krzysztof, Bocwinska, Dorota, Bojakowska-Jaremek, Kamila, Dec, Malgorzata, Krawczyk, Malgorzata, Rudzinska, Monika, Szczygiel, Elzbieta, Szczudlik, Andrzej, Wasielewska, Anna, Wã³jcik, Magdalena, Bryl, Anna, Ciesielska, Anna, Klimberg, Aneta, Marcinkowski, Jerzy, Samara, Husam, Sempolowicz, Justyna, Gogol, Anna, Janik, Piotr, Kwiecinski, Hubert, Jamrozik, Zygmunt, Antczak, Jakub, Jachinska, Katarzyna, Krysa, Wioletta, Rakowicz, Maryla, Richter, Przemyslaw, Rola, Rafal, Ryglewicz, Danuta, Sienkiewicz-Jarosz, Halina, Stepniak, Iwona, Sulek, Anna, Zdzienicka, Elzbieta, Zieora-Jakutowicz, Karolina, Ferreira, Joaquim J, Coelho, Miguel, Mendes, Tiago, Valadas, Anabela, Andrade, Carlo, Gago, Miguel, Garrett, Carolina, Guerra, Maria RosÃ¡lia, Herrera, Carmen DurÃ¡n, Garcia, Patrocinio Moreno, Barbera, Miquel Aguilar, Guia, Dolors Badene, Hernanz, Laura Casa, Catena, Judit LÃ³pez, Ferrer, Pilar QuilÃ©z, Sebastiã¡n, Ana Rojo, Carruesco, Gemma Tome, Bas, Jordi, Busquets, Nãºria, Calopa, Matilde, Robert, Misericordia Floriach, Viladrich, Celia Mareca, Idiago, JesÃºs Miguel Ruiz, Riballo, Antonio Villa, Cubo, Esther, Polo, Cecilia Gil, Mariscal, Natividad, Rivadeneyra, Perez Jessica, Barrero, Francisco, Morales, Bla, Fenollar, Marãa, Garcãa, RocÃo GarcÃa-Ramo, Ortega, Paloma, Villanueva, Clara, Alegre, Javier, Bascuã±ana, Mã³nica, Caldentey, Juan Garcia, Ventura, Marta FatÃ¡, Ribas, Guillermo GarcÃa, de YÃ©benes, Justo GarcÃa, Moreno, JosÃ© Luis LÃ³pez-SendÃ³n, Frech, Fernando Alonso, Ruãz, Pedro J. GarcÃa, MartÃnez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, MarÃa JosÃ© Saiz, Sã¡nchez, Vicenta, Perea, MarÃa Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, MarÃa Martirio Antequera, Moreau, Laura Vivanco, GonzÃ¡lez GonzÃ¡lez, Sonia, Guisasola, Luis MenÃ©ndez, Salvador, Carlo, Martãn, Esther SuarÃ©z San, Ramirez, InÃ©s Legarda, Gorospe, Aranzazãº, Lopera, MÃ³nica Rodriguez, Arques, Penelope Nava, Rodrãguez, MarÃa JosÃ© Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, JosÃ© ChacÃ³n, Redondo, Lui, Carrillo, Fã¡tima, Teresa CÃ¡ceres, Marãa, Mir, Pablo, Suarez, MarÃa JosÃ© Lama, Vargas-GonzÃ¡lez, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen PeirÃ³, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, HÃ¸sterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-LingefjÃ¤rd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators
Subjects: 0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.
Published: 2017
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108. CJD mimics and chameleons

Author: Simon Mead and Peter Rudge
Subjects: medicine.medical_specialty, Neurological examination, Disease, Review, Cerebrospinal fluid pleocytosis, rapidly progressive dementia, Creutzfeldt-Jakob Syndrome, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Animals, Humans, 030212 general & internal medicine, Intensive care medicine, Rapidly progressive dementia, medicine.diagnostic_test, Symptom management, business.industry, Electroencephalography, General Medicine, Magnetic Resonance Imaging, Hyperintensity, nervous system diseases, Phenotype, Referral centre, Disease Progression, Neurology (clinical), Presentation (obstetrics), Nervous System Diseases, business, Neuroscience, 030217 neurology & neurosurgery
Abstract: Rapidly progressive dementia mimicking Creutzfeldt-Jakob disease (CJD) is a relatively rare presentation but a rewarding one to become familiar with, as the potential diagnoses range from the universally fatal to the completely reversible. Patients require urgent decisions about assessment and investigation and have quickly evolving needs for treatments and support, through symptom management and end-of-life care in most cases. We have based this pragmatic review on the experiences of a specialist prion referral centre in the UK, which, unsurprisingly, is strongly biased towards seeing patients with CJD. Cases eventually proven not to have prion disease might be described as 'CJD-mimics'; being referred from UK neurologists, these are the most challenging cases. CJD in its classical presentation is very rarely mimicked; however, it is highly heterogeneous, and atypical forms can mimic virtually all common neurodegenerative syndromes. Warning features of a mimic include generalised seizures, hyponatraemia, fever, a facial movement disorder, a normal neurological examination and a modestly rapid presentation. Contrast-enhancing lesions or MRI signal hyperintensity outside the striatum, thalamus or cortex and a cerebrospinal fluid pleocytosis are key investigation pointers to a CJD mimic.
Published: 2017

109. White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

Author: Rachelle Shafei, Albert Lladó, Benjamin Bender, Luisa Benussi, Elisabeth Wlasich, Martha S. Foiani, Isabel Santana, Christen Shoesmith, Ione O.C. Woollacott, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Pietro Tiraboschi, Mario Masellis, Sergi Borrego-Écija, Giorgio G. Fumagalli, Ron Keren, Sandro Sorbi, Rick van Minkelen, Vesna Jelic, Ekaterina Rogaeva, Mollie Neason, Enrico Premi, Timothy Rittman, Lieke H.H. Meeter, Giacomina Rossi, Veronica Redaelli, Roberta Ghidoni, Begoña Indakoetxea, Johannes Levin, Håkan Thonberg, Rhian S Convery, Henrik Zetterberg, Gemma Lombardi, Giuseppe Di Fede, Chiara Fenoglio, Jose Bras, Daniela Galimberti, Simon Mead, Miren Zulaica, David M. Cash, Gabriel Miltenberger, Markus Otto, Simon Ducharme, Myriam Barandiaran, Katrina M. Moore, Alessandro Padovani, Thomas E. Cope, Elizabeth Finger, Maria Carmela Tartaglia, Martin N. Rossor, M. Jorge Cardoso, Sara Mitchell, Rik Vandenberghe, Pedro Rosa-Neto, John C. van Swieten, Sarah Anderl-Straub, Maria Rosário Almeida, Zigor Diaz, Robart Bartha, Maria de Arriba, Caroline V. Greaves, Philip Vandamme, Giorgio Giaccone, Adrian Danek, Miguel Tábuas-Pereira, Carolina Maruta, Roberto Gasparotti, Jennifer M. Nicholas, Martina Bocchetta, Elisa Semler, Valentina Bessi, C. Ferreira, Robert Laforce, Sandra V. Loosli, Ana Verdelho, Paola Caroppo, Jaume Olives, Giuliano Binetti, Carolin Heller, Jorge Villanua, Stefano Gazzina, Amanda Heslegrave, Alazne Gabilondo, Sandra E. Black, Y.A.L. Pijnenburg, Mikel Tainta, Carolyn Timberlake, Sónia Afonso, Matthis Synofzik, Janne M. Papma, Sebastien Ourselin, Núria Bargalló, Barbara Borroni, Ricardo Taipa, Hans-Otto Karnarth, Camilla Ferrari, David F. Tang-Wai, Diana Duro, Catharina Prix, Serge Gauthier, Sara Prioni, Carlo Wilke, Michele Veldsman, Alexandre de Mendonça, Andrea Arighi, Christopher C Butler, Raquel Sánchez-Valle, Toby Flanagan, Carole H. Sudre, Jason D. Warren, Rita Guerreiro, Linn Öijerstedt, Beatriz Santiago, Rosa Rademakers, Miguel Castelo-Branco, Fabrizio Tagliavini, Maria João Leitão, Anna Antonell, Mathieu Vandenbulcke, Rose Bruffaerts, Jessica L. Panman, Alexander Gerhard, Tobias Hoegen, Ana Gorostidi, Silvana Archetti, James B. Rowe, Michela Pievani, Elio Scarpini, Giovanni B. Frisoni, Benedetta Nacmias, Sonja Schönecker, Maura Cosseddu, Christin Andersson, Caroline Graff, Morris Freedman, Fermin Moreno, Mircea Balasa, Lize C. Jiskoot, Sudre, Carole H [0000-0001-5753-428X], Apollo - University of Cambridge Repository, Rowe, James [0000-0001-7216-8679], and Neurology
Subjects: Oncology, Male, SEGMENTATION, PROTEIN, physiopathology [Frontotemporal Dementia], DISEASE, 0302 clinical medicine, White matter hyperintensities, blood [Glial Fibrillary Acidic Protein], Longitudinal Studies, education.field_of_study, Regular Article, Neurology, Frontotemporal Dementia, Disease Progression, GRN, medicine.medical_specialty, lcsh:Computer applications to medicine. Medical informatics, MRI, Magnetic Resonance Imaging, White matter, 03 medical and health sciences, AGE, Humans, neurofilament protein L, education, Aged, CSF, Cerebrospinal fluid, Science & Technology, Trail Making Test, Frontotemporal dementia, Dementia, Progranulin, medicine.disease, POLYMORPHISM, Case-Control Studies, Asymptomatic Diseases, Mutation, Neurosciences & Neurology, Neurology (clinical), GENFI, 030217 neurology & neurosurgery, Executive dysfunction, blood [Frontotemporal Dementia], GFAP, Glial Fibrillary Acidic Protein, blood [Neurofilament Proteins], lcsh:RC346-429, genetics [Progranulins], Executive Function, Progranulins, pathology [Gray Matter], Neurofilament Proteins, BRAIN ATROPHY, GM, Grey Matter, Gray Matter, genetics [Frontotemporal Dementia], genetics [Nerve Tissue Proteins], 05 social sciences, Organ Size, Middle Aged, Magnetic Resonance Imaging, White Matter, genetics [Membrane Proteins], medicine.anatomical_structure, FTD, Frontotemporal dementia, GENFI, GENetic Frontotemporal dementia Initiative, lcsh:R858-859.7, Female, Life Sciences & Biomedicine, Adult, Heterozygote, Cognitive Neuroscience, Population, Prodromal Symptoms, Neuroimaging, PHENOTYPES, Nerve Tissue Proteins, MUTATION CARRIERS, WM, White Matter, Grey matter, diagnostic imaging [Frontotemporal Dementia], 050105 experimental psychology, diagnostic imaging [White Matter], Atrophy, TMEM106B protein, human, Internal medicine, mental disorders, Glial Fibrillary Acidic Protein, medicine, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, ddc:610, lcsh:Neurology. Diseases of the nervous system, business.industry, GFAP protein, human, WMH, White Matter Hyperintensity, diagnostic imaging [Gray Matter], Membrane Proteins, Hyperintensity, GRN, Progranulin, TMEM106B, ddc:618.97, GRN protein, human, business
Abstract: Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published
Published: 2019
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110. Genetic Factors in Mammalian Prion Diseases

Author: Sarah E. Lloyd, Simon Mead, and John Collinge
Subjects: animal diseases, Bovine spongiform encephalopathy, Scrapie, Genome-wide association study, Disease, Biology, medicine.disease_cause, Prion Proteins, PRNP, Prion Diseases, 03 medical and health sciences, Mice, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Genetic Predisposition to Disease, Genetic Testing, Selection, Genetic, Genetic Association Studies, 030304 developmental biology, Mammals, 0303 health sciences, Mutation, Polymorphism, Genetic, Sheep, Goats, Chronic wasting disease, medicine.disease, nervous system diseases, Disease Models, Animal, Kuru, Cattle, 030217 neurology & neurosurgery
Abstract: Mammalian prion diseases are a group of neurodegenerative conditions caused by infection of the central nervous system with proteinaceous agents called prions, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; kuru; inherited prion disease; sheep scrapie; bovine spongiform encephalopathy; and chronic wasting disease. Prions are composed of misfolded and multimeric forms of the normal cellular prion protein (PrP). Prion diseases require host expression of the prion protein gene ( PRNP) and a range of other cellular functions to support their propagation and toxicity. Inherited forms of prion disease are caused by mutation of PRNP, whereas acquired and sporadically occurring mammalian prion diseases are controlled by powerful genetic risk and modifying factors. Whereas some PrP amino acid variants cause the disease, others confer protection, dramatically altered incubation times, or changes in the clinical phenotype. Multiple mechanisms, including interference with homotypic protein interactions and the selection of the permissible prion strains in a host, play a role. Several non- PRNP factors have now been uncovered that provide insights into pathways of disease susceptibility or neurotoxicity.
Published: 2019

111. Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease

Author: Sudha Seshadri, John Hardy, Wolfgang Maier, Janet C Harwood, Emily Baker, Carol Brayne, Julie Williams, Lesley Jones, Gerard D. Schellenberg, Reinhard Heun, Frank Jessen, Valentina Escott-Price, Matthew Hill, Oliver Peters, John Powell, Dobril Ivanov, Peter Passmore, Martin Dichgans, Lutz Frölich, Alfredo Ramirez, Aura Frizzati, Alison Goate, Kevin Morgan, Paul Morgan, Carlos Cruchaga, Ganna Leonenko, Gianfranco Spalletta, Paola Bossù, Michael Gill, Clive Holmes, Simon Mead, Detelina Grozeva, Peter Holmans, Philippe Amouyel, Rebecca Sims, Nicholas D. Allen, Baker, Emily [0000-0001-5691-597X], Grozeva, Detelina [0000-0003-3239-8415], Brayne, Carol [0000-0001-5307-663X], Mead, Simon [0000-0002-4326-1468], Ramirez, Alfredo [0000-0003-4991-763X], Ivanov, Dobril [0000-0001-6271-6301], Hill, Matthew [0000-0001-6776-8709], Holmans, Peter [0000-0003-0870-9412], Schellenberg, Gerard D [0000-0003-1115-2475], Apollo - University of Cambridge Repository, van Duijn, Cornelia [0000-0002-2374-9204], and Williams, Julie [0000-0002-4069-0259]
Subjects: 0301 basic medicine, Male, DNA Repair, Gene Expression, Social Sciences, genetics [Alzheimer Disease], genetics [Cholesterol], Genome-wide association study, Alzheimer's Disease, Biochemistry, IGAP consortia, pathology [Centrosome], pathology [Alzheimer Disease], 0302 clinical medicine, Sociology, metabolism [Centrosome], Consortia, Medicine and Health Sciences, genetics [Amyloid beta-Peptides], Genetics, Regulation of gene expression, metabolism [Inflammation], Multidisciplinary, biology, metabolism [Proteins], Neurodegenerative Diseases, Nuclear Receptor Subfamily 1, Group F, Member 1, Genomics, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Circadian Rhythm, Circadian Rhythms, Cholesterol, Neurology, Medicine, Female, metabolism [Alzheimer Disease], Research Article, medicine.medical_specialty, genetics [Circadian Rhythm], Amyloid beta, Science, Lipoproteins, metabolism [Amyloid beta-Peptides], Single-nucleotide polymorphism, genetics [Energy Metabolism], Polymorphism, Single Nucleotide, GERAD Consortium, Apolipoprotein Genes, Molecular Genetics, genetics [Inflammation], 03 medical and health sciences, Alzheimer Disease, genetics [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], Molecular genetics, Mental Health and Psychiatry, medicine, Genome-Wide Association Studies, GERAD/PERADES, Dementia, Humans, genetics [DNA Damage], Gene Regulation, ddc:610, genetics [DNA Repair], Gene, Molecular Biology, EADI Consortium, pathology [Inflammation], Centrosome, Inflammation, Amyloid beta-Peptides, Genome, Human, Biology and Life Sciences, Proteins, Computational Biology, Human Genetics, metabolism [Cholesterol], medicine.disease, Genome Analysis, ADGC Consortium, genetics [Proteins], 030104 developmental biology, metabolism [Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha], CHARGE Consortium, biology.protein, Energy Metabolism, Chronobiology, 030217 neurology & neurosurgery, genetics [Nuclear Receptor Subfamily 1, Group F, Member 1], metabolism [Nuclear Receptor Subfamily 1, Group F, Member 1], DNA Damage, Genome-Wide Association Study
Abstract: A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates. Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423 . The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.
Published: 2019
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112. Prion disease diagnosis using subject-specific imaging biomarkers within a multi-kernel Gaussian process

Author: Frederik Barkhof, Alexander J.M. Foulkes, Tze How Mok, Harpreet Hyare, Jonathan M. Schott, Akin Nihat, Catherine F. Slattery, Marc Modat, Liane S Canas, M. Jorge Cardoso, Carole H. Sudre, John S. Thornton, Enrico De Vita, John Collinge, Sebastien Ourselin, Simon Mead, Ross W. Paterson, Radiology and nuclear medicine, and Amsterdam Neuroscience - Neurodegeneration
Subjects: Male, animal diseases, Disease, Gene mutation, Bioinformatics, Clinical onset, Severity of Illness Index, lcsh:RC346-429, 0302 clinical medicine, Inherited Creutzfeldt–Jakob disease, Diagnosis, Image Processing, Computer-Assisted, Medicine, Sporadic Creutzfeldt–Jakob disease, Subject specific, 05 social sciences, food and beverages, Brain, Neurodegenerative Diseases, Regular Article, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Phenotype, Neurology, Disease Progression, lcsh:R858-859.7, Female, Adult, Multi kernel, Prion diseases, Cognitive Neuroscience, Neuroimaging, lcsh:Computer applications to medicine. Medical informatics, 050105 experimental psychology, Diagnosis, Differential, 03 medical and health sciences, Young Adult, Subjects’ stratification, mental disorders, Dementia, Humans, 0501 psychology and cognitive sciences, Radiology, Nuclear Medicine and imaging, Gaussian process, lcsh:Neurology. Diseases of the nervous system, Aged, business.industry, fungi, medicine.disease, nervous system diseases, Clinical diagnosis, Neurology (clinical), Differential diagnosis, Atrophy, business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Highlights • Subject-specific imaging biomarkers can be used to characterize Prion disease. • Gaussian process can be used for the staging of prion disease patients. • Probabilistic diagnosis are indicative of the patients symptoms progression. • Gaussian process are effective for differential diagnosis., Prion diseases are a group of rare neurodegenerative conditions characterised by a high rate of progression and highly heterogeneous phenotypes. Whilst the most common form of prion disease occurs sporadically (sporadic Creutzfeldt–Jakob disease, sCJD), other forms are caused by prion protein gene mutations, or exposure to prions in the diet or by medical procedures, such us surgeries. To date, there are no accurate quantitative imaging biomarkers that can be used to predict the future clinical diagnosis of a healthy subject, or to quantify the progression of symptoms over time. Besides, CJD is commonly mistaken for other forms of dementia. Due to the heterogeneity of phenotypes and the lack of a consistent geometrical pattern of disease progression, the approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of prion disease. In this paper, using a tailored framework, we aim to classify and stratify patients with prion disease, according to the severity of their illness. The framework is initialised with the extraction of subject-specific imaging biomarkers. The extracted biomakers are then combined with genetic and demographic information within a Gaussian Process classifier, used to calculate the probability of a subject to be diagnosed with prion disease in the next year. We evaluate the effectiveness of the proposed method in a cohort of patients with inherited and sporadic forms of prion disease. The model has shown to be effective in the prediction of both inherited CJD (92% of accuracy) and sporadic CJD (95% of accuracy). However the model has shown to be less effective when used to stratify the different stages of the disease, in which the average accuracy is 85%, whilst the recall is 59%. Finally, our framework was extended as a differential diagnosis tool to identify both forms of CJD among another neurodegenerative disease. In summary we have developed a novel method for prion disease diagnosis and prediction of clinical onset using multiple sources of features, which may have use in other disorders with heterogeneous imaging features.
Published: 2019
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113. Enteral feeding is associated with longer survival in the advanced stages of prion disease

Author: Kirsty McNiven, Peter Rudge, John Collinge, Veronica O’Donnell, Tze How Mok, Simon Mead, Selam Tesfamichael, and Akin Nihat
Subjects: 0301 basic medicine, medicine.medical_specialty, Palliative care, RIG, business.industry, General Engineering, Disease, Enteral administration, PEG, Clinical trial, prion, CJD, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Parenteral nutrition, enteral, Internal medicine, medicine, Neurodisability, Etiology, Original Article, business, 030217 neurology & neurosurgery, Cohort study
Abstract: To report the frequency, complications, survival and motivations for enteral feeding in UK patients with prion diseases. We analysed data from an ongoing prospective observational cohort study of UK patients with prion diseases (n = 635). Gastrostomy-treated cases were matched by age, gender, disease aetiology, severity, duration and a genetic predictor of survival (ratio 1:3.1). The main outcome was survival (unadjusted log-rank test); secondary outcomes were future functional impairments, complications and retrospective carer interviews to determine qualitative benefits and motivations. Enteral feeding is uncommon in UK patients with prion diseases (n = 26/635; 4.1%), but more frequent in acquired (7/41, 17.1%) and inherited (7/128, 5.5%) compared with sporadic disease (12/466, 2.6%; P = 3 × 10−5 chi-squared), and used mostly at advanced stages. Enteral feeding was complicated by infection and the need for reinsertions, but associated with markedly longer survival at advanced neurodisability (median 287 days, range 41–3877 versus 17 days, range 0–2356; log-rank test in three aetiologies each P, We analysed data from a prospective observational cohort study of UK patients with prion disease. Using a matched case–control design, we found enteral feeding prolongs the akinetic-mute phase of all types of prion disease, but does not appear to preserve useful functions. Enteral feeding was complicated by infections and reinsertions., Graphical Abstract Graphical Abstract
Published: 2019

114. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Author: van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till F M, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ifgc, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavanramasamy, Kwok, John B. J., Carol, Dobson-Stone, Brooks, William S., Schofield, Peterr., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Laurenbartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigiforloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karinnilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, DavidM. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robertperneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, George-Hyslop, Peterst., Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, William, Deschamps, Tim, Vanlangenhove, Marc, Cruts, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuelmayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Annarichardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Fran-cesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Davidknopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, Vanswieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philipscheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolosorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florencepasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrioskapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni, Ironside, James W, van Berckel, Bart N M, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, Boeve, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel J T, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande A L, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild I A, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, Clarimón, Jordi, Christensen, Kaare, Ertekin-Taner, Nilüfer, Scholz, Sonja W, Ramirez, Alfredo, Ruiz, Agustín, Slagboom, Eline, van der Flier, Wiesje M, Holstege, Henne, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Sociology, The Social Context of Aging (SoCA), Universidad de Cantabria, DESGESCO Dementia Genetics, EADB Alzheimer Dis European, IFGC Int FTD-Genomics, IPDGC Int Parkinson Dis Genomics, RiMod-FTD Risk Modifying, Netherlands Brain Bank NBB, GIFT Genetic Invest, van der Lee, Sven J [0000-0003-1606-8643], Andlauer, Till FM [0000-0002-2917-5889], Tesi, Niccolo [0000-0002-1413-5091], Scheltens, Philip [0000-0002-1046-6408], Holstege, Henne [0000-0002-7688-3087], Apollo - University of Cambridge Repository, Amsterdam Neuroscience - Neurodegeneration, Neurology, Epidemiology and Data Science, Radiology and nuclear medicine, Other Research, Divisions, APH - Societal Participation & Health, APH - Aging & Later Life, Human genetics, Amsterdam Reproduction & Development (AR&D), APH - Personalized Medicine, and APH - Methodology
Subjects: 0301 basic medicine, Parkinson's disease, Dementia with Lewy bodies, genetics [Alzheimer Disease], Disease, metabolism [Microglia], Bioinformatics, Neurodegenerative disease, 0302 clinical medicine, genetics [Lewy Body Disease], pathology [Brain], genetics [Parkinson Disease], Missense mutation, genetics [Frontotemporal Dementia], ALZHEIMER’S DISEASE, Brain, Parkinson Disease, purl.org/becyt/ford/3.1 [https], Alzheimer's disease, Phospholipase C Gamma 2, Biobank, 3. Good health, genetics [Amyotrophic Lateral Sclerosis], genetics [Phospholipase C gamma], purl.org/becyt/ford/3 [https], immunology [Brain], Microglia, Alzheimer’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia, Longevity, Multiple sclerosis, PLCG2, Parkinson’s disease, Progressive supranuclear palsy, Lewy Body Disease, Risk, education, Neuroimaging, Pathology and Forensic Medicine, PARKINSON’S DISEASE, 03 medical and health sciences, Cellular and Molecular Neuroscience, SDG 3 - Good Health and Well-being, Alzheimer Disease, genetics [Dementia], medicine, Humans, Genetic Predisposition to Disease, ddc:610, Alleles, Original Paper, Phospholipase C gamma, business.industry, genetics [Multiple Sclerosis], medicine.disease, 030104 developmental biology, metabolism [Brain], Mutation, Dementia, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery, genetics [Longevity], Genome-Wide Association Study
Abstract: ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.
Published: 2019
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115. Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Author: Nigel J. Cairns, Merel O. Mol, Gregory D. Jenkins, Leonard Petrucelli, Nilufer Ertekin-Taner, Stuart Pickering-Brown, Carlos Cruchaga, Edward B. Lee, Jonathan D. Glass, John C. van Swieten, Jonathan D. Rohrer, Keith A. Josephs, Patrizia Rizzu, Johannes Prudlo, Edward D. Huey, Cristina T. Vicente, Shulan Tian, Claire Troakes, Ging-Yuek Robin Hsiung, Julie S. Snowden, Lawrence S. Honig, Jean Paul G. Vonsattel, Yan W. Asmann, Matthis Synofzik, Sigrun Roeber, Jeroen van Rooij, Ralph B. Perkerson, Eric M. Reiman, Charles L. White, Ethan G. Geier, Billie J. Matchett, Robert A. Rissman, Julia Keith, David J. Irwin, Manuela Neumann, Dieter Edbauer, M.-Marsel Mesulam, Jochen Herms, Vivianna M. Van Deerlin, Jordan Grafman, Melissa E. Murray, Oscar L. Lopez, Bernardino Ghetti, Rosa Rademakers, Bradley F. Boeve, Ekaterina Rogaeva, Sara Rollinson, Marla Gearing, Geoffrey L. Ahern, Zachary C. Fogarty, Peter Heutink, Yingxue Ren, Javier Simón-Sánchez, David G. Mann, Bryan K. Woodruff, Ryan J. Uitti, Martin R. Farlow, Lea T. Grinberg, Murray Grossman, Julia Kofler, Ian R. A. Mackenzie, Jennifer S. Yokoyama, Lorne Zinman, Matt Baker, John Q. Trojanowski, Zbigniew K. Wszolek, Cyril Pottier, Changiz Geula, Thomas Arzberger, Dennis W. Dickson, Joanna M. Biernacka, William W. Seeley, Caroline Graff, Olivier Piguet, John B.J. Kwok, Joseph E. Parisi, Safa Al-Sarraj, Harro Seelaar, Elizabeth Christopher, Ronald C. Petersen, Linn Öijerstedt, Anna Karydas, Salvatore Spina, Carlo Wilke, Marka van Blitterswijk, Simon Mead, Janine Diehl-Schmid, Bret M. Evers, David S. Knopman, Kevin F. Bieniek, John R. Hodges, Anthony Batzler, Mariely DeJesus-Hernandez, Elizabeth Finger, Thomas G. Beach, EunRan Suh, Maria Carmela Tartaglia, Sandra Weintraub, Shannon K. McDonnell, Bruce L. Miller, Glenda M. Halliday, Andy King, Eileen H. Bigio, Neill R. Graff-Radford, Richard J. Caselli, and Neurology
Subjects: Male, 0301 basic medicine, Potassium Channels, genetics [Dipeptidyl-Peptidases and Tripeptidyl-Peptidases], genetics [Progranulins], Progranulins, 0302 clinical medicine, Loss of Function Mutation, Risk Factors, genetics [Nerve Tissue Proteins], Genetics, DNA Repeat Expansion, genetics [Potassium Channels], Intracellular Signaling Peptides and Proteins, physiology [Protein Serine-Threonine Kinases], Middle Aged, Frontal Lobe, physiology [Progranulins], metabolism [Frontal Lobe], Frontotemporal Dementia, Female, physiology [Nerve Tissue Proteins], genetics [Frontotemporal Lobar Degeneration], immunology [TDP-43 Proteinopathies], Societies, Scientific, genetics [White People], Nerve Tissue Proteins, genetics [Protein Serine-Threonine Kinases], Single-nucleotide polymorphism, Locus (genetics), Human leukocyte antigen, Protein Serine-Threonine Kinases, physiology [Proteins], Biology, White People, Article, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, HLA-DQ Antigens, immunology [Frontotemporal Lobar Degeneration], Genetic variation, mental disorders, genetics [HLA-DQ Antigens], Humans, Genetic Predisposition to Disease, RNA, Messenger, ddc:610, Allele, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Genotyping, Aged, Whole genome sequencing, C9orf72 Protein, biosynthesis [RNA, Messenger], Sequence Analysis, RNA, genetics [TDP-43 Proteinopathies], Proteins, nutritional and metabolic diseases, genetics [Proteins], nervous system diseases, 030104 developmental biology, Genetic marker, TDP-43 Proteinopathies, Human medicine, Neurology (clinical), Frontotemporal Lobar Degeneration, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n >= 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.
Published: 2019
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116. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study

Author: Emma L van der Ende, Lieke H Meeter, Jackie M Poos, Jessica L Panman, Lize C Jiskoot, Elise G P Dopper, Janne M Papma, Frank Jan de Jong, Inge M W Verberk, Charlotte Teunissen, Dimitris Rizopoulos, Carolin Heller, Rhian S Convery, Katrina M Moore, Martina Bocchetta, Mollie Neason, David M Cash, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Chris Butler, Simon Ducharme, Alex Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Giovanni B Frisoni, Stefano Cappa, Yolande A L Pijnenburg, Jonathan D Rohrer, John C van Swieten, Martin N. Rossor, Jason D. Warren, Nick C. Fox, Ione O.C. Woollacott, Rachelle Shafei, Caroline Greaves, Rita Guerreiro, Jose Bras, David L. Thomas, Jennifer Nicholas, Simon Mead, Rick van Minkelen, Myriam Barandiaran, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, Maria de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanua, Zigor Diaz, Sergi Borrego-Ecija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Nuria Bargallo, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David Tang-Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelic, Hakan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, Hans-Otto Karnath, Benjamin Bender, Rose Bruffaerts, Philip Vandamme, Mathieu Vandenbulcke, Catarina B. Ferreira, Gabriel Miltenberger, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Duro, Maria Rosario Almeida, Miguel Castelo-Branco, Maria João Leitão, Miguel Tabuas-Pereira, Beatriz Santiago, Serge Gauthier, Sonja Schonecker, Elisa Semler, Sarah Anderl-Straub, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Michela Pievani, Gemma Lombardi, Benedetta Nacmias, Camilla Ferrari, Valentina Bessi, Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Neurology, Amsterdam Reproduction & Development (AR&D), Pediatric surgery, Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Divisions, and Epidemiology
Subjects: 0301 basic medicine, Adult, blood [Frontotemporal Dementia], Male, medicine.medical_specialty, Neurofilament light, C9orf72 Protein/genetics, blood [Neurofilament Proteins], diagnostic imaging [Frontotemporal Dementia], Cohort Studies, 03 medical and health sciences, Neurofilament Proteins/blood/genetics, 0302 clinical medicine, Atrophy, C9orf72, Neurofilament Proteins, Aged, Biomarkers, C9orf72 Protein, Female, Frontotemporal Dementia, Humans, Longitudinal Studies, Middle Aged, Internal medicine, medicine, Frontotemporal Dementia/blood/diagnostic imaging/genetics, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], blood [Biomarkers], business.industry, Neuropsychology, medicine.disease, genetics [Neurofilament Proteins], 030104 developmental biology, ddc:618.97, Biomarker (medicine), Neurology (clinical), business, 030217 neurology & neurosurgery, Biomarkers/blood, Cohort study, Frontotemporal dementia
Abstract: BACKGROUND: Neurofilament light chain (NfL) is a promising blood biomarker in genetic frontotemporal dementia, with elevated concentrations in symptomatic carriers of mutations in GRN, C9orf72, and MAPT. A better understanding of NfL dynamics is essential for upcoming therapeutic trials. We aimed to study longitudinal NfL trajectories in people with presymptomatic and symptomatic genetic frontotemporal dementia.METHODS: We recruited participants from 14 centres collaborating in the Genetic Frontotemporal Dementia Initiative (GENFI), which is a multicentre cohort study of families with genetic frontotemporal dementia done across Europe and Canada. Eligible participants (aged ≥18 years) either had frontotemporal dementia due to a pathogenic mutation in GRN, C9orf72, or MAPT (symptomatic mutation carriers) or were healthy at-risk first-degree relatives (either presymptomatic mutation carriers or non-carriers), and had at least two serum samples with a time interval of 6 months or more. Participants were excluded if they had neurological comorbidities that were likely to affect NfL, including cerebrovascular events. We measured NfL longitudinally in serum samples collected between June 8, 2012, and Dec 8, 2017, through follow-up visits annually or every 2 years, which also included MRI and neuropsychological assessments. Using mixed-effects models, we analysed NfL changes over time and correlated them with longitudinal imaging and clinical parameters, controlling for age, sex, and study site. The primary outcome was the course of NfL over time in the various stages of genetic frontotemporal dementia.FINDINGS: We included 59 symptomatic carriers and 149 presymptomatic carriers of a mutation in GRN, C9orf72, or MAPT, and 127 non-carriers. Nine presymptomatic carriers became symptomatic during follow-up (so-called converters). Baseline NfL was elevated in symptomatic carriers (median 52 pg/mL [IQR 24-69]) compared with presymptomatic carriers (9 pg/mL [6-13]; pINTERPRETATION: Our findings show the value of blood NfL as a disease progression biomarker in genetic frontotemporal dementia and suggest that longitudinal NfL measurements could identify mutation carriers approaching symptom onset and capture rates of brain atrophy. The characterisation of NfL over the course of disease provides valuable information for its use as a treatment effect marker.FUNDING: ZonMw and the Bluefield project.
Published: 2019
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117. Age at onset in genetic prion disease and the design of preventive clinical trials

Author: Michael D. Geschwind, Christiane Stehmann, Janna Kenny, Sabina Capellari, Ryusuke Ae, Sonia M Vallabh, Leonel T. Takada, Masahito Yamada, Piero Parchi, Tadashi Tsukamoto, Steven J. Collins, Jamie Fong, Nobuo Sanjo, Claudia Ponto, Jean Louis Laplanche, Inga Zerr, Tobias Knipper, Jean Philippe Brandel, Margaret C. Orseth, Peter Hermann, Yosikazu Nakamura, Simon Mead, Stéphane Haïk, Miguel Calero, Tetsuyuki Kitamoto, Tsuyoshi Hamaguchi, Jesús de Pedro-Cuesta, Ignazio Roiter, Roberto Chiesa, Eric Vallabh Minikel, Jiri G. Safar, Hidehiro Mizusawa, Minikel E.V., Vallabh S.M., Orseth M.C., Brandel J.-P., Haik S., Laplanche J.-L., Zerr I., Parchi P., Capellari S., Safar J., Kenny J., Fong J.C., Takada L.T., Ponto C., Hermann P., Knipper T., Stehmann C., Kitamoto T., Ae R., Hamaguchi T., Sanjo N., Tsukamoto T., Mizusawa H., Collins S.J., Chiesa R., Roiter I., de Pedro-Cuesta J., Calero M., Geschwind M.D., Yamada M., Nakamura Y., and Mead S.
Subjects: 0301 basic medicine, Adult, Male, Creutzfeldt-Jakob disease, human prions, PRNP gene, clinical trials, biomarkers, neurodegenerative diseases, Adolescent, Genotype, Penetrance, Disease, Kaplan-Meier Estimate, Bioinformatics, Article, Prion Proteins, PRNP, Prion Diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Medicine, Humans, Young adult, Age of Onset, Child, Aged, Proportional Hazards Models, Aged, 80 and over, Clinical Trials as Topic, Surrogate endpoint, Proportional hazards model, business.industry, Middle Aged, 3. Good health, Clinical trial, 030104 developmental biology, Research Design, Mutation, Female, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.
Published: 2019

118. Quantitative EEG parameters correlate with the progression of human prion diseases

Author: Andrew G.B. Thompson, Tim Wehner, Olivier Joly, John Collinge, Simon Mead, Marie-Claire Porter, Joanna Kenny, Jessica Lowe, Peter Rudge, and Edit Franko
Subjects: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Statistics as Topic, Disease, Electroencephalography, Creutzfeldt-Jakob Syndrome, Prion Diseases, Cohort Studies, Correlation, 03 medical and health sciences, 0302 clinical medicine, Reference Values, Internal medicine, medicine, Humans, Dementia, Longitudinal Studies, Prospective Studies, Neurodegeneration, Prospective cohort study, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Signal Processing, Computer-Assisted, Cognition, Middle Aged, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Disease Progression, Female, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, Cohort study
Abstract: Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials.
Published: 2016
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119. Video self-reflection and coach development in New Zealand

Author: Simon Mead, Lynn Kidman, and Kirsten Spencer
Subjects: Semi-structured interview, business.industry, Research methodology, 05 social sciences, Applied psychology, Professional development, 050301 education, Physical Therapy, Sports Therapy and Rehabilitation, Advertising, Reflective teaching, 030229 sport sciences, Coaching, Education, 03 medical and health sciences, 0302 clinical medicine, Self-reflection, Orthopedics and Sports Medicine, Video technology, Psychology, business, 0503 education, Qualitative research
Abstract: Drawing on data from semi-structured interviews with New Zealand coaches (N = 6), this study examined how video self-reflection (VSR) was perceived as a tool for learning within ‘on-going’ coach de...
Published: 2016
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120. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes

Author: Patricia Vázquez Rodríquez, Eileen Wehmann, Katrina M. Dick, Claire J. Lansdall, Alicia Wilcox, Karalyn Patterson, Kate Dawson, Ian Coyle-Gilchrist, Simon Mead, Carol Brayne, James B. Rowe, Julie Wiggins, Patterson, Karalyn [0000-0003-1927-7424], Brayne, Carol [0000-0001-5307-663X], Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Risk, medicine.medical_specialty, Pediatrics, Population, Disease, Article, Progressive supranuclear palsy, 03 medical and health sciences, 0302 clinical medicine, mental disorders, medicine, Aphasia, Prevalence, Corticobasal degeneration, Humans, Psychiatry, education, Survival analysis, Aged, education.field_of_study, business.industry, Incidence (epidemiology), Incidence, Age Factors, Frontotemporal lobar degeneration, Syndrome, Middle Aged, medicine.disease, Survival Analysis, United Kingdom, 3. Good health, 030104 developmental biology, Phenotype, Female, Neurology (clinical), Supranuclear Palsy, Progressive, Frontotemporal Lobar Degeneration, business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: Objectives: To estimate the lifetime risk, prevalence, incidence, and mortality of the principal clinical syndromes associated with frontotemporal lobar degeneration (FTLD) using revised diagnostic criteria and including intermediate clinical phenotypes. Methods: Multisource referral over 2 years to identify all diagnosed or suspected cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS) in 2 UK counties (population 1.69 million). Diagnostic confirmation used current consensus diagnostic criteria after interview and reexamination. Results were adjusted to the 2013 European standard population. Results: The prevalence of FTD, PSP, and CBS was 10.8/100,000. The incidence and mortality were very similar, at 1.61/100,000 and 1.56/100,000 person-years, respectively. The estimated lifetime risk is 1 in 742. Survival following diagnosis varied widely: from PSP 2.9 years to semantic variant FTD 9.1 years. Age-adjusted prevalence peaked between 65 and 69 years at 42.6/100,000: the age-adjusted prevalence for persons older than 65 years is double the prevalence for those between 40 and 64 years. Fifteen percent of those screened had a relevant genetic mutation. Conclusions: Key features of this study include the revised diagnostic criteria with improved specificity and sensitivity, an unrestricted age range, and simultaneous assessment of multiple FTLD syndromes. The prevalence of FTD, PSP, and CBS increases beyond 65 years, with frequent genetic causes. The time from onset to diagnosis and from diagnosis to death varies widely among syndromes, emphasizing the challenge and importance of accurate and timely diagnosis. A high index of suspicion for FTLD syndromes is required by clinicians, even for older patients.
Published: 2016

121. A novel prion protein variant in a patient with semantic dementia

Author: Laszlo L. P. Hosszu, John Collinge, Ione O.C. Woollacott, Martin N. Rossor, Peter Rudge, Simon Mead, Carolin Koriath, Jonathan D. Rohrer, Gary Adamson, and Joanna Kenny
Subjects: 0301 basic medicine, PRION, Neurogenetics, Semantic dementia, Bioinformatics, PRNP, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Medicine, Dementia, Cognitive decline, Exome sequencing, NEUROGENETICS, SEMANTIC DEMENTIA, business.industry, Genetic heterogeneity, DEMENTIA, CREUTZFELDT-JAKOB DISEASE, PostScript, medicine.disease, nervous system diseases, Psychiatry and Mental health, 030104 developmental biology, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: Prion diseases are a group of fatal neurodegenerative diseases that can be sporadic, inherited or acquired. Inherited prion diseases are caused by mutations in the prion protein gene, PRNP , usually single nucleotide substitutions or structural variants of an octapeptide repeat encoding region. Although the classical presentation of sporadic Creutzfeldt Jakob disease (CJD) is rapidly progressive ataxia, myoclonus and cognitive decline, the presentation of genetic cases is variable and decline can be much slower. Prion diseases can mimic many neurodegenerative diseases. Genetic dementias are pleiotropic, with similar clinical syndromes being caused by mutations in different genes; additionally, mutations in a single gene may cause diverse clinical phenotypes. Due to the diagnostic difficulties arising from this clinical and genetic heterogeneity, next-generation sequencing technologies including gene panels and exome sequencing are helpful in elucidating genetic causes of dementia.1 Here we report a novel variant in PRNP in a patient diagnosed with semantic dementia, a variant of frontotemporal dementia (FTD). Patients with semantic dementia develop progressive loss of semantic knowledge resulting in significant early language impairment, with subsequent wider cognitive impairment and behavioural problems. MRI appearances are characteristic with focal asymmetric anteroinferior temporal lobe atrophy. The predominant histopathological finding is accumulation of Tar DNA-binding protein 43 (TDP-43) deposits in the temporal and frontal lobes, although other pathologies, including Alzheimer’s disease, are occasionally observed.2 A Mendelian genetic aetiology is rarely documented. A woman in her seventh decade presented with a 1-year history of rapidly progressive language problems and behavioural change. She had particular difficulty naming objects and suffered from impaired comprehension, but had preserved recognition of faces and …
Published: 2017
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122. Variant Creutzfeldt–Jakob Disease in a Patient with Heterozygosity at PRNP Codon 129

Author: Zane Jaunmuktane, Jonathan D. F. Wadsworth, Benjamin R Wakerley, Simon Mead, Catherine Morgan, Farhad Golestani, Mok Th, Sebastian Brandner, Susan Joiner, John Collinge, Tracy Campbell, H. Rolf Jäger, and Peter Rudge
Subjects: 0301 basic medicine, Genetics, business.industry, animal diseases, Heterozygote advantage, General Medicine, Disease, Creutzfeldt-Jakob Syndrome, Bioinformatics, nervous system diseases, PRNP, Loss of heterozygosity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, mental disorders, Variant Creutzfeldt–Jakob disease, Medicine, Prion protein, business, Gene, 030217 neurology & neurosurgery
Abstract: In this case study, variant Creutzfeldt–Jakob disease (CJD) is shown to occur in a young man with heterozygosity, rather than homozygosity, at codon 129 of the prion protein gene (PRNP).
Published: 2017
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123. Spontaneous generation of prions and transmissible PrP amyloid in a humanised transgenic mouse model of A117V GSS

Author: John Collinge, Andrew Tomlinson, Sebastian Brandner, Tatiana Jakubcova, Shyma Hamdan, Jacqueline M. Linehan, Andrew Grimshaw, Akin Nihat, Jonathan D. F. Wadsworth, Michelle Smidak, Simon Mead, Emmanuel A. Asante, and Asif Jeelani
Subjects: 0301 basic medicine, Aging, animal diseases, Mutant, medicine.disease_cause, Biochemistry, Animal Diseases, Prion Diseases, Transgenic Model, 0302 clinical medicine, Zoonoses, Medicine and Health Sciences, Biology (General), Brain Diseases, Mutation, General Neuroscience, Homozygote, Brain, Neurodegenerative Diseases, Animal Models, Middle Aged, Animal Prion Diseases, Infectious Diseases, Experimental Organism Systems, Neurology, General Agricultural and Biological Sciences, Adult, Genetically modified mouse, Amyloid, Heterozygote, Prions, QH301-705.5, Transgene, Mice, Transgenic, Mouse Models, Biology, Research and Analysis Methods, General Biochemistry, Genetics and Molecular Biology, PRNP, 03 medical and health sciences, Model Organisms, medicine, Animals, Humans, Animal Models of Disease, Codon, General Immunology and Microbiology, Point mutation, Biology and Life Sciences, Proteins, Virology, Primer, nervous system diseases, 030104 developmental biology, Animal Studies, Amyloid Proteins, Zoology, 030217 neurology & neurosurgery, Scrapie
Abstract: The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrPC) and the scrapie conformation (PrPSc). PrPC features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrPSc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrPSc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrPSc can template PrPC and coerce it to adopt the PrPSc conformation and (2) PrPSc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrPSc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein., This Primer explores the implications of a study that describes the first murine model of familial human prion disease, demonstrating the emergence and propagation of two PrP amyloid conformers; of these, one causes neurodegeneration while the other does not. With its many conformers, PrP is a truly protean protein.
Published: 2020
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124. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Author: Jiang, Shan, Wen, Natalie, Zeran, Li, Dube, Umber, Del Aguila, Jorge, Budde, John, Martinez, Rita, Hsu, Simon, Fernandez, Maria V, Cairns, Nigel J, Harari, Oscar, Cruchaga, Carlos, Karch, Celeste MRaffaele Ferrari, Dena, G Hernandez, Michael, A Nalls, Jonathan, D Rohrer, Adaikalavan, Ramasamy, John B, J Kwok, Carol, Dobson-Stone, William, S Brooks, Peter, R Schofield, Glenda, M Halliday, John, R Hodges, Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Eric, Haan, Isabel, Hernández, Agustín, Ruiz, Mercè, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Nigel, J Cairns, Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, Jordi, Clarimón, Alberto, Lleó, Rafael, Blesa, Maria Landqvist Waldö, Karin, Nilsson, Christer, Nilsson, Ian R, A Mackenzie, Ging-Yuek, R Hsiung, David M, A Mann, Jordan, Grafman, Christopher, M Morris, Johannes, Attems, Timothy, D Griffiths, Ian, G McKeith, Alan, J Thomas, Pietrini, P, Edward, D Huey, Eric, M Wassermann, Atik, Baborie, Evelyn, Jaros, Michael, C Tierney, Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Lorenzo, Pinessi, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, James, B Rowe, Johannes C, M Schlachetzki, James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Vivianna, M Van Deerlin, Murray, Grossman, John, Q Trojanowski, Julie van der Zee, William, Deschamps, Tim Van Langenhove, Marc, Cruts, Christine Van Broeckhoven, Stefano, F Cappa, Isabelle Le Ber, Didier, Hannequin, Véronique, Golfier, Martine, Vercelletto, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Jørgen, E Nielsen, Lena, E Hjermind, Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Martin, N Rossor, Nick, C Fox, Jason, D Warren, Maria Grazia Spillantini, Huw, R Morris, Patrizia, Rizzu, Peter, Heutink, Julie, S Snowden, Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Amalia, C Bruni, Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dennis, W Dickson, Neill, R Graff-Radford, Ronald, C Petersen, David, Knopman, Keith, A Josephs, Bradley, F Boeve, Joseph, E Parisi, William, W Seeley, Bruce, L Miller, Anna, M Karydas, Howard, Rosen, John, C van Swieten, Elise G, P Dopper, Harro, Seelaar, Yolande A, L Pijnenburg, Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Annibale, A Puca, Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Florence, Pasquier, Adeline, Rollin, Vincent, Deramecourt, Florence, Lebert, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Andrew, B Singleton, John, Hardy, and Parastoo, Momeni
Subjects: 0301 basic medicine, Male, Tau protein, Induced Pluripotent Stem Cells, tau Proteins, medicine.disease_cause, Article, lcsh:RC321-571, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, Receptors, GABA, medicine, Animals, Humans, Induced pluripotent stem cell, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biological Psychiatry, Aged, Aged, 80 and over, Neurons, Mutation, biology, Brain, Frontotemporal lobar degeneration, Human brain, medicine.disease, 3. Good health, Cell biology, Mice, Inbred C57BL, Psychiatry and Mental health, 030104 developmental biology, medicine.anatomical_structure, biology.protein, Female, Tauopathy, Supranuclear Palsy, Progressive, CRISPR-Cas Systems, Frontotemporal Lobar Degeneration, Transcriptome, Frontotemporal dementia, Signal Transduction
Abstract: Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P −3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.
Published: 2018

125. Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease

Author: Kaj Blennow, Yuying Liang, Ronald Druyeh, Chris Frost, Henrik Zetterberg, Teresa Poole, Natalie S. Ryan, Simon Mead, Amanda Heslegrave, Nick C. Fox, Antoinette O'Connor, Philip S.J. Weston, and Jonathan M. Schott
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, Longitudinal study, Heterozygote, Neurology, Search terms, Cognitive Neuroscience, Neurofilament light, Prodromal Symptoms, Disease, [111] neurofilament light, lcsh:RC346-429, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Neurofilament Proteins, Internal medicine, medicine, PSEN1, Humans, Longitudinal Studies, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, [26] Alzheimer’s disease, [111] blood, business.industry, Research, Neurodegeneration, Middle Aged, medicine.disease, 030104 developmental biology, Familial Alzheimer's disease, Biomarker (medicine), Female, [111] longitudinal, Neurology (clinical), [91] autosomal dominant, business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Background To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer’s disease (FAD) and to assess when NfL concentration first increases. Methods NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO). Results There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased (p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time. Conclusions There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer’s disease. Electronic supplementary material The online version of this article (10.1186/s13195-019-0472-5) contains supplementary material, which is available to authorized users.
Published: 2018

126. The most problematic symptoms of prion disease - an analysis of carer experiences

Author: Liz, Ford, Peter, Rudge, Kathy, Robinson, John, Collinge, Michele, Gorham, and Simon, Mead
Subjects: Adult, Male, Communication, Middle Aged, United Kingdom, Article, Deglutition, Prion Diseases, Interviews as Topic, Self Care, Affect, Eating, Cognition, Caregivers, Memory, Activities of Daily Living, Disease Progression, Humans, Female, Longitudinal Studies, Mobility Limitation, Fecal Incontinence, Aged
Abstract: OBJECTIVES: Prion diseases are rare dementias that most commonly occur sporadically, but can be inherited or acquired, and for which there is no cure. We sought to understand which prion disease symptoms are most problematic for carers to inform choices in the development of outcome measures. DESIGN: Self-completed questionnaire, with follow-up of a subset of participants by structured interview. SETTING: A nested study in the UK National Prion Monitoring Cohort, a longitudinal observational study. PARTICIPANTS AND MEASUREMENTS: 71 carers, of people with different prion diseases with a wide range of disease severity, identified 236 of their four most problematic symptoms by questionnaire, and were grouped into ten domains. Structured interviews were then done to qualitatively explore these experiences. Eleven family carers of people with prion disease were selected, including those representative of a range of demographics and disease subtypes, and with people with prion disease living or recently deceased. Interviews were transcribed and formally studied. RESULTS: The six most problematic symptom domains were: mobility and coordination; mood and behaviour; personal care and continence; eating and swallowing; communication; and cognition and memory. The prevalence of these symptoms varied significantly by disease stage and type. A formal analysis of structured interviews to explore these domains is reported. CONCLUSIONS: We make suggestions about how healthcare professionals can focus their support for people with prion disease. Clinical trials that aim to generate evidence regarding therapies that might confer meaningful benefits to carers should consider including outcome measures that monitor the symptomatic domains we have identified as problematic.
Published: 2018

127. Review: Clinical, genetic and neuroimaging features of frontotemporal dementia

Author: Simon Mead, Rhian S Convery, and Jonathan D. Rohrer
Subjects: 0301 basic medicine, Histology, Tau protein, Pathology and Forensic Medicine, Primary progressive aphasia, 03 medical and health sciences, 0302 clinical medicine, Neuroimaging, C9orf72, Physiology (medical), mental disorders, medicine, Humans, biology, business.industry, Genetic disorder, Posterior cortical atrophy, medicine.disease, 030104 developmental biology, Aphasia, Primary Progressive, Neurology, Frontotemporal Dementia, biology.protein, Neurology (clinical), business, Motor neurone disease, Neuroscience, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: Frontotemporal dementia (FTD) is a heterogeneous group of disorders causing neurodegeneration within a network of areas centred on the frontal and temporal lobes. Clinically, patients present with behavioural symptoms (behavioural variant FTD) or language disturbance (primary progressive aphasia), although there is an overlap with motor neurone disease and atypical parkinsonian disorders. Whilst neuroimaging commonly reveals abnormalities in the frontal and temporal lobes, a closer review identifies a more complex picture with variable asymmetry of neuronal loss, widespread subcortical involvement and in many cases more posterior cortical atrophy. An autosomal-dominant genetic disorder is found in around a third of people with mutations in progranulin, C9orf72 and the microtubule-associated protein tau being the commonest causes. In the other two-thirds, the disorder is sporadic, although recent genome-wide association studies have started to identify genetic risk factors within this group. Much of this knowledge has been understood only in the past 10 years and so this review will discuss the current knowledge about the clinical, genetic and neuroimaging features of FTD.
Published: 2018

128. Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura

Author: Gargi, Banerjee, Matthew E, Adams, Zane, Jaunmuktane, G, Alistair Lammie, Ben, Turner, Mushtaq, Wani, Inder M S, Sawhney, Henry, Houlden, Simon, Mead, Sebastian, Brandner, and David J, Werring
Subjects: Adult, Male, Hemangioma, Cavernous, Central Nervous System, Amyloid beta-Peptides, Skull Fractures, Iatrogenic Disease, Middle Aged, Brief Communication, Embolization, Therapeutic, Magnetic Resonance Imaging, Parotid Neoplasms, Cerebral Amyloid Angiopathy, Cancer Survivors, mental disorders, Cadaver, Humans, Female, Papilloma, Choroid Plexus, Dura Mater, Age of Onset, Brief Communications, Craniotomy
Abstract: Amyloid‐β transmission has been described in patients both with and without iatrogenic Creutzfeldt–Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid‐β pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid‐β cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid‐β seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1–7 ANN NEUROL 2019;85:284–290.
Published: 2018

129. Age of onset in genetic prion disease and the design of preventive clinical trials

Author: Piero Parchi, Hidehiro Mizusawa, Claudia Ponto, Nobuo Sanjo, Janna Kenny, Inga Zerr, Jean Louis Laplanche, Tobias Knipper, Miguel Calero, Jiri G. Safar, Yosikazu Nakamura, Stéphane Haïk, Simon Mead, Sabina Capellari, Leonel T. Takada, Ignazio Roiter, Christiane Stehmann, Tadashi Tsukamoto, Sonia M Vallabh, Jamie Fong, Tsuyoshi Hamaguchi, Masahito Yamada, Margaret C. Orseth, Eric Vallabh Minikel, Steven J. Collins, Michael D. Geschwind, Ryusuke Ae, Tetsuyuki Kitamoto, Jean Philippe Brandel, Peter Hermann, Roberto Chiesa, and Jesús de Pedro-Cuesta
Subjects: 0303 health sciences, medicine.medical_specialty, Surrogate endpoint, business.industry, Disease, 3. Good health, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Drug development, Randomized controlled trial, law, Clinical endpoint, medicine, Biomarker (medicine), Age of onset, Intensive care medicine, business, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data fromN=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.
Published: 2018
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130. Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

Author: Janet C Harwood, Michael Gill, Detelina Grozeva, Peter Holmans, Aura Frizzati, Rebecca Sims, John Hardy, Genetic, Ganna Leonenko, Nicholas D. Allen, Alfredo Ramirez, John Powell, Carol Brayne, Lesley Jones, Clive Holmes, Paola Bossù, Carlos Cruchaga, Julie Williams, R. Heun, Alison Goate, Matthew Hill, Emily Baker, Valentina Escott-Price, Wolfgang Maier, Paul Morgan, Peter Passmore, Kevin Morgan, Simon Mead, Cornelia M. van Duijn, Dobril Ivanov, Gianfranco Spalletta, and Igap consortia
Subjects: Genetics, 0303 health sciences, education.field_of_study, GENCODE, Population, Genomics, Genome-wide association study, Single-nucleotide polymorphism, ZNF423, Biology, 03 medical and health sciences, 0302 clinical medicine, PPARGC1A Gene, education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimer’s Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.Three novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimer’s disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.
Published: 2018
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131. P4‐240: STOP‐GAIN VARIANT IN MICROGLIA‐EXPRESSED GENE GMIP IS ASSOCIATED WITH EARLY‐ONSET ALZHEIMER'S DISEASE

Author: Isabel Santana, Carlos Cruchaga, Sven J. van der Lee, Keeley J. Brookes, John Hardy, Adgc, Joshua C. Bis, Adam C. Naj, Jose Bras, Miguel Pereira, Wiesje M. Flier, Lenore J. Launer, Bruce L. Miller, Valerio Napolioni, Susana Carmona, Gerard D. Schellenberg, Tamar Guetta-Baranes, Henne Holstege, Yuning Chen, Joel H. Kramer, Richard H. Myers, Rita Guerreiro, Anna Karydas, Jennifer S. Yokoyama, J. Nicholas Cochran, Michael D. Greicius, Sudha Seshadri, Yongha Kim, James Turton, Sultan Chaudhury, Gil D. Rabinovici, Raiyan R. Khan, Ethan G. Geier, Kevin Morgan, Cornelia M. van Duijn, Simon Mead, Maria Victoria Fernandez, Summer S. Han, Marc Hulsman, Jason A. Chen, Andre Altmann, and Giovanni Coppola
Subjects: Microglia, Epidemiology, business.industry, Health Policy, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, Gene expression, Immunology, medicine, Early-onset Alzheimer's disease, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2018
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132. O2‐04‐04: LONGITUDINAL MEASUREMENT OF SERUM NEUROFILAMENT LIGHT CONCENTRATION IN FAMILIAL ALZHEIMER'S DISEASE

Author: Ronald Druyeh, Nick C. Fox, Antoinette O'Connor, Amanda Heslegrave, Martin N. Rossor, Henrik Zetterberg, Simon Mead, Jonathan M. Schott, Yuying Liang, Teresa Poole, Natalie S. Ryan, Philip Sj. Weston, and Kaj Blennow
Subjects: Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Neurofilament light, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Familial Alzheimer's disease, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2018
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133. Clinical trials

Author: Simon, Mead and Fabrizio, Tagliavini
Subjects: Clinical Trials as Topic, Drug Discovery, Humans, Prion Diseases
Abstract: Arguably the most important goal of prion research is the discovery of a safe and effective treatment for the human diseases. The final stages of the pathway to develop a treatment require clinical trials. Choices about how a trial is designed and conducted have a large impact on the chances of success. The gold-standard large randomized double-blind placebo-controlled study, which minimizes sources of bias and has been incredibly successful in other diseases, has been hard to achieve in Creutzfeldt-Jakob disease principally because of the rarity and rapidity of the clinical syndrome. To date, clinical trials have been restricted to repurposed compounds, doxycycline, quinacrine, pentosan polysulfate (PPS), and flupertine. In most cases, these trials have used survival as an endpoint, which, whilst clearcut, has limitations. Biomarkers have played a strong role in diagnosis and entry criteria, but only a limited role as secondary outcome measures. Recent developments suggest some possible improvements in trial design by use of new outcome measures that have more favorable properties, and biomarkers of neuronal damage and/or prion seeding activity. Alternative patient populations, including those at risk of genetic forms of prion disease, warrant more consideration. In the future, improved trial designs will be employed to test compounds designed specifically to treat prion diseases.
Published: 2018

134. The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study

Author: Michael Hornberger, Eneida Mioshi, T. Swinn, John R. Hodges, Kate Dawson, Emma Devenney, James B. Rowe, Simon Mead, Apollo - University of Cambridge Repository, and Rowe, James [0000-0001-7216-8679]
Subjects: 0301 basic medicine, Male, Longitudinal study, medicine.medical_specialty, Pediatrics, Neurology, Neuroimaging, Neuropsychological Tests, Phenocopy syndrome, lcsh:RC346-429, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Cognition, C9orf72, medicine, Genetics, Dementia, Humans, Behaviour, Longitudinal Studies, lcsh:Neurology. Diseases of the nervous system, Aged, Phenocopy, C9orf72 Protein, business.industry, General Medicine, Syndrome, Middle Aged, medicine.disease, Prognosis, Magnetic Resonance Imaging, 030104 developmental biology, Phenotype, FOS: Biological sciences, Frontotemporal Dementia, Cohort, Disease Progression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Research Article, Frontotemporal dementia
Abstract: Background This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. Methods Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke’s Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up. In addition, we obtained very long term follow-up data in 6 cases. A mixed model analysis approach determined the pattern of change in cognition and behaviour over time in phenocopy cases compared to 27 probable bvFTD cases. Results All 16 patients were screened for the C9orf72 expansion that was present in only one (6.25%). Of the 6 cases available for very long-term follow-up (13 - 21 years) none showed progression to frank dementia. Moreover, there was a decrease in the caregiver ratings of behavioural symptoms over time. Phenocopy cases showed significantly slower rates of progression compared to probable bvFTD patients (p
Published: 2018
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135. Reply to: Intrinsic Toxicity of Antibodies to the Globular Domain of the Prion Protein

Author: Silvia A. Purro, Simon Mead, Azadeh Khalili-Shirazi, Andrew J. Nicoll, and John Collinge
Subjects: 0301 basic medicine, Amyloid beta-Peptides, biology, Chemistry, Prions, Antibodies, Prion Proteins, Domain (software engineering), 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Toxicity, Biophysics, biology.protein, Prion protein, Antibody, 030217 neurology & neurosurgery, Biological Psychiatry
Published: 2018

136. Imaging biomarkers for the diagnosis of Prion disease

Author: Enrico De Vita, John S. Thornton, Carole H. Sudre, Frederik Barkhof, Simon Mead, Sebastien Ourselin, M. Jorge Cardoso, Liane S Canas, Benjamin C. Yvernault, Marc Modat, Radiology and nuclear medicine, and Amsterdam Neuroscience - Brain Imaging
Subjects: Inherited Creutzfeldt-Jakob disease, medicine.diagnostic_test, business.industry, Disease progression, medicine, Dementia, Magnetic resonance imaging, Sporadic Creutzfeldt-Jakob disease, Disease, Cognitive impairment, business, medicine.disease, Bioinformatics
Abstract: Prion diseases are a group of progressive neurodegenerative conditions which cause cognitive impairment and neurological deficits. To date, there is no accurate measure that can be used to diagnose this illness, or to quantify the evolution of symptoms over time. Prion disease, due to its rarity, is in fact commonly mistaken for other types of dementia. A robust tool to diagnose and quantify the progression of the disease is key as it would lead to more appropriately timed clinical trials, and thereby improve patients' quality of life. The approaches used to study other types of neurodegenerative diseases are not satisfactory to capture the progression of human form of Prion disease. This is due to the large heterogeneity of phenotypes of Prion disease and to the lack of consistent geometrical pattern of disease progression. In this paper, we aim to identify and select imaging biomarkers that are relevant for the diagnostic on Prion disease. We extract features from magnetic resonance imaging data and use genetic and demographic information from a cohort affected by genetic forms of the disease. The proposed framework consists of a multi-modal subjectspecific feature extraction step, followed by a Gaussian Process classifier used to calculate the probability of a subject to be diagnosed with Prion disease. We show that the proposed method improves the characterisation of Prion disease.
Published: 2018
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137. Gaussian Processes with optimal kernel construction for neuro-degenerative clinical onset prediction

Author: Benjamin C. Yvernault, Tom Veale, Liane S Canas, Tammie L.S. Benzinger, Simon Mead, David M. Cash, Sebastien Ourselin, Marc Modat, and Erika Molteni
Subjects: genetic structures, Computer science, business.industry, food and beverages, Context (language use), Pattern recognition, Function (mathematics), Covariance, Explained variation, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Data point, Bayesian information criterion, Kernel (statistics), symbols, Artificial intelligence, business, Gaussian process, 030217 neurology & neurosurgery
Abstract: Gaussian Processes (GP) are a powerful tool to capture the complex time-variations of a dataset. In the context of medical imaging analysis, they allow a robust modelling even in case of highly uncertain or incomplete datasets. Predictions from GP are dependent of the covariance kernel function selected to explain the data variance. To overcome this limitation, we propose a framework to identify the optimal covariance kernel function to model the data.The optimal kernel is defined as a composition of base kernel functions used to identify correlation patterns between data points. Our approach includes a modified version of the Compositional Kernel Learning (CKL) algorithm, in which we score the kernel families using a new energy function that depends both the Bayesian Information Criterion (BIC) and the explained variance score. We applied the proposed framework to model the progression of neurodegenerative diseases over time, in particular the progression of autosomal dominantly-inherited Alzheimer's disease, and use i t to predict the time to clinical onset of subjects carrying genetic mutation.
Published: 2018
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138. Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study

Author: David J. Irwin, Nilufer Ertekin-Taner, Sara Rollinson, Mads Kjolby, John Hardy, Julia Kofler, Robert A. Rissman, Bernardino Ghetti, Stuart Pickering-Brown, Jonathan Glass, Carlos Cruchaga, Jonathan D. Rohrer, Keith A. Josephs, Maura Gallo, Parastoo Momeni, Emilia J. Sitek, Matthis Synofzik, Sandro Sorbi, Carlo Wilke, Oscar L. Lopez, Nigel J. Cairns, Miren Zulaica, Peter Heutink, Leonard Petrucelli, Bret M. Evers, Luisa Benussi, Jeroen van Rooij, Olivier Piguet, Sandra E. Black, Bradley F. Boeve, Cyril Pottier, Eric M. Reiman, Melissa E. Murray, Ralph B. Perkerson, Daniela Galimberti, Thomas G. Beach, Giorgio G. Fumagalli, Giacomina Rossi, David M. A. Mann, John B.J. Kwok, Harro Seelaar, Edward B. Lee, Jean-Paul Vonsattel, Didier Hannequin, Rosa Rademakers, John R. Hodges, Nicole A. Finch, John Q. Trojanowski, David S. Knopman, Yingxue Ren, Albert Lladó, Anders Nykjaer, Claire Troakes, Linn Öijerstedt, EunRan Suh, Isabelle Le Ber, Juliane Winkelmann, Ian R. Mackenzie, Glenda M. Halliday, William W. Seeley, Salvatore Spina, Simon Mead, Elio Scarpini, Fabrizio Tagliavini, Bruce L. Miller, Mariely DeJesus-Hernandez, Dennis W. Dickson, Elizabeth Christopher, Mario Masellis, Florence Pasquier, Roberta Ghidoni, Janine Diehl-Schmid, Silvia Bagnoli, Barbara Borroni, Adam L. Boxer, Adrian L. Oblak, Elizabeth Finger, Carol F. Lippa, Giuliano Binetti, Eileen H. Bigio, Vivianna M. Van Deerlin, Anna Karydas, William S. Brooks, Julie S. Snowden, Anna Richardson, Lea T. Grinberg, Manuela Neumann, Jordan Grafman, Zbigniew K. Wszolek, Edward D. Huey, Caroline Graff, John C. van Swieten, Sandra Weintraub, Raffaele Maletta, Ekaterina Rogaeva, Fermin Moreno, Raffaele Ferrari, Charles L. White, Adolfo López de Munain, Neill R. Graff-Radford, Camilla Ferrari, Jill R. Murell, Marwan N. Sabbagh, Raquel Sánchez-Valle, Marka van Blitterswijk, Alessandro Padovani, Peter Johannsen, Daniel J. Serie, Francesca Frangipane, Safa Al-Sarraj, Anna Antonell, Kevin F. Bieniek, Tsz H. Wong, Ging-Yuek Robin Hsiung, Jarosław Sławek, Matthew B. Baker, Gregory D. Jenkins, Ronald C. Petersen, Murray Grossman, Benedetta Nacmias, Tammee M. Parsons, Lawrence S. Honig, Maria Anfossi, Richard J. Caselli, Changiz Geula, Marla Gearing, M.-Marsel Mesulam, Xiaolai Zhou, Joanna M. Biernacka, Joseph E. Parisi, Irene Piaceri, Jorgen E. Nielsen, Amalia C. Bruni, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Erasmus MC other, and Neurology
Subjects: 0301 basic medicine, Oncology, Male, RNA, Messenger/metabolism, Genome-wide association study, Disease, Gene mutation, genetics [Progranulins], 0302 clinical medicine, Progranulins, Cerebellum, GFRA2 protein, human, Medicine, Age of Onset, genetics [Genetic Predisposition to Disease], Genetic Predisposition to Disease/genetics, Frontotemporal lobar degeneration, metabolism [Cerebellum], Middle Aged, 3. Good health, Frontotemporal Dementia, Female, genetics [Frontotemporal Lobar Degeneration], Frontotemporal dementia, medicine.medical_specialty, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mutation/genetics, Genetic counseling, genetics [Mutation], Progranulins/genetics, metabolism [RNA, Messenger], Article, 03 medical and health sciences, Internal medicine, Humans, Genetic Predisposition to Disease, ddc:610, RNA, Messenger, Cerebellum/metabolism, Aged, business.industry, metabolism [Progranulins], Case-control study, genetics [Glial Cell Line-Derived Neurotrophic Factor Receptors], Odds ratio, medicine.disease, metabolism [Frontotemporal Lobar Degeneration], metabolism [Glial Cell Line-Derived Neurotrophic Factor Receptors], 030104 developmental biology, Case-Control Studies, Mutation, GRN protein, human, Frontotemporal Lobar Degeneration/genetics, Neurology (clinical), Human medicine, Frontotemporal Lobar Degeneration, business, Glial Cell Line-Derived Neurotrophic Factor Receptors/genetics, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. Methods: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p−5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. Findings: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46–0·63; p=3·54 × 10−16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30–1·71; p=1·58 × 10−8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. Interpretation: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.
Published: 2018
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139. Clinical trials

Author: Simon Mead and Fabrizio Tagliavini
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030217 neurology & neurosurgery
Published: 2018
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140. Analysis of shared heritability in common disorders of the brain

Author: Erneri, Anttila, Brendan, Bulik-Sullivan, Hilary, K Finucane, Raymond, K Walters, Jose, Bras, Laramie, Duncan, Valentina, Escott-Price, Guido, J Falcone, Padhraig, Gormley, Rainer, Malik, Nikolaos, A Patsopoulos, Stephan, Ripke, Zhi, Wei, Dongmei, Yu, Phil, H Lee, Patrick, Turley, Benjamin, Grenier-Boley, Vincent, Chouraki, Yoichiro, Kamatani, Claudine, Berr, Luc, Letenneur, Didier, Hannequin, Philippe, Amouyel, Anne, Boland, Jean-Francois, Deleuze, Emmanuelle, Duron, Badri, N Vardarajan, Christiane, Reitz, Alison, M Goate, Matthew, J Huentelman, M Ilyas Kamboh, Eric, B Larson, Ekaterina, Rogaeva, Peter St George-Hyslop, Hakon, Hakonarson, Walter, A Kukull, Lindsay, A Farrer, Lisa, L Barnes, Thomas, G Beach, F Yesim Demirci, Elizabeth, Head, Christine, M Hulette, Gregory, A Jicha, John SK Kauwe, Jeffrey, A Kaye, James, B Leverenz, Allan, I Levey, Andrew, P Lieberman, Vernon, S Pankratz, Wayne, W Poon, Joseph, F Quinn, Andrew, J Saykin, Lon, S Schneider, Amanda, G Smith, Joshua, A Sonnen, Robert, A Stern, Vivianna, M Van Deerlin, Linda, J Van Eldik, Denise, Harold, Giancarlo, Russo, David, C Rubinsztein, Anthony, Bayer, Magda, Tsolaki, Petra, Proitsi, Nick, C Fox, Harald, Hampel, Michael, J Owen, Simon, Mead, Peter, Passmore, Kevin, Morgan, Markus, M Nöthen, Jonathan, M Schott, Martin, Rossor, Michelle, K Lupton, Per, Hoffmann, Johannes, Kornhuber, Brian, Lawlor, Andrew, Mcquillin, Ammar, Al-Chalabi, Joshua, C Bis, Agustin, Ruiz, Mercè, Boada, Sudha, Seshadri, Alexa, Beiser, Kenneth, Rice, Sven, J van der Lee, Philip, L De Jager, Daniel, H Geschwind, Matthias, Riemenschneider, Steffi, Riedel-Heller, Jerome, I Rotter, Gerhard, Ransmayr, Bradley, T Hyman, Carlos, Cruchaga, Montserrat, Alegret, Bendik, Winsvold, Priit, Palta, Kai-How, Farh, Ester, Cuenca-Leon, Nicholas, Furlotte, Tobias, Kurth, Lannie, Ligthart, Gisela, M Terwindt, Tobias, Freilinger, Caroline, Ran, Scott, D Gordon, Guntram, Borck, Hieab HH Adams, Terho, Lehtimäki, Juho, Wedenoja, Julie, E Buring, Markus, Schürks, Maria, Hrafnsdottir, Jouke-Jan, Hottenga, Brenda, Penninx, Ville, Artto, Mari, Kaunisto, Salli, Vepsäläinen, Nicholas, G Martin, Grant, W Montgomery, Mitja, I Kurki, Eija, Hämäläinen, Hailiang, Huang, Jie, Huang, Cynthia, Sandor, Striano, Pasquale, Zara, Federico, Caleb, Webber, Bertram, Muller-Myhsok, Stefan, Schreiber, Veikko, Salomaa, Elizabeth, Loehrer, Hartmut, Göbel, Alfons, Macaya, Patricia, Pozo-Rosich, Thomas, Hansen, Thomas, Werge, Jaakko, Kaprio, Andres, Metspalu, Christian, Kubisch, Michel, D Ferrari, Andrea, C Belin, Arn MJM van den Maagdenberg, John-Anker, Zwart, Dorret, Boomsma, Nicholas, Eriksson, Jes, Olesen, Daniel, I Chasman, Dale, R Nyholt, Richard, Anney, Andreja, Avbersek, and Larry, Baum
Subjects: Brain Diseases, Quantitative Trait, Phenotype, Risk Factors, Mental Disorders, Genetic Variation, Humans, Genome-Wide Association Study, Quantitative Trait, Heritable, Heritable
Published: 2018

141. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

Author: A. Sarah Walker, Joanna Kenny, Matthew Ellis, Angela Richard-Loendt, John Collinge, Jonathan D. F. Wadsworth, Simon Mead, Zane Jaunmuktane, Andrew J. Nicoll, Sebastian Brandner, Peter Rudge, Francesca Launchbury, and Jacqueline M. Linehan
Subjects: Adult, Pathology, medicine.medical_specialty, Prions, Iatrogenic Disease, Population, Autopsy, Disease, Grey matter, Creutzfeldt-Jakob Syndrome, Alzheimer Disease, Risk Factors, medicine, Humans, Gray Matter, education, Alleles, education.field_of_study, Amyloid beta-Peptides, Multidisciplinary, Human Growth Hormone, business.industry, Case-control study, Middle Aged, medicine.disease, Cerebral Amyloid Angiopathy, medicine.anatomical_structure, Case-Control Studies, Blood Vessels, Endothelium, Vascular, Cerebral amyloid angiopathy, Alzheimer's disease, Drug Contamination, business
Abstract: More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions. Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-β (Aβ) pathology. The Aβ deposition in the grey matter was typical of that seen in Alzheimer's disease and Aβ in the blood vessel walls was characteristic of cerebral amyloid angiopathy and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE ε4 or other high-risk alleles associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study showed minimal or no Aβ pathology in cases of similar age range, or a decade older, without APOE ε4 risk alleles. We also analysed pituitary glands from individuals with Aβ pathology and found marked Aβ deposition in multiple cases. Experimental seeding of Aβ pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate. The marked deposition of parenchymal and vascular Aβ in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of Aβ pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to Aβ and other proteopathic seeds associated with neurodegenerative and other human diseases.
Published: 2015
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142. Review: An update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations

Author: Tamas Revesz, Jonathan D. Rohrer, Simon Mead, and Tammaryn Lashley
Subjects: medicine.medical_specialty, Histology, biology, business.industry, Valosin-containing protein, nutritional and metabolic diseases, Disease, Frontotemporal lobar degeneration, medicine.disease, nervous system diseases, Pathology and Forensic Medicine, Progressive supranuclear palsy, Neurology, Physiology (medical), mental disorders, medicine, biology.protein, Corticobasal degeneration, Neurology (clinical), Amyotrophic lateral sclerosis, business, Psychiatry, Pathological, Neuroscience, Frontotemporal dementia
Abstract: The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided.
Published: 2015
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143. Recent US Case of Variant Creutzfeldt-Jakob Disease—Global Implications

Author: Alicia Parker, Joseph S. Kass, Ryan A. Maddox, Yvonne Cohen, Simon Mead, Michael P. Fischer, Aarthi Ram, Lawrence B. Schonberger, Haitham M. Hussein, Luis Concha-Marambio, Ermias D. Belay, Claudio Soto, Clay Goodman, Pierluigi Gambetti, and Atul Maheshwari
Subjects: Male, Epidemiology, Biopsy, pulvinar sign, global health, lcsh:Medicine, mad cow disease, Disease, Creutzfeldt-Jakob Syndrome, Electrocardiography, PMCA, Variant Creutzfeldt–Jakob disease, Global health, Transmission (medicine), Brain, Diagnostic test, Immunohistochemistry, Magnetic Resonance Imaging, Infectious Diseases, Population Surveillance, Perspective, Female, Infectious agent, Adult, Microbiology (medical), medicine.medical_specialty, Bovine spongiform encephalopathy, lcsh:Infectious and parasitic diseases, mental disorders, medicine, Animals, Humans, lcsh:RC109-216, bovine spongiform encephalopathy, Intensive care medicine, Recent US Case of Variant Creutzfeldt-Jakob Disease—Global Implications, business.industry, lcsh:R, medicine.disease, Virology, United States, United Kingdom, Creutzfeldt-Jakob disease, nervous system diseases, cortical ribbon sign, Prions and related diseases, Cattle, Tomography, X-Ray Computed, business
Abstract: A recently diagnosed case highlights the need for continued global surveillance., Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient’s exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.
Published: 2015

144. The cognitive profile of prion disease: a prospective clinical and imaging study

Author: Harpreet Hyare, Simon Mead, Andrew G.B. Thompson, Ana Lukic, Jessica Lowe, Renata J Tinelli, Peter Rudge, Lisa Cipolotti, John Collinge, Marie-Claire Porter, Enrico De Vita, Diana Caine, Caine, D., Tinelli, R., Hyare, H., De Vita, E., Lowe, J., Lukic, A., Thompson, A., Porter, M., Cipolotti, L., Rudge, P., Collinge, J., and Mead, S.
Subjects: Pediatrics, medicine.medical_specialty, Settore M-PSI/02 - Psicobiologia E Psicologia Fisiologica, business.industry, General Neuroscience, Neuropsychology, Cognition, Disease, Prion diseases, cognitive decline, Bioinformatics, PRNP, Clinical trial, Basal ganglia, medicine, Neurology (clinical), Differential diagnosis, Cognitive decline, business, Research Articles
Abstract: Objectives Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt-Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large-scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases. Methods A tailored short cognitive examination of all of the patients (n = 81), with detailed neuropsychological testing in a subset with mild disease (n = 30) and correlation with demographic, clinical, genetic (PRNP mutation and polymorphic codon 129 genotype), and other variables (MRI brain signal change in cortex, basal ganglia or thalamus; quantitative research imaging, cerebrospinal fluid 14-3-3 protein). Results Comparison with healthy controls showed patients to be impaired on all tasks. Principal components analysis showed a major axis of fronto-parietal dysfunction that accounted for approximately half of the variance observed. This correlated strongly with volume reduction in frontal and parietal gray matter on MRI. Examination of individual patients' performances confirmed early impairment on this axis, suggesting characteristic cognitive features in mild disease: prominent executive impairment, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed. Interpretation Taken together with typical neurological features, these results complete a profile that should improve differential diagnosis in a clinical setting. We propose a tailored neuropsychological battery for early recognition of clinical onset of symptoms with potential for use in clinical trials involving at-risk individuals.
Published: 2015
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145. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis

Author: Adrian M. Isaacs, Janice L. Holton, Sarah Mizielinska, Pietro Fratta, Katie Sidle, Jonathan D. Rohrer, Simon Mead, Selina Wray, Jason D. Warren, Richard W. Orrell, Tamas Revesz, Tammaryn Lashley, John Hardy, and Martin N. Rossor
Subjects: Adult, Male, DNA Repeat Expansion, C9orf72 Protein, business.industry, Amyotrophic Lateral Sclerosis, Neurodegeneration, Proteins, Disease, Middle Aged, medicine.disease, TARDBP, C9orf72, Frontotemporal Dementia, medicine, Humans, Female, Neurology (clinical), Bipolar disorder, Amyotrophic lateral sclerosis, business, Neuroscience, Aged, Frontotemporal dementia
Abstract: C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.
Published: 2015
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146. Convergent genetic and expression data implicate immunity in Alzheimer's disease

Author: John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology
Subjects: Pathway analysis, Epidemiology, ALIGATOR, Alzheimer's disease, Cholesterol metabolism, Dementia, Endocytosis, Immune response, Neurodegeneration, Ubiquitination, Weighted gene co-expression network analysis, Medizin, Genome-wide association study, genetics [Alzheimer Disease], Gene expression, Genetics, education.field_of_study, Health Policy, Brain, Single Nucleotide, 3. Good health, Psychiatry and Mental Health, Algorithms, Alzheimer Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Alzheimer’s disease, metabolism [Alzheimer Disease], Population, Genomics, Biology, Aligator, Article, Biological pathway, SDG 3 - Good Health and Well-being, medicine, ddc:610, Polymorphism, education, medicine.disease, Protein ubiquitination, metabolism [Brain], Human medicine
Abstract: © 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).
Published: 2015
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147. Plasma tau is increased in frontotemporal dementia

Author: Martha S, Foiani, Ione Oc, Woollacott, Carolin, Heller, Martina, Bocchetta, Amanda, Heslegrave, Katrina M, Dick, Lucy L, Russell, Charles R, Marshall, Simon, Mead, Jonathan M, Schott, Nick C, Fox, Jason D, Warren, Henrik, Zetterberg, and Jonathan D, Rohrer
Subjects: Male, Brain, Neuroimaging, tau Proteins, Middle Aged, Magnetic Resonance Imaging, Case-Control Studies, Frontotemporal Dementia, mental disorders, Humans, Female, Neurodegeneration, Aged
Abstract: Background Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life. Methods This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression. Results Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration. Conclusion Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.
Published: 2017

148. Methods for Molecular Diagnosis of Human Prion Disease

Author: Jonathan D F, Wadsworth, Gary, Adamson, Susan, Joiner, Lara, Brock, Caroline, Powell, Jacqueline M, Linehan, Jonathan A, Beck, Sebastian, Brandner, Simon, Mead, and John, Collinge
Subjects: Brain Chemistry, Base Sequence, Formates, Staining and Labeling, Tissue Embedding, Immunoblotting, Brain, Gene Expression, High-Throughput Nucleotide Sequencing, Microtomy, Immunohistochemistry, Prion Proteins, Prion Diseases, Open Reading Frames, Mutation, Anti-Infective Agents, Local, Humans, Electrophoresis, Polyacrylamide Gel
Abstract: Human prion diseases are associated with a range of clinical presentations, and they are classified by both clinicopathological syndrome and etiology, with subclassification according to molecular criteria. Here, we describe updated procedures that are currently used within the MRC Prion Unit at UCL to determine a molecular diagnosis of human prion disease. Sequencing of the PRNP open reading frame to establish the presence of pathogenic mutations is described, together with detailed methods for immunoblot or immunohistochemical determination of the presence of abnormal prion protein in the brain or peripheral tissues.
Published: 2017

149. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author: John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
Subjects: 0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract: International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Published: 2017
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150. [P1–335]: THEMES AND VARIATIONS IN PPA: A CLINICAL AND NEUROBIOLOGICAL ANALYSIS OF THE UCL COHORT

Author: Charles R. Marshall, Martina Bocchetta, Miriam H. Cohen, Chris J.D. Hardy, Rebecca L. Bond, Katrina M. Dick, Catherine J. Mummery, Martin N. Rossor, Lucy L. Russell, Carolin Koriath, Jason D. Warren, Ione O.C. Woollacott, Emilie V. Brotherhood, Ross W. Paterson, Catherine F. Slattery, Jennifer L. Agustus, S. Harding, Nick C. Fox, Jonathan D. Rohrer, Elizabeth Gordon, Simon Mead, Jonathan M. Schott, Sebastian J. Crutch, Alexander J.M. Foulkes, Amelia M. Carton, and Camilla N. Clark
Subjects: Gerontology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Cohort, Neurology (clinical), Geriatrics and Gerontology, Psychology
Published: 2017
Full Text: View/download PDF

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