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5. Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6

Author

Jones, Emma, Hill, Elizabeth, Linehan, Jacqueline, Nazari, Tamsin, Caulder, Adam, Codner, Gemma F., Hutchison, Marie, Mackenzie, Matthew, Farmer, Michael, Coysh, Thomas, De Oliveira, Michael Wiggins, Al-Doujaily, Huda, Sandberg, Malin, Viré, Emmanuelle, Cunningham, Thomas J., Asante, Emmanuel A., Brandner, Sebastian, Collinge, John, and Mead, Simon

Published
2024
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11. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes

Author

Reus, Lianne M, Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Consortium, International FTD-Genomics, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, Pietro, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, and Gu, Wei

Subjects
Biological Sciences, Genetics, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Dementia, Neurodegenerative, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Prevention, Alzheimer's Disease Related Dementias (ADRD), Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Neurological, Frontotemporal Dementia, Gene Expression, Humans, International FTD-Genomics Consortium, 17q21.31 inversion region, Dorsolateral prefrontal cortex, Expression quantitative trait loci, Frontotemporal dementia, SEC22B, Transcriptome-wide association study, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.

Published
2021

14. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

Author

Ferrari, Raffaele, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Ramasamy, Adaikalavan, Kwok, John B.J., Dobson-Stone, Carol, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J., Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian R.A., Hsiung, Ging-Yuek R., Mann, David M.A., Grafman, Jordan, Morris, Christopher M., Attems, Johannes, Griffiths, Timothy D., McKeith, Ian G., Thomas, Alan J., Pietrini, P., Huey, Edward D., Wassermann, Eric M., Baborie, Atik, Jaros, Evelyn, Tierney, Michael C., Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B., Schlachetzki, Johannes C.M., Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M., Grossman, Murray, Trojanowski, John Q., van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F., Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E., Hjermind, Lena E., Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Spillantini, Maria Grazia, Morris, Huw R., Rizzu, Patrizia, Heutink, Peter, Snowden, Julie S., Rollinson, Sara, Richardson, Anna, Gerhard, Alexander, Bruni, Amalia C., Maletta, Raffaele, Frangipane, Francesca, Cupidi, Chiara, Bernardi, Livia, Anfossi, Maria, Gallo, Maura, Conidi, Maria Elena, Smirne, Nicoletta, Rademakers, Rosa, Baker, Matt, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Knopman, David, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Rosen, Howard, van Swieten, John C., Dopper, Elise G.P., Seelaar, Harro, Pijnenburg, Yolande A.L., Scheltens, Philip, Logroscino, Giancarlo, Capozzo, Rosa, Novelli, Valeria, Puca, Annibale A., Franceschi, Massimo, Postiglione, Alfredo, Milan, Graziella, Sorrentino, Paolo, Kristiansen, Mark, Chiang, Huei-Hsin, Graff, Caroline, Pasquier, Florence, Rollin, Adeline, Deramecourt, Vincent, Lebert, Florence, Kapogiannis, Dimitrios, Ferrucci, Luigi, Pickering-Brown, Stuart, Singleton, Andrew B., Hardy, John, Momeni, Parastoo, Ge, Yi-Jun, Ou, Ya-Nan, Deng, Yue-Ting, Wu, Bang-Sheng, Yang, Liu, Zhang, Ya-Ru, Chen, Shi-Dong, Huang, Yu-Yuan, Dong, Qiang, Tan, Lan, and Yu, Jin-Tai

Published
2023
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24. Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Author

Mead, Simon, Khalili-Shirazi, Azadeh, Potter, Caroline, Mok, Tzehow, Nihat, Akin, Hyare, Harpreet, Canning, Stephanie, Schmidt, Christian, Campbell, Tracy, Darwent, Lee, Muirhead, Nicola, Ebsworth, Nicolette, Hextall, Patrick, Wakeling, Madeleine, Linehan, Jacqueline, Libri, Vincenzo, Williams, Bryan, Jaunmuktane, Zane, Brandner, Sebastian, Rudge, Peter, and Collinge, John

Published
2022
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25. Cognitive Impairment and Dementia

Author

Warren, Jason, primary, Collinge, John, additional, Fox, Nick, additional, Mead, Simon, additional, Mummery, Catherine, additional, Rohrer, Jonathan, additional, Rossor, Martin, additional, Schott, Jonathan, additional, and Weil, Rimona, additional

Published
2024
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26. Highly infectious prions are not directly neurotoxic

Author

Benilova, Iryna, Reilly, Madeleine, Terry, Cassandra, Wenborn, Adam, Schmidt, Christian, Marinho, Aline T., Risse, Emmanuel, Al-Doujaily, Huda, De Oliveira, Michael Wiggins, Sandberg, Malin K., Wadsworth, Jonathan D. F., Jat, Parmjit S., and Collinge, John

Published
2020

28. Identification of novel risk loci and causal insights for sporadic Creutzfeldt-Jakob disease: a genome-wide association study

Author

Jones, Emma, Hummerich, Holger, Viré, Emmanuelle, Uphill, James, Dimitriadis, Athanasios, Speedy, Helen, Campbell, Tracy, Norsworthy, Penny, Quinn, Liam, Whitfield, Jerome, Linehan, Jacqueline, Jaunmuktane, Zane, Brandner, Sebastian, Jat, Parmjit, Nihat, Akin, How Mok, Tze, Ahmed, Parvin, Collins, Steven, Stehmann, Christiane, Sarros, Shannon, Kovacs, Gabor G, Geschwind, Michael D, Golubjatnikov, Aili, Frontzek, Karl, Budka, Herbert, Aguzzi, Adriano, Karamujić-Čomić, Hata, van der Lee, Sven J, Ibrahim-Verbaas, Carla A, van Duijn, Cornelia M, Sikorska, Beata, Golanska, Ewa, Liberski, Pawel P, Calero, Miguel, Calero, Olga, Sanchez-Juan, Pascual, Salas, Antonio, Martinón-Torres, Federico, Bouaziz-Amar, Elodie, Haïk, Stéphane, Laplanche, Jean-Louis, Brandel, Jean-Phillipe, Amouyel, Phillipe, Lambert, Jean-Charles, Parchi, Piero, Bartoletti-Stella, Anna, Capellari, Sabina, Poleggi, Anna, Ladogana, Anna, Pocchiari, Maurizio, Aneli, Serena, Matullo, Giuseppe, Knight, Richard, Zafar, Saima, Zerr, Inga, Booth, Stephanie, Coulthart, Michael B, Jansen, Gerard H, Glisic, Katie, Blevins, Janis, Gambetti, Pierluigi, Safar, Jiri, Appleby, Brian, Collinge, John, and Mead, Simon

Published
2020
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29. Potential human transmission of amyloid β pathology: surveillance and risks

Author

Lauwers, Elsa, Lalli, Giovanna, Brandner, Sebastian, Collinge, John, Compernolle, Veerle, Duyckaerts, Charles, Edgren, Gustaf, Haïk, Stéphane, Hardy, John, Helmy, Adel, Ivinson, Adrian J, Jaunmuktane, Zane, Jucker, Mathias, Knight, Richard, Lemmens, Robin, Lin, I-Chun, Love, Seth, Mead, Simon, Perry, V Hugh, Pickett, James, Poppy, Guy, Radford, Sheena E, Rousseau, Frederic, Routledge, Carol, Schiavo, Giampietro, Schymkowitz, Joost, Selkoe, Dennis J, Smith, Colin, Thal, Dietmar R, Theys, Tom, Tiberghien, Pierre, van den Burg, Peter, Vandekerckhove, Philippe, Walton, Clare, Zaaijer, Hans L, Zetterberg, Henrik, and De Strooper, Bart

Published
2020
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37. Ascertainment Bias Causes False Signal of Anticipation in Genetic Prion Disease

Author

Minikel, Eric Vallabh, Zerr, Inga, Collins, Steven J, Ponto, Claudia, Boyd, Alison, Klug, Genevieve, Karch, André, Kenny, Joanna, Collinge, John, Takada, Leonel T, Forner, Sven, Fong, Jamie C, Mead, Simon, and Geschwind, Michael D

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Clinical Research, Transmissible Spongiform Encephalopathy (TSE), Rare Diseases, Neurosciences, Brain Disorders, Infectious Diseases, Emerging Infectious Diseases, Neurodegenerative, Human Genome, Neurological, Adolescent, Adult, Age of Onset, Aged, Anticipation, Genetic, Bias, Child, Computer Simulation, Creutzfeldt-Jakob Syndrome, Female, Genetic Diseases, Inborn, Humans, Male, Middle Aged, Models, Statistical, Mutation, Pedigree, Prion Proteins, Prions, Retrospective Studies, Young Adult, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G > A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested.

Published
2014

38. Frontotemporal dementia and its subtypes: a genome-wide association study

Author

Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N

Subjects
Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Brain Disorders, Alzheimer's Disease Related Dementias (ADRD), Genetics, Neurodegenerative, Dementia, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Aging, Human Genome, Clinical Research, Rare Diseases, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Aetiology, Neurological, Adult, Aged, Aged, 80 and over, Female, Frontotemporal Dementia, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Neurology & Neurosurgery, Clinical sciences
Abstract

BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p

Published
2014

39. Two mouse models of Alzheimer’s disease accumulate amyloid at different rates and have distinct Aβ oligomer profiles unaltered by ablation of cellular prion protein

Author

Purro, Silvia A., primary, Farmer, Michael, additional, Noble, Elizabeth, additional, Sarell, Claire J., additional, Powell, Megan, additional, Yip, Daniel, additional, Giggins, Lauren, additional, Zakka, Leila, additional, Thomas, David X., additional, Farrow, Mark, additional, Nicoll, Andrew J., additional, Walsh, Dominic, additional, and Collinge, John, additional

Published
2023
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40. Characterisation and prion transmission study in mice with genetic reduction of sporadic Creutzfeldt-Jakob disease risk gene Stx6

Author

Jones, Emma, primary, Hill, Elizabeth, additional, Linehan, Jacqueline, additional, Nazari, Tamsin, additional, Caulder, Adam, additional, Codner, Gemma F., additional, Hutchison, Marie, additional, Mackenzie, Matthew, additional, Farmer, Michael, additional, Coysh, Thomas, additional, De Oliveira, Michael Wiggins, additional, Al-Doujaily, Huda, additional, Sandberg, Malin, additional, Viré, Emmanuelle, additional, Cunningham, Thomas J., additional, Asante, Emmanuel A., additional, Brandner, Sebastian, additional, Collinge, John, additional, and Mead, Simon, additional

Published
2023
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41. Genome wide association study of clinical duration and age at onset of sporadic CJD

Author

Hummerich, Holger, primary, Speedy, Helen, additional, Campbell, Tracy, additional, Darwent, Lee, additional, Hill, Elizabeth, additional, Collins, Steven, additional, Stehmann, Christiane, additional, Kovacs, Gabor G, additional, Geschwind, Michael D, additional, Frontzek, Karl, additional, Budka, Herbert, additional, Gelpi, Ellen, additional, Aguzzi, Adriano, additional, van der Lee, Sven J, additional, van Duijn, Cornelia M, additional, Liberski, Pawel P, additional, Calero, Miguel, additional, Sanchez Juan, Pascual, additional, Bouaziz Amar, Elodie, additional, Laplanche, Jean Louis, additional, Haik, Stephane, additional, Brandel, Jean Phillipe, additional, Mammana, Angela, additional, Capellari, Sabina, additional, Poleggi, Anna, additional, Ladogana, Anna, additional, Pocchiari, Maurizio, additional, Zafar, Saima, additional, Booth, Stephanie, additional, Jansen, Gerard H, additional, Areskeviciute, Ausrine, additional, Lobner Lund, Eva, additional, Glisic, Katie, additional, Parchi, Piero, additional, Hermann, Peter, additional, Zerr, Inga, additional, Appleby, Brian S, additional, Collinge, John, additional, and Mead, Simon, additional

Published
2023
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46. Prion disease

Author

Nihat, Akin, additional, Mok, TzeHow, additional, and Collinge, John, additional

Published
2020
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50. FUS pathology defines the majority of tau- and TDP-43-negative frontotemporal lobar degeneration.

Author

Urwin, Hazel, Josephs, Keith A, Rohrer, Jonathan D, Mackenzie, Ian R, Neumann, Manuela, Authier, Astrid, Seelaar, Harro, Van Swieten, John C, Brown, Jeremy M, Johannsen, Peter, Nielsen, Jorgen E, Holm, Ida E, FReJA Consortium, Dickson, Dennis W, Rademakers, Rosa, Graff-Radford, Neill R, Parisi, Joseph E, Petersen, Ronald C, Hatanpaa, Kimmo J, White, Charles L, Weiner, Myron F, Geser, Felix, Van Deerlin, Vivianna M, Trojanowski, John Q, Miller, Bruce L, Seeley, William W, van der Zee, Julie, Kumar-Singh, Samir, Engelborghs, Sebastiaan, De Deyn, Peter P, Van Broeckhoven, Christine, Bigio, Eileen H, Deng, Han-Xiang, Halliday, Glenda M, Kril, Jillian J, Munoz, David G, Mann, David M, Pickering-Brown, Stuart M, Doodeman, Valerie, Adamson, Gary, Ghazi-Noori, Shabnam, Fisher, Elizabeth MC, Holton, Janice L, Revesz, Tamas, Rossor, Martin N, Collinge, John, Mead, Simon, and Isaacs, Adrian M

Subjects
FReJA Consortium, Hippocampus, Frontal Lobe, Humans, Dyskinesias, RNA-Binding Protein FUS, tau Proteins, DNA-Binding Proteins, Prevalence, Sequence Analysis, DNA, Mental Disorders, Age of Onset, Mutation, Adult, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, Sequence Analysis, DNA, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Through an international consortium, we have collected 37 tau- and TAR DNA-binding protein 43 (TDP-43)-negative frontotemporal lobar degeneration (FTLD) cases, and present here the first comprehensive analysis of these cases in terms of neuropathology, genetics, demographics and clinical data. 92% (34/37) had fused in sarcoma (FUS) protein pathology, indicating that FTLD-FUS is an important FTLD subtype. This FTLD-FUS collection specifically focussed on aFTLD-U cases, one of three recently defined subtypes of FTLD-FUS. The aFTLD-U subtype of FTLD-FUS is characterised clinically by behavioural variant frontotemporal dementia (bvFTD) and has a particularly young age of onset with a mean of 41 years. Further, this subtype had a high prevalence of psychotic symptoms (36% of cases) and low prevalence of motor symptoms (3% of cases). We did not find FUS mutations in any aFTLD-U case. To date, the only subtype of cases reported to have ubiquitin-positive but tau-, TDP-43- and FUS-negative pathology, termed FTLD-UPS, is the result of charged multivesicular body protein 2B gene (CHMP2B) mutation. We identified three FTLD-UPS cases, which are negative for CHMP2B mutation, suggesting that the full complement of FTLD pathologies is yet to be elucidated.

Published
2010

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