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1. Repeated cognitive assessments show stable function over time in patients with ALS

Author: Öijerstedt, Linn, Foucher, Juliette, Lovik, Anikó, Yazdani, Solmaz, Juto, Alexander, Kläppe, Ulf, Fang, Fang, and Ingre, Caroline
Published: 2024
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2. Altered plasma protein profiles in genetic FTD – a GENFI study

Author: Ullgren, Abbe, Öijerstedt, Linn, Olofsson, Jennie, Bergström, Sofia, Remnestål, Julia, van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B., Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tirabosch, Pietro, Santana, Isabel, Ducharme, Simon, Butler, Chris R., Gerhard, Alexander, Otto, Markus, Bouzigues, Arabella, Russell, Lucy, Swift, Imogen J., Sogorb-Esteve, Aitana, Heller, Carolin, Rohrer, Jonathan D., Månberg, Anna, Nilsson, Peter, and Graff, Caroline
Published: 2023
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3. The usage of population and disease registries as pre-screening tools for clinical trials, a systematic review

Author: Foucher, Juliette, Azizi, Louisa, Öijerstedt, Linn, Kläppe, Ulf, and Ingre, Caroline
Published: 2024
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4. ECAS correlation with metabolic alterations on FDG-PET imaging in ALS

Author: Foucher, Juliette, primary, Öijerstedt, Linn, additional, Lovik, Anikó, additional, Sun, Jiawei, additional, Ismail, Muhammad-Al-Mustafa, additional, Sennfält, Stefan, additional, Savitcheva, Irina, additional, Estenberg, Ulrika, additional, Pagani, Marco, additional, Fang, Fang, additional, Pereira, Joana B., additional, and Ingre, Caroline, additional
Published: 2024
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5. C9orf72, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts

Author: Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, and Van Broeckhoven, Christine
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Rare Diseases, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Frontotemporal Dementia (FTD), Genetics, Clinical Research, Dementia, Neurological, Age of Onset, Aged, Aged, 80 and over, Aphasia, Primary Progressive, C9orf72 Protein, Cohort Studies, DNA Repeat Expansion, Europe, Female, Frontotemporal Dementia, Frontotemporal Lobar Degeneration, Geography, Humans, Male, Mediterranean Region, Middle Aged, Principal Component Analysis, Scandinavian and Nordic Countries, Syndrome, International FTD-Genetics Consortium, Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
Published: 2020

6. Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., and Russell, Lucy L.
Published: 2023
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7. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Author: Esteve, Aitana Sogorb, Heller, Carolin, Greaves, Caroline V., Zetterberg, Henrik, Swift, Imogen J., Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Premi, Enrico, Pengo, Marta, Mattioli, Irene, Cantoni, Valentina, Dukart, Juergen, Gasparotti, Roberto, Buratti, Emanuele, Padovani, Alessandro, Bocchetta, Martina, Todd, Emily G., Bouzigues, Arabella, Cash, David M., Convery, Rhian S., Russell, Lucy L., Foster, Phoebe, Thomas, David L., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Jr, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Tsvetanov, Kamen A., Vandenberghe, Rik, Finger, Elizabeth, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D., and Borroni, Barbara
Published: 2023
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8. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.

Author: Moore, Katrina M, Nicholas, Jennifer, Grossman, Murray, McMillan, Corey T, Irwin, David J, Massimo, Lauren, Van Deerlin, Vivianna M, Warren, Jason D, Fox, Nick C, Rossor, Martin N, Mead, Simon, Bocchetta, Martina, Boeve, Bradley F, Knopman, David S, Graff-Radford, Neill R, Forsberg, Leah K, Rademakers, Rosa, Wszolek, Zbigniew K, van Swieten, John C, Jiskoot, Lize C, Meeter, Lieke H, Dopper, Elise Gp, Papma, Janne M, Snowden, Julie S, Saxon, Jennifer, Jones, Matthew, Pickering-Brown, Stuart, Le Ber, Isabelle, Camuzat, Agnès, Brice, Alexis, Caroppo, Paola, Ghidoni, Roberta, Pievani, Michela, Benussi, Luisa, Binetti, Giuliano, Dickerson, Bradford C, Lucente, Diane, Krivensky, Samantha, Graff, Caroline, Öijerstedt, Linn, Fallström, Marie, Thonberg, Håkan, Ghoshal, Nupur, Morris, John C, Borroni, Barbara, Benussi, Alberto, Padovani, Alessandro, Galimberti, Daniela, Scarpini, Elio, Fumagalli, Giorgio G, Mackenzie, Ian R, Hsiung, Ging-Yuek R, Sengdy, Pheth, Boxer, Adam L, Rosen, Howie, Taylor, Joanne B, Synofzik, Matthis, Wilke, Carlo, Sulzer, Patricia, Hodges, John R, Halliday, Glenda, Kwok, John, Sanchez-Valle, Raquel, Lladó, Albert, Borrego-Ecija, Sergi, Santana, Isabel, Almeida, Maria Rosário, Tábuas-Pereira, Miguel, Moreno, Fermin, Barandiaran, Myriam, Indakoetxea, Begoña, Levin, Johannes, Danek, Adrian, Rowe, James B, Cope, Thomas E, Otto, Markus, Anderl-Straub, Sarah, de Mendonça, Alexandre, Maruta, Carolina, Masellis, Mario, Black, Sandra E, Couratier, Philippe, Lautrette, Geraldine, Huey, Edward D, Sorbi, Sandro, Nacmias, Benedetta, Laforce, Robert, Tremblay, Marie-Pier L, Vandenberghe, Rik, Damme, Philip Van, Rogalski, Emily J, Weintraub, Sandra, Gerhard, Alexander, Onyike, Chiadi U, Ducharme, Simon, Papageorgiou, Sokratis G, Ng, Adeline Su Lyn, Brodtmann, Amy, Finger, Elizabeth, and Guerreiro, Rita
Subjects: FTD Prevention Initiative, Humans, Disease Progression, tau Proteins, Retrospective Studies, Cohort Studies, Family, Age of Onset, Phenotype, Mutation, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, Progranulins, Clinical Research, Rare Diseases, Dementia, Aging, Brain Disorders, Genetic Testing, Neurodegenerative, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Prevention, Genetics, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract: BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
Published: 2020

9. TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers

Author: Khoshnood, Behzad, Ullgren, Abbe, Laffita-Mesa, Jose, Öijerstedt, Linn, Patra, Kalicharan, Nennesmo, Inger, and Graff, Caroline
Published: 2022
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10. 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: Pottier, Cyril, Ren, Yingxue, Perkerson, Ralph B, Baker, Matt, Jenkins, Gregory D, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, van Rooij, Jeroen GJ, Murray, Melissa E, Christopher, Elizabeth, McDonnell, Shannon K, Fogarty, Zachary, Batzler, Anthony, Tian, Shulan, Vicente, Cristina T, Matchett, Billie, Karydas, Anna M, Hsiung, Ging-Yuek Robin, Seelaar, Harro, Mol, Merel O, Finger, Elizabeth C, Graff, Caroline, Öijerstedt, Linn, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Prudlo, Johannes, Rizzu, Patrizia, Simon-Sanchez, Javier, Edbauer, Dieter, Roeber, Sigrun, Diehl-Schmid, Janine, Evers, Bret M, King, Andrew, Mesulam, M Marsel, Weintraub, Sandra, Geula, Changiz, Bieniek, Kevin F, Petrucelli, Leonard, Ahern, Geoffrey L, Reiman, Eric M, Woodruff, Bryan K, Caselli, Richard J, Huey, Edward D, Farlow, Martin R, Grafman, Jordan, Mead, Simon, Grinberg, Lea T, Spina, Salvatore, Grossman, Murray, Irwin, David J, Lee, Edward B, Suh, EunRan, Snowden, Julie, Mann, David, Ertekin-Taner, Nilufer, Uitti, Ryan J, Wszolek, Zbigniew K, Josephs, Keith A, Parisi, Joseph E, Knopman, David S, Petersen, Ronald C, Hodges, John R, Piguet, Olivier, Geier, Ethan G, Yokoyama, Jennifer S, Rissman, Robert A, Rogaeva, Ekaterina, Keith, Julia, Zinman, Lorne, Tartaglia, Maria Carmela, Cairns, Nigel J, Cruchaga, Carlos, Ghetti, Bernardino, Kofler, Julia, Lopez, Oscar L, Beach, Thomas G, Arzberger, Thomas, Herms, Jochen, Honig, Lawrence S, Vonsattel, Jean Paul, Halliday, Glenda M, Kwok, John B, White, Charles L, Gearing, Marla, Glass, Jonathan, Rollinson, Sara, Pickering-Brown, Stuart, Rohrer, Jonathan D, Trojanowski, John Q, Van Deerlin, Vivianna, Bigio, Eileen H, Troakes, Claire, Al-Sarraj, Safa, Asmann, Yan, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, and Seeley, William W
Subjects: Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Brain Disorders, Rare Diseases, Human Genome, Alzheimer's Disease Related Dementias (ADRD), Dementia, Prevention, Genetics, Frontotemporal Dementia (FTD), Neurodegenerative, Acquired Cognitive Impairment, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, DNA Repeat Expansion, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Female, Frontal Lobe, Frontotemporal Lobar Degeneration, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ Antigens, Humans, Intracellular Signaling Peptides and Proteins, Loss of Function Mutation, Male, Middle Aged, Nerve Tissue Proteins, Potassium Channels, Progranulins, Protein Serine-Threonine Kinases, Proteins, RNA, Messenger, Risk Factors, Sequence Analysis, RNA, Societies, Scientific, TDP-43 Proteinopathies, White People, Whole-genome sequencing FTLD-TDP, TBK1, DPP6, UNC13A, HLA, Immunity, Clinical Sciences, Neurology & Neurosurgery
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

11. A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Author: Zhang, Ming, Ferrari, Raffaele, Tartaglia, Maria Carmela, Keith, Julia, Surace, Ezequiel I, Wolf, Uri, Sato, Christine, Grinberg, Mark, Liang, Yan, Xi, Zhengrui, Dupont, Kyle, McGoldrick, Philip, Weichert, Anna, McKeever, Paul M, Schneider, Raphael, McCorkindale, Michael D, Manzoni, Claudia, Rademakers, Rosa, Graff-Radford, Neill R, Dickson, Dennis W, Parisi, Joseph E, Boeve, Bradley F, Petersen, Ronald C, Miller, Bruce L, Seeley, William W, van Swieten, John C, van Rooij, Jeroen, Pijnenburg, Yolande, van der Zee, Julie, Van Broeckhoven, Christine, Le Ber, Isabelle, Van Deerlin, Vivianna, Suh, EunRan, Rohrer, Jonathan D, Mead, Simon, Graff, Caroline, Öijerstedt, Linn, Pickering-Brown, Stuart, Rollinson, Sara, Rossi, Giacomina, Tagliavini, Fabrizio, Brooks, William S, Dobson-Stone, Carol, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Binetti, Giuliano, Benussi, Luisa, Ghidoni, Roberta, Nacmias, Benedetta, Sorbi, Sandro, Bruni, Amalia C, Galimberti, Daniela, Scarpini, Elio, Rainero, Innocenzo, Rubino, Elisa, Clarimon, Jordi, Lleó, Alberto, Ruiz, Agustin, Hernández, Isabel, Pastor, Pau, Diez-Fairen, Monica, Borroni, Barbara, Pasquier, Florence, Deramecourt, Vincent, Lebouvier, Thibaud, Perneczky, Robert, Diehl-Schmid, Janine, Grafman, Jordan, Huey, Edward D, Mayeux, Richard, Nalls, Michael A, Hernandez, Dena, Singleton, Andrew, Momeni, Parastoo, Zeng, Zhen, Hardy, John, Robertson, Janice, Zinman, Lorne, Rogaeva, Ekaterina, and International FTD-Genomics Consortium (IFGC)
Subjects: International FTD-Genomics Consortium, Humans, Amyotrophic Lateral Sclerosis, Age of Onset, DNA Methylation, Gene Expression Regulation, CpG Islands, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Frontotemporal Dementia, C9orf72 Protein, C9orf72, genetic association, age of onset, amyotrophic lateral sclerosis, frontotemporal dementia, Polymorphism, Single Nucleotide, Neurology & Neurosurgery, Medical and Health Sciences, Psychology and Cognitive Sciences
Abstract: The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
Published: 2018

12. Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

Author: Afonso, Sónia, Almeida, Maria Rosario, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bouzigues, Arabella, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Lombardi, Jolina, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Gazzina, Stefano, Grassi, Mario, Premi, Enrico, Alberici, Antonella, Benussi, Alberto, Archetti, Silvana, Gasparotti, Roberto, Bocchetta, Martina, Cash, David M., Todd, Emily G., Peakman, Georgia, Convery, Rhian S., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Jr, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B., Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R., Santana, Isabel, Gerhard, Alexander, Ber, Isabelle Le, Pasquier, Florence, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Sorbi, Sandro, Otto, Markus, Rohrer, Jonathan D., and Borroni, Barbara
Published: 2022
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13. Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort

Author: Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Foster, Phoebe H., Russell, Lucy L., Peakman, Georgia, Convery, Rhian S., Bouzigues, Arabella, Greaves, Caroline V., Bocchetta, Martina, Cash, David M., van Swieten, John C., Jiskoot, Lize C., Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tagliavini, Fabrizio, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, and Rohrer, Jonathan D.
Published: 2022
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14. Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study

Author: Schneider, Raphael, McKeever, Paul, Kim, TaeHyung, Graff, Caroline, van Swieten, John Cornelis, Karydas, Anna, Boxer, Adam, Rosen, Howie, Miller, Bruce L, Laforce, Robert, Galimberti, Daniela, Masellis, Mario, Borroni, Barbara, Zhang, Zhaolei, Zinman, Lorne, Rohrer, Jonathan Daniel, Tartaglia, Maria Carmela, Robertson, Janice, Andersson, Christin, Archetti, Silvana, Arighi, Andrea, Benussi, Luisa, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Cash, David, Cosseddu, Maura, Dick, Katrina, Fallström, Marie, Ferreira, Carlos, Fenoglio, Chiara, Fox, Nick, Freedman, Morris, Frisoni, Giovanni, Fumagalli, Giorgio, Gazzina, Stefano, Ghidoni, Roberta, Grisoli, Marina, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Lombardi, Gemma, Maruta, Carolina, Meeter, Lieke, van Minkelen, Mendonça A Rick, Nacmias, Benedetta, Öijerstedt, Linn, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rossi, Giacomina, Rossor, Martin, Row, James, Scarpini, Elio, Tagliavini, Fabrizio, Sorbi, Sandro, Tang-Wai, David, Thomas, David, Thonberg, Hakan, Tiraboschi, Pietro, Verdelho, Ana, and Warren, Jason
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Dementia, Genetics, Neurodegenerative, Alzheimer's Disease, Biotechnology, Prevention, Rare Diseases, Aging, Brain Disorders, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Neurological, Biomarkers, Down-Regulation, Exosomes, Female, Frontotemporal Dementia, Humans, Male, MicroRNAs, tau Proteins, Genetic FTD Initiative, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract: ObjectiveTo determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD.MethodsGENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age.ResultsIn the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98).ConclusionsExosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.
Published: 2018

15. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author: Meeter, Lieke HH, Gendron, Tania F, Sias, Ana C, Jiskoot, Lize C, Russo, Silvia P, Kaat, Laura Donker, Papma, Janne M, Panman, Jessica L, van der Ende, Emma L, Dopper, Elise G, Franzen, Sanne, Graff, Caroline, Boxer, Adam L, Rosen, Howard J, Sanchez‐Valle, Raquel, Galimberti, Daniela, Pijnenburg, Yolande AL, Benussi, Luisa, Ghidoni, Roberta, Borroni, Barbara, Laforce, Robert, del Campo, Marta, Teunissen, Charlotte E, van Minkelen, Rick, Rojas, Julio C, Coppola, Giovanni, Geschwind, Dan H, Rademakers, Rosa, Karydas, Anna M, Öijerstedt, Linn, Scarpini, Elio, Binetti, Giuliano, Padovani, Alessandro, Cash, David M, Dick, Katrina M, Bocchetta, Martina, Miller, Bruce L, Rohrer, Jonathan D, Petrucelli, Leonard, van Swieten, John C, and Lee, Suzee E
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Research, Neurodegenerative, Dementia, Brain Disorders, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurological, Clinical Sciences, Clinical and health psychology
Abstract: ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.
Published: 2018

16. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Rossor, Martin N., Fox, Nick C., Woollacott, Ione O.C., Shafei, Rachelle, Heller, Carolin, Guerreiro, Rita, Bras, Jose, Thomas, David L., Mead, Simon, Meeter, Lieke, Panman, Jessica, Papma, Janne, Poos, Jackie, van Minkelen, Rick, Pijnenburg, Yolanda, Barandiaran, Myriam, Indakoetxea, Begoña, Gabilondo, Alazne, Tainta, Mikel, de Arriba, Maria, Gorostidi, Ana, Zulaica, Miren, Villanua, Jorge, Diaz, Zigor, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Cosseddu MPsych, Maura, Gazzina, Stefano, Padovani, Alessandro, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, Keren, Ron, Tang-Wai, Daid, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Thonberg, Hakan, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnarth, Hans-Otto, Bender, Benjamin, Bruffaerts, Rose, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B., Miltenberger, Gabriel, Maruta MPsych, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Giaccone, Giorgio, Muscio, Cristina, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro NPsych, Diana, Almeida, Maria R., Castelo-Branco, Miguel, Leitão, Maria J., Tabuas-Pereira, Miguel, Santiago, Beatriz, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Thompson, Paul, Langheinrich, Tobias, Prix, Catharina, Hoegen, Tobias, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Semler, Elisa, Anderl-Straub, Sarah, Russell, Lucy L., Greaves, Caroline V., Bocchetta, Martina, Nicholas, Jennifer, Convery, Rhian S., Moore, Katrina, Cash, David M., van Swieten, John, Jiskoot, Lize, Moreno, Fermin, Sanchez-Valle, Raquel, Borroni, Barbara, Laforce, Robert, Jr., Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Rotondo, Emanuela, Galimberti, Daniela, Rowe, James B., Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Danek, Adrian, Otto, Markus, Warren, Jason D., and Rohrer, Jonathan D.
Published: 2020
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17. Single-cell multimodal analysis in a case with reduced penetrance of Progranulin-Frontotemporal Dementia

Author: Natarajan, Karthick, Eisfeldt, Jesper, Hammond, Maria, Laffita-Mesa, José Miguel, Patra, Kalicharan, Khoshnood, Behzad, Öijerstedt, Linn, and Graff, Caroline
Published: 2021
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18. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Author: Heller, Carolin, Convery, Rhian S, Woollacott, Ione OC, Shafei, Rachelle M, Graff-Radford, Jonathan, Jones, David T, Dheel, Christina M, Savica, Rodolfo, Lapid, Maria I, Baker, Matt, Fields, Julie A, Gavrilova, Ralitza, Domoto-Reilly, Kimiko, Poos, Jackie M, Van der Ende, Emma L, Panman, Jessica L, Donker Kaat, Laura, Seelaar, Harro, Richardson, Anna, Frisoni, Giovanni, Mega, Anna, Fostinelli, Silvia, Chiang, Huei-Hsin, Alberici, Antonella, Arighi, Andrea, Fenoglio, Chiara, Heuer, Hilary, Miller, Bruce, Karydas, Anna, Fong, Jamie, João Leitão, Maria, Santiago, Beatriz, Duro, Diana, Ferreira, Carlos, Gabilondo, Alazne, De Arriba, Maria, Tainta, Mikel, Zulaica, Miren, Ferreira, Catarina, Semler, Elisa, Ludolph, Albert, Landwehrmeyer, Bernhard, Volk, Alexander E, Miltenberger, Gabriel, Verdelho, Ana, Afonso, Sónia, Tartaglia, Maria Carmela, Freedman, Morris, Rogaeva, Ekaterina, Ferrari, Camilla, Piaceri, Irene, Bessi, Valentina, Lombardi, Gemma, St-Onge, Frédéric, Doré, Marie-Claire, Bruffaerts, Rose, Vandenbulcke, Mathieu, Van den Stock, Jan, Mesulam, M Marsel, Bigio, Eileen, Koros, Christos, Papatriantafyllou, John, Kroupis, Christos, Stefanis, Leonidas, Shoesmith, Christien, Robertson, Erik, Coppola, Giovanni, Da Silva Ramos, Eliana Marisa, Geschwind, Daniel, Moore, Katrina M, Nicholas, Jennifer, Grossman, Murray, McMillan, Corey T, Irwin, David J, Massimo, Lauren, Van Deerlin, Vivianna M, Warren, Jason D, Fox, Nick C, Rossor, Martin N, Mead, Simon, Bocchetta, Martina, Boeve, Bradley F, Knopman, David S, Graff-Radford, Neill R, Forsberg, Leah K, Rademakers, Rosa, Wszolek, Zbigniew K, van Swieten, John C, Jiskoot, Lize C, Meeter, Lieke H, Dopper, Elise GP, Papma, Janne M, Snowden, Julie S, Saxon, Jennifer, Jones, Matthew, Pickering-Brown, Stuart, Le Ber, Isabelle, Camuzat, Agnès, Brice, Alexis, Caroppo, Paola, Ghidoni, Roberta, Pievani, Michela, Benussi, Luisa, Binetti, Giuliano, Dickerson, Bradford C, Lucente, Diane, Krivensky, Samantha, Graff, Caroline, Öijerstedt, Linn, Fallström, Marie, Thonberg, Håkan, Ghoshal, Nupur, Morris, John C, Borroni, Barbara, Benussi, Alberto, Padovani, Alessandro, Galimberti, Daniela, Scarpini, Elio, Fumagalli, Giorgio G, Mackenzie, Ian R, Hsiung, Ging-Yuek R, Sengdy, Pheth, Boxer, Adam L, Rosen, Howie, Taylor, Joanne B, Synofzik, Matthis, Wilke, Carlo, Sulzer, Patricia, Hodges, John R, Halliday, Glenda, Kwok, John, Sanchez-Valle, Raquel, Lladó, Albert, Borrego-Ecija, Sergi, Santana, Isabel, Almeida, Maria Rosário, Tábuas-Pereira, Miguel, Moreno, Fermin, Barandiaran, Myriam, Indakoetxea, Begoña, Levin, Johannes, Danek, Adrian, Rowe, James B, Cope, Thomas E, Otto, Markus, Anderl-Straub, Sarah, de Mendonça, Alexandre, Maruta, Carolina, Masellis, Mario, Black, Sandra E, Couratier, Philippe, Lautrette, Geraldine, Huey, Edward D, Sorbi, Sandro, Nacmias, Benedetta, Laforce, Robert, Jr, Tremblay, Marie-Pier L, Vandenberghe, Rik, Damme, Philip Van, Rogalski, Emily J, Weintraub, Sandra, Gerhard, Alexander, Onyike, Chiadi U, Ducharme, Simon, Papageorgiou, Sokratis G, Ng, Adeline Su Lyn, Brodtmann, Amy, Finger, Elizabeth, Guerreiro, Rita, Bras, Jose, and Rohrer, Jonathan D
Published: 2020
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19. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study

Author: Rossor, Martin N., Warren, Jason D., Fox, Nick C., Woollacott, Ione O.C., Shafei, Rachelle, Greaves, Caroline, Guerreiro, Rita, Bras, Jose, Thomas, David L., Nicholas, Jennifer, Mead, Simon, van Minkelen, Rick, Barandiaran, Myriam, Indakoetxea, Begoña, Gabilondo, Alazne, Tainta, Mikel, de Arriba, Maria, Gorostidi, Ana, Zulaica, Miren, Villanua, Jorge, Diaz, Zigor, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Cosseddu, Maura, Gazzina, Stefano, Padovani, Alessandro, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, Keren, Ron, Tang-Wai, David, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Thonberg, Hakan, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnath, Hans-Otto, Bender, Benjamin, Bruffaerts, Rose, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B., Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro, Diana, Rosario Almeida, Maria, Castelo-Branco, Miguel, João Leitão, Maria, Tabuas-Pereira, Miguel, Santiago, Beatriz, Gauthier, Serge, Schonecker, Sonja, Semler, Elisa, Anderl-Straub, Sarah, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Pievani, Michela, Lombardi, Gemma, Nacmias, Benedetta, Ferrari, Camilla, Bessi, Valentina, van der Ende, Emma L, Meeter, Lieke H, Poos, Jackie M, Panman, Jessica L, Jiskoot, Lize C, Dopper, Elise G P, Papma, Janne M, de Jong, Frank Jan, Verberk, Inge M W, Teunissen, Charlotte, Rizopoulos, Dimitris, Heller, Carolin, Convery, Rhian S, Moore, Katrina M, Bocchetta, Martina, Neason, Mollie, Cash, David M, Borroni, Barbara, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Jr, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Carmela Tartaglia, Maria, Rowe, James B, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris, Ducharme, Simon, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Frisoni, Giovanni B, Cappa, Stefano, Pijnenburg, Yolande A L, Rohrer, Jonathan D, and van Swieten, John C
Published: 2019
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20. Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia

Author: Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Cosseddu, Maura, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Dick, Katrina M., Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Flanagana, Toby, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Ghidoni, Roberta, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans-Otto, Keren, Ron, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Nacmias, Benedetta, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Padovani, Alessandro, Panman, Jessica, Papma, Janne, Pievani, Michela, Pijnenburg, Yolande, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rosser, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Vandamme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Rittman, Timothy, Borchert, Robin, Jones, Simon, van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni B., Laforce, Robert, Jr., Finger, Elizabeth, Mendonça, Alexandre, Sorbi, Sandro, Rohrer, Jonathan D., and Rowe, James B.
Published: 2019
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21. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

Author: Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Dick, Katrina M., Duro, Diana, Fenoglio, Chiara, Ferreira, Carlos, Ferreira, Catarina B., Flanagan, Toby, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gauthier, Serge, Ghidoni, Roberta, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans-Otto, Keren, Ron, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Nacmias, Benedetta, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Panman, Jessica, Papma, Janne, Patzig, Maximilian, Pievani, Michela, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Tang-Wai, David, Thomas, David L., Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Vandamme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Zetterberg, Henrik, Zulaica, Miren, Premi, Enrico, Calhoun, Vince D., Diano, Matteo, Gazzina, Stefano, Cosseddu, Maura, Alberici, Antonella, Archetti, Silvana, Paternicò, Donata, Gasparotti, Roberto, van Swieten, John, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Jr., Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris, Ducharme, Simon, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Frisoni, Giovanni, Cappa, Stefano, Sorbi, Sandro, Padovani, Alessandro, Rohrer, Jonathan D., and Borroni, Barbara
Published: 2019
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22. Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study

Author: Pérez-Millan, Agnès, Borrego-Écija, Sergi, van Swieten, John C., Jiskoot, Lize, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Tiraboschi, Pietro, Seelaar, Harro, Langheinrich, Tobias, Rohrer, Jonathan D., Sala-Llonch, Roser, Sánchez-Valle, Raquel, GENFI The Genetic FTD Initiative, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V., Timberlake, Carolyn, Ferreira, Catarina B., Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L., Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Poos, Jackie, M. Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L., Leitão, Maria João, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Shafei, Rachelle, Convery, Rhian S., van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, The Genetic FTD Initiative, GENFI, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Tiraboschi, Pietro, Shafei, Rachelle, Convery, Rhian S, van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V, Timberlake, Carolyn, Ferreira, Catarina B, Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L, Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Poos, Jackie, M Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L, and Leitão, Maria João
Subjects: diagnostic imaging [Brain Stem], pathology [Motor Neurons], diagnostic imaging [Motor Neuron Disease], diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [White Matter], pathology [Brain Stem], Neurology, pathology [White Matter], pathology [Frontotemporal Dementia], Mutation, C9orf72, Humans, genetics [Motor Neuron Disease], ddc:610, Human medicine, Neurology (clinical), genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Brainstem, GENFI, Frontotemporal dementia
Abstract: Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.
Published: 2022

23. Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Author: Young, Alexandra L., Bocchetta, Martina, Russell, Lucy L., Convery, Rhian S., Peakman, Georgia, Todd, Emily, Cash, David M., Greaves, Caroline V., van Swieten, John, Jiskoot, Lize, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, Borroni, Barbara, Laforce, Robert, Jr, Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Galimberti, Daniela, Rowe, James B., Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Williams, Steven C.R., Alexander, Daniel C., Rohrer, Jonathan D., Rossor, Martin N., Fox, Nick C., Warren, Jason D., Woollacott, Ione, Shafei, Rachelle, Heller, Carolin, Swift, Imogen J, Moore, Katrina, Guerreiro, Rita, Bras, Jose, Thomas, David L., Nicholas, Jennifer, Mead, Simon, Meeter, Lieke, Panman, Jessica, Papma, Janne M., Poos, Jackie, van Minkelen, Rick, Pijnenburg, Yolande, Barandiaran, Myriam, Indakoetxea, Begoña, Gabilondo, Alazne, Tainta, Mikel, de Arriba, María, Gorostidi, Ana, Zulaica, Miren, Villanua, Jorge, Díaz, Zigor, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, Antonell, Anna, Bargalló, Nuria, Premi, Enrico, Cosseddu, Maura, Gazzina, Stefano, Padovani, Alessandro, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, Keren, Ron, Tang-Wai, David, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Thonberg, Hakan, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnath, Hans Otto, Bender, Benjamin, Bruffaerts, Rose, Van Damme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B., Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro, Diana, Almeida, Maria Rosario, Branco, Miguel Castelo, Leitão, Maria João, Pereira, Miguel Tábuas, Santiago, Beatriz, Gauthier, Serge, Neto, Pedro Rosa, Veldsman, Michele, Thompson, Paul, Prix, Catharina, Hoegen, Tobias, Mag.rer.nat, Elisabeth Wlasich, Loosli, Sandra, Schönecker, Sonja, Dr.hum.bio, Elisa Semler, Psych, Dipl., Anderl-Straub, Sarah, Psych, Dipl., Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, and Bessi, Valentina
Published: 2021
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24. Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Samra, Kiran, primary, MacDougall, Amy M., additional, Bouzigues, Arabella, additional, Bocchetta, Martina, additional, Cash, David M., additional, Greaves, Caroline V., additional, Convery, Rhian S., additional, van Swieten, John C., additional, Jiskoot, Lize, additional, Seelaar, Harro, additional, Moreno, Fermin, additional, Sanchez-Valle, Raquel, additional, Laforce, Robert, additional, Graff, Caroline, additional, Masellis, Mario, additional, Tartaglia, Maria Carmela, additional, Rowe, James B., additional, Borroni, Barbara, additional, Finger, Elizabeth, additional, Synofzik, Matthis, additional, Galimberti, Daniela, additional, Vandenberghe, Rik, additional, de Mendonça, Alexandre, additional, Butler, Chris R., additional, Gerhard, Alex, additional, Ducharme, Simon, additional, Le Ber, Isabelle, additional, Tiraboschi, Pietro, additional, Santana, Isabel, additional, Pasquier, Florence, additional, Levin, Johannes, additional, Otto, Markus, additional, Sorbi, Sandro, additional, Rohrer, Jonathan D., additional, Russell, Lucy L., additional, Nelson, Annabel, additional, Thomas, David L., additional, Todd, Emily, additional, Benotmane, Hanya, additional, Nicholas, Jennifer, additional, Shafei, Rachelle, additional, Timberlake, Carolyn, additional, Cope, Thomas, additional, Rittman, Timothy, additional, Benussi, Alberto, additional, Premi, Enrico, additional, Gasparotti, Roberto, additional, Archetti, Silvana, additional, Gazzina, Stefano, additional, Cantoni, Valentina, additional, Arighi, Andrea, additional, Fenoglio, Chiara, additional, Scarpini, Elio, additional, Fumagalli, Giorgio, additional, Borracci, Vittoria, additional, Rossi, Giacomina, additional, Giaccone, Giorgio, additional, Di Fede, Giuseppe, additional, Caroppo, Paola, additional, Prioni, Sara, additional, Redaelli, Veronica, additional, Tang-Wai, David, additional, Rogaeva, Ekaterina, additional, Castelo-Branco, Miguel, additional, Freedman, Morris, additional, Keren, Ron, additional, Black, Sandra, additional, Mitchell, Sara, additional, Shoesmith, Christen, additional, Bartha, Robart, additional, Rademakers, Rosa, additional, Poos, Jackie, additional, Papma, Janne M., additional, Giannini, Lucia, additional, van Minkelen, Rick, additional, Pijnenburg, Yolande, additional, Nacmias, Benedetta, additional, Ferrari, Camilla, additional, Polito, Cristina, additional, Lombardi, Gemma, additional, Bessi, Valentina, additional, Veldsman, Michele, additional, Andersson, Christin, additional, Thonberg, Hakan, additional, Öijerstedt, Linn, additional, Jelic, Vesna, additional, Thompson, Paul, additional, Langheinrich, Tobias, additional, Lladó, Albert, additional, Antonell, Anna, additional, Olives, Jaume, additional, Balasa, Mircea, additional, Bargalló, Nuria, additional, Borrego-Ecija, Sergi, additional, Verdelho, Ana, additional, Maruta, Carolina, additional, Ferreira, Catarina B., additional, Miltenberger, Gabriel, additional, do Couto, Frederico Simões, additional, Gabilondo, Alazne, additional, Gorostidi, Ana, additional, Villanua, Jorge, additional, Cañada, Marta, additional, Tainta, Mikel, additional, Zulaica, Miren, additional, Barandiaran, Myriam, additional, Alves, Patricia, additional, Bender, Benjamin, additional, Wilke, Carlo, additional, Graf, Lisa, additional, Vogels, Annick, additional, Vandenbulcke, Mathieu, additional, Van Damme, Philip, additional, Bruffaerts, Rose, additional, Poesen, Koen, additional, Rosa-Neto, Pedro, additional, Gauthier, Serge, additional, Camuzat, Agnès, additional, Brice, Alexis, additional, Bertrand, Anne, additional, Funkiewiez, Aurélie, additional, Rinaldi, Daisy, additional, Saracino, Dario, additional, Colliot, Olivier, additional, Sayah, Sabrina, additional, Prix, Catharina, additional, Wlasich, Elisabeth, additional, Wagemann, Olivia, additional, Loosli, Sandra, additional, Schönecker, Sonja, additional, Hoegen, Tobias, additional, Lombardi, Jolina, additional, Anderl-Straub, Sarah, additional, Rollin, Adeline, additional, Kuchcinski, Gregory, additional, Bertoux, Maxime, additional, Lebouvier, Thibaud, additional, Deramecourt, Vincent, additional, Santiago, Beatriz, additional, Duro, Diana, additional, Leitão, Maria João, additional, Almeida, Maria Rosario, additional, Tábuas-Pereira, Miguel, additional, and Afonso, Sónia, additional
Published: 2023
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25. C9orf72, AAO and ancestry help discriminating behavioural from language variants in FTLD cohorts

Author: Costa, Beatrice, Manzoni, Claudia, Bernal-Quiros, Manuel, Kia, Demis A, Aguilar, Miquel, Alvarez, Ignacio, Alvarez, Victoria, Andreassen, Ole, Anfossi, Maria, Bagnoli, Silvia, Benussi, Luisa, Bernardi, Livia, Binetti, Giuliano, Blackburn, Daniel, Boada, Mercè, Borroni, Barbara, Bowns, Lucy, Bråthen, Geir, Bruni, Amalia C, Chiang, Huei-Hsin, Clarimon, Jordi, Colville, Shuna, Conidi, Maria E, Cope, Tom E, Cruchaga, Carlos, Cupidi, Chiara, Di Battista, Maria Elena, Diehl-Schmid, Janine, Diez-Fairen, Monica, Dols-Icardo, Oriol, Durante, Elisabetta, Flisar, Dušan, Frangipane, Francesca, Galimberti, Daniela, Gallo, Maura, Gallucci, Maurizio, Ghidoni, Roberta, Graff, Caroline, Grafman, Jordan H, Grossman, Murray, Hardy, John, Hernández, Isabel, Holloway, Guy JT, Huey, Edward D, Illán-Gala, Ignacio, Karydas, Anna, Khoshnood, Behzad, Kramberger, Milica G, Kristiansen, Mark, Lewis, Patrick A, Lleó, Alberto, Madhan, Gaganjit K, Maletta, Raffaele, Maver, Aleš, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce, Mol, Merel O, Momeni, Parastoo, Moreno-Grau, Sonia, Morris, Chris M, Nacmias, Benedetta, Nilsson, Christer, Novelli, Valeria, Öijerstedt, Linn, Padovani, Alessandro, Pal, Suvankar, Panchbhaya, Yasmin, Pastor, Pau, Peterlin, Borut, Piaceri, Irene, Pickering-Brown, Stuart, Pijnenburg, Yolande AL, Puca, Annibale A, Rainero, Innocenzo, Rendina, Antonella, Richardson, Anna MT, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rossi, Giacomina, Rossmeier, Carola, Rowe, James B, Rubino, Elisa, Ruiz, Agustín, Sanchez-Valle, Raquel, Sando, Sigrid B, Santillo, Alexander F, Saxon, Jennifer, Scarpini, Elio, Serpente, Maria, Smirne, Nicoletta, Sorbi, Sandro, Suh, EunRan, Tagliavini, Fabrizio, Thompson, Jennifer C, Trojanowski, John Q, Van Deerlin, Vivianna M, Van der Zee, Julie, Van Broeckhoven, Christine, van Rooij, Jeroen, Van Swieten, John C, Veronesi, Arianna, Vitale, Emilia, Waldö, Maria L, Woodward, Cathy, Yokoyama, Jennifer, Escott-Price, Valentina, Polke, James M, and Ferrari, Raffaele
Published: 2020
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26. Early neurotransmitters changes in prodromal frontotemporal dementia

Author: Premi, Enrico, Pengo, Marta, Mattioli, Irene, Cantoni, Valentina, Dukart, Juergen, Gasparotti, Roberto, Buratti, Emanuele, Padovani, Alessandro, Bocchetta, Martina, Todd, Emily G., Bouzigues, Arabella, Cash, David M., Convery, Rhian S., Russell, Lucy L., Thomas, David L., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Tsvetanov, Kamen A., Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D., Borroni, Barbara, Foster, Phoebe, Tiraboschi, Pietro, Esteve, Aitana Sogorb, Heller, Carolin, Greaves, Caroline V., Zetterberg, Henrik, Swift, Imogen J., Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Repositório da Universidade de Lisboa, Bruffaerts, Rose, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Heller, Carolin, Greaves, Caroline V, Zetterberg, Henrik, Swift, Imogen J, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, and Borrego-Ecija, Sergi
Subjects: Serotonin, Positron emission tomography, Frontotemporal dementia, Frontotemporal lobar degeneration, Genes, Magnetic resonance imaging, Mutation, Neurotransmitters, C9orf72 Protein, Dopamine, Medizin, tau Proteins, diagnostic imaging [Frontotemporal Dementia], Acetylcholine, genetics [tau Proteins], methods [Magnetic Resonance Imaging], Pick Disease of the Brain, Neurology, ddc:570, Humans, Human medicine, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein]
Abstract: Crown Copyright © 2023 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). Conclusions: This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms., This work is supported by JPND grant “GENFI-prox” (2019–02248), the Centre d'Investigation Clinique (ICM, France) and the Centre pour l'Acquisition et le Traitement des Images platform (CATI, France), the UK Medical Research Council, the Italian Ministry of Health (CoEN015 and Ricerca Corrente), and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, and the Italian Ministry of Health (GR-2018-12365105). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Alzheimer's Society grant (AS-PG-16-007), and the Bluefield Project. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198).
Published: 2023

27. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

Author: Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Moreno, Fermin, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Sanchez-Valle, Raquel, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Laforce, Robert, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Graff, Caroline, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Masellis, Mario, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, De Mendonça, Alexandre, Butler, Christopher R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Genetic FTD Initiative (GENFI), Erasmus MC other, Radiology & Nuclear Medicine, Clinical Genetics, Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, and Miltenberger, Gabriel
Subjects: Progranulin, Medizin, genetics [Mutation], tau Proteins, diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, Settore BIO/13 - Biologia Applicata, C9orf72, progranulin, Genetics, Humans, genetics, Language Development Disorders, ddc:610, tau, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Frontotemporal dementia, Language, Tau, language, C9orf72 Protein, Magnetic Resonance Imaging, genetics [tau Proteins], Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurology (clinical), Atrophy
Abstract: Funder: CIBERNED, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative Schorling Foundation, Funder: Swedish Alzheimer Foundation, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Miriam Marks Brain Research UK, BACKGROUND: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. METHODS: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. RESULTS: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. CONCLUSIONS: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
Published: 2023
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28. 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: Pottier, Cyril, Zhou, Xiaolai, Perkerson, Ralph B, III, Baker, Matt, Jenkins, Gregory D, Serie, Daniel J, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, López de Munain, Adolfo, Zulaica, Miren, Moreno, Fermin, Le Ber, Isabelle, Pasquier, Florence, Hannequin, Didier, Sánchez-Valle, Raquel, Antonell, Anna, Lladó, Albert, Parsons, Tammee M, Finch, NiCole A, Finger, Elizabeth C, Lippa, Carol F, Huey, Edward D, Neumann, Manuela, Heutink, Peter, Synofzik, Matthis, Wilke, Carlo, Rissman, Robert A, Slawek, Jaroslaw, Sitek, Emilia, Johannsen, Peter, Nielsen, Jørgen E, Ren, Yingxue, van Blitterswijk, Marka, DeJesus-Hernandez, Mariely, Christopher, Elizabeth, Murray, Melissa E, Bieniek, Kevin F, Evers, Bret M, Ferrari, Camilla, Rollinson, Sara, Richardson, Anna, Scarpini, Elio, Fumagalli, Giorgio G, Padovani, Alessandro, Hardy, John, Momeni, Parastoo, Ferrari, Raffaele, Frangipane, Francesca, Maletta, Raffaele, Anfossi, Maria, Gallo, Maura, Petrucelli, Leonard, Suh, EunRan, Lopez, Oscar L, Wong, Tsz H, van Rooij, Jeroen G J, Seelaar, Harro, Mead, Simon, Caselli, Richard J, Reiman, Eric M, Noel Sabbagh, Marwan, Kjolby, Mads, Nykjaer, Anders, Karydas, Anna M, Boxer, Adam L, Grinberg, Lea T, Grafman, Jordan, Spina, Salvatore, Oblak, Adrian, Mesulam, M-Marsel, Weintraub, Sandra, Geula, Changiz, Hodges, John R, Piguet, Olivier, Brooks, William S, Irwin, David J, Trojanowski, John Q, Lee, Edward B, Josephs, Keith A, Parisi, Joseph E, Ertekin-Taner, Nilüfer, Knopman, David S, Nacmias, Benedetta, Piaceri, Irene, Bagnoli, Silvia, Sorbi, Sandro, Gearing, Marla, Glass, Jonathan, Beach, Thomas G, Black, Sandra E, Masellis, Mario, Rogaeva, Ekaterina, Vonsattel, Jean-Paul, Honig, Lawrence S, Kofler, Julia, Bruni, Amalia C, Snowden, Julie, Mann, David, Pickering-Brown, Stuart, Diehl-Schmid, Janine, Winkelmann, Juliane, Galimberti, Daniela, Graff, Caroline, Öijerstedt, Linn, Troakes, Claire, Al-Sarraj, Safa, Cruchaga, Carlos, Cairns, Nigel J, Rohrer, Jonathan D, Halliday, Glenda M, Kwok, John B, van Swieten, John C, White, Charles L, III, Ghetti, Bernardino, Murell, Jill R, Mackenzie, Ian R A, Hsiung, Ging-Yuek R, Borroni, Barbara, Rossi, Giacomina, Tagliavini, Fabrizio, Wszolek, Zbigniew K, Petersen, Ronald C, Bigio, Eileen H, Grossman, Murray, Van Deerlin, Vivianna M, Seeley, William W, Miller, Bruce L, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, Biernacka, Joanna M, and Rademakers, Rosa
Published: 2018
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29. Patterns of gray matter atrophy in genetic frontotemporal dementia: results from the GENFI study

Author: Andersson, Christin, Archetti, Silvana, Arighi, Andrea, Benussi, Luisa, Black, Sandra, Cosseddu, Maura, Fallström, Marie, Ferreira, Carlos, Fenoglio, Chiara, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gazzina, Stefano, Ghidoni, Roberta, Grisoli, Marina, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Lombardi, Gemma, Maruta, Carolina, Mead, Simon, Meeter, Lieke, van Minkelen, Rick, Nacmias, Benedetta, Öijerstedt, Linn, Padovani, Alessandro, Panman, Jessica, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rossi, Giacomina, Rossor, Martin, Scarpini, Elio, Tang-Wai, David, Tartaglia, Carmela, Thonberg, Hakan, Tiraboschi, Pietro, Verdelho, Ana, Warren, Jason, Cash, David M., Bocchetta, Martina, Thomas, David L., Dick, Katrina M., van Swieten, John C., Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni B., Laforce, Robert, Jr., Finger, Elizabeth, de Mendonça, Alexandre, Sorbi, Sandro, Rossor, Martin N., Ourselin, Sebastien, and Rohrer, Jonathan D.
Published: 2018
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30. Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Author: Staffaroni, Adam M, Quintana, Melanie, Heller, Carolin, Boeve, Bradley F, Rosen, Howard J, Rohrer, Jonathan D, Boxer, Adam L, Initiative, Frontotemporal Dementia Prevention, Apostolova, Liana, Barmada, Sami, Boeve, Bradley, Bozoki, Andrea, Clark, Annie L, Clark, David, Coppola, Giovanni, Darby, Ryan, Dickson, Dennis, Faber, Kelley, Fagan, Anne, Galasko, Douglas R, Grant, Ian M, Huang, Eric, Kerwin, Diana, Taylor, Jack Carson, Lapid, Maria, Lee, Suzee, Leger, Gabriel, Masdeux, Joseph C, McGinnis, Scott, Mendez, Mario, Onyike, Chiadi, Pascual, M Belen, Pressman, Peter, Rademakers, Rosa, Wise, Amy, Ramanan, Vijay, Ritter, Aaron, Seeley, William W, Syrjanen, Jeremy, Taylor, Jack C, Weintraub, Sandra, Esteve, Aitana Sogorb, Nelson, Annabel, Greaves, Caroline V, Thomas, David L, Ong, Elise, Benotmane, Hanya, Zetterberg, Henrik, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Forsberg, Leah, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Brushaber, Danielle, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Rojas, Julio C, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, VandeVrede, Lawren, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Ljubenkov, Peter, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Wendelberger, Barbara, Kramer, Joel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Casaletto, Kaitlin B, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Appleby, Brian, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Bordelon, Yvette, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Botha, Hugo, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Dickerson, Bradford C, Domoto-Reilly, Kimiko, Fields, Julie A, Foroud, Tatiana, Gavrilova, Ralitza, Heuer, Hilary W, Geschwind, Daniel, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathon, Graff-Radford, Neill, Grossman, Murray, Hall, Matthew G H, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David, Russell, Lucy L, Jones, David T, Kantarci, Kejal, Kaufer, Daniel, Knopman, David S, Kremers, Walter, Lago, Argentina Lario, Lapid, Maria I, Litvan, Irene, Lucente, Diane, Mackenzie, Ian R, Cobigo, Yann, Mendez, Mario F, Mester, Carly, Miller, Bruce L, Onyike, Chiadi U, Ramanan, Vijay K, Ramos, Eliana Marisa, Rao, Meghana, Rascovsky, Katya, Rankin, Katherine P, Wolf, Amy, Roberson, Erik D, Savica, Rodolfo, Tartaglia, M Carmela, Wong, Bonnie, Cash, David M, Bouzigues, Arabella, Swift, Imogen J, Peakman, Georgia, Bocchetta, Martina, Goh, Sheng-Yang Matt, Todd, Emily G, Convery, Rhian S, Rowe, James B, Borroni, Barbara, Galimberti, Daniela, Tiraboschi, Pietro, Masellis, Mario, Finger, Elizabeth, van Swieten, John C, Seelaar, Harro, Petrucelli, Leonard, Jiskoot, Lize C, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Gendron, Tania F, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, Kornak, John, Frontotemporal Dementia Prevention Initiative (FPI) Investigators, and Neurology
Subjects: Clinical Trials as Topic, C9orf72 Protein, biomarkers, genetics [Mutation], tau Proteins, General Medicine, Article, General Biochemistry, Genetics and Molecular Biology, genetics [tau Proteins], Chemistry, Frontotemporal Dementia, Mutation, Disease Progression, Humans, ddc:610, Human medicine, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Biomarkers, dementia
Abstract: Data availability: The datasets analyzed for the current study reflect collaborative efforts of two research consortia: ALLFTD and GENFI. Each consortium provides clinical data access based on established policies for data use: processes for request are available for review at allftd.org/data for ALLFTD data and by emailing genfi@ucl.ac.uk. Certain data elements from both consortia (for example raw MRI images) may be restricted due to the potential for identifiability in the context of the sensitive nature of the genetic data. The deidentified combined dataset will be available for request through the FTD Prevention Initiative in 2023 (https://www.thefpi.org/). Code availability: Custom R code is available at https://doi.org/10.5281/zenodo.6687486. Copyright © The Author(s). Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects. Data collection and dissemination of the data presented in this paper were supported by the ALLFTD Consortium (U19: AG063911, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL and LEFFTDS Consortia (ARTFL: U54 NS092089, funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke). The manuscript was reviewed by the ALLFTD Executive Committee for scientific content. The authors acknowledge the invaluable contributions of the study participants and families as well as the assistance of the support staffs at each of the participating sites. This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, Larry L. Hillblom Foundation (2018-A-025-FEL (A.M.S.)), the National Institutes of Health (AG038791 (A.L.B.), AG032306 (H.J.R.), AG016976 (W.K.), AG062677 (Ron C. Peterson), AG019724 (B.L.M.), AG058233 (Suzee E. Lee), AG072122 (Walter Kukull), P30 AG062422 (B.L.M.), K12 HD001459 (N.G.), K23AG061253 (A.M.S.), AG062422 (RCP), K24AG045333 (H.J.R.)) and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886 (T.F.)) awarded by the National Institute on Aging (NIA), were used in this study. This work was also supported by Medical Research Council UK GENFI grant MR/M023664/1 (J.D.R.), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres and a JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project 739510. J.D.R. and L.L.R. are also supported by the National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is also supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). RC and C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care), the Wellcome Trust (220258), the Cambridge Centre for Parkinson-plus and the Medical Research Council (SUAG/092 G116768); I.L.B. is supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN, and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project 739510). J.L. is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). R.S.-V. was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to R.S.-V.). M.M. was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, by Canadian Institutes of Health Research operating grants (MOP- 371851 and PJT-175242) and by funding from the Weston Brain Institute. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 Synergy 390857198). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.
Published: 2022

31. Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort

Author: Samra, Kiran, MacDougall, Amy M, Bouzigues, Arabella, Bocchetta, Martina, Cash, David M, Greaves, Caroline V, Convery, Rhian S, Hardy, Chris, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize C, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R, Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Warren, Jason D, Rohrer, Jonathan D, Russell, Lucy L, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Arriba, María de, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Cerveau, Institut du, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Minkelen, Rick van, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Damme, Philip Van, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, GENetic Frontotemporal dementia Initiative (GENFI), Bruffaerts, Rose, Bocchetta, Martina [0000-0003-1814-5024], Cash, David M [0000-0001-7833-616X], Seelaar, Harro [0000-0003-1989-7527], Jiskoot, Lize C [0000-0002-1120-1858], Sanchez-Valle, Raquel [0000-0001-7750-896X], Graff, Caroline [0000-0002-9949-2951], Borroni, Barbara [0000-0001-9340-9814], Synofzik, Matthis [0000-0002-2280-7273], Vandenberghe, Rik [0000-0001-6237-2502], Gerhard, Alexander [0000-0002-8071-6062], Ducharme, Simon [0000-0002-7309-1113], Pasquier, Florence [0000-0001-9880-9788], Apollo - University of Cambridge Repository, Neurology, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, du Cerveau, Institut, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Damme, Philip Van, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, and Mead, Simon
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, SDG 3 - Good Health and Well-being, Medizin, MAPT, primary progressive aphasia, ddc:610, c9orf72, GRN, Biological Psychiatry
Abstract: Funder: Alzheimer's Research UK, Funder: Bluefield Project, Funder: Royal National Institute, Funder: Weston Brain Institute and Ontario Brain Institute, Funder: Alzheimer Nederland and the Bluefield, Funder: Alzheimer's Society, Funder: Dementia Research Centre, Funder: Medical Research Council, Funder: National Institute for Health Research University College London/Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: Alzheimer Foundation, Funder: Alzheimer's Society and Alzheimer's Research UK, Funder: Association for Frontotemporal Dementias Research Grant 2009, Funder: Brain Research UK, Funder: Dementia Research Institute Ltd, Funder: The Wolfson Foundation, Funder: UK Dementia Research Institute, Funder: UK Dementia Research Institute Ltd, Funder: Deaf People Dunhill Medical Trust Pauline Ashley Fellowship, Funder: Frontotemporal Dementia Research Studentships, Funder: Germany’s Federal Ministry of Education and Research, Funder: Miriam Marks Brain Research UK Senior Fellowship, Funder: Tau Consortium and the Center for Networked Biomedical Research, Funder: Mady Browaeys Fund for Research into Frontotemporal Dementia, Funder: Brain Foundation and Stockholm County Council ALF, Funder: Deutsche Forschungsgemeinschaft German Research Foundation under Germany’s Excellence Strategy, Funder: Alzheimer’s Research UK, Funder: Memory of David Blechner, Funder: Swedish FTD Inititative-Schörling Foundation, Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.
Published: 2023

32. Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort

Author: Bocchetta, Martina, Todd, Emily G, Bouzigues, Arabella, Cash, David M, Nicholas, Jennifer M, Convery, Rhian S, Russell, Lucy L, Thomas, David L, Malone, Ian B, Iglesias, Juan Eugenio, Van Swieten, John C, Jiskoot, Lize C, Seelaar, Harro, Borroni, Barbara, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, De Mendonca, Alexandre, Santana, Isabel, Butler, Chris R, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Bocchetta, Martina [0000-0003-1814-5024], Todd, Emily G [0000-0003-1551-5691], Cash, David M [0000-0001-7833-616X], Malone, Ian B [0000-0001-7512-7856], Jiskoot, Lize C [0000-0002-1120-1858], Seelaar, Harro [0000-0003-1989-7527], Borroni, Barbara [0000-0001-9340-9814], Sanchez-Valle, Raquel [0000-0001-7750-896X], Synofzik, Matthis [0000-0002-2280-7273], Graff, Caroline [0000-0002-9949-2951], Vandenberghe, Rik [0000-0001-6237-2502], Ducharme, Simon [0000-0002-7309-1113], Gerhard, Alexander [0000-0002-8071-6062], Danek, Adrian [0000-0001-8857-5383], Pasquier, Florence [0000-0001-9880-9788], Apollo - University of Cambridge Repository, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, and Balasa, Mircea
Subjects: Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, SDG 3 - Good Health and Well-being, brain volumetry, diffusion imaging, genetic frontotemporal dementia, MRI imaging, Medizin, presymptomatic stage, ddc:610, Biological Psychiatry
Abstract: Funder: Deutsche Forschungsgemeinschaft, Funder: Dementia Research Institute, Funder: Leonard Wolfson Experimental Neurology Centre, Funder: Canadian Institutes of Health Research, Funder: Medical Research Council, Funder: Miriam Marks Brain Research UK Senior Fellowship, Funder: Wolfson Foundation, Funder: Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie, Funder: NVIDIA, Funder: Alzheimer's Research UK, Funder: Alzheimer's Society and Alzheimer's Research, Funder: Brain Research UK, Funder: University College London, Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.
Published: 2023

33. Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Author: Finger, Elizabeth, Malik, Rubina, Bocchetta, Martina, Coleman, Kristy, Graff, Caroline, Borroni, Barbara, Masellis, Mario, Laforce, Robert, Greaves, Caroline V., Russell, Lucy L., Convery, Rhian S., Bouzigues, Arabella, Cash, David M., Otto, Markus, Synofzik, Matthis, Rowe, James B., Galimberti, Daniela, Tiraboschi, Pietro, Bartha, Robert, Shoesmith, Christen, Tartaglia, Maria Carmela, van Swieten, John C., Seelaar, Harro, Jiskoot, Lize C., Sorbi, Sandro, Butler, Chris R., Gerhard, Alexander, Sanchez-Valle, Raquel, De Mendonça, Alexandre, Moreno, Fermin, Vandenberghe, Rik, Le Ber, Isabelle, Levin, Johannes, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D., Ducharme, Simon, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L., Todd, Emily G., Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Genetic FTD Initiative, GENFI, the Genetic FTD Initiative (GENFI), Repositório da Universidade de Lisboa, Bocchetta, Martina [0000-0003-1814-5024], Graff, Caroline [0000-0002-9949-2951], Borroni, Barbara [0000-0001-9340-9814], Cash, David M [0000-0001-7833-616X], Synofzik, Matthis [0000-0002-2280-7273], Seelaar, Harro [0000-0003-1989-7527], Jiskoot, Lize C [0000-0002-8120-7366], Gerhard, Alexander [0000-0002-8071-6062], Sanchez-Valle, Raquel [0000-0001-7750-896X], Vandenberghe, Rik [0000-0001-6237-2502], Pasquier, Florence [0000-0001-9880-9788], Ducharme, Simon [0000-0002-7309-1113], Apollo - University of Cambridge Repository, Neurology, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L, Todd, Emily G, Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, and Borrego-Ecija, Sergi
Subjects: Adult, C9orf72 Protein, neurodevelopment, Nocturnal pulsed oximetry, Medizin, Brain, Neurodegenerative Diseases, tau Proteins, Amyotrophic lateral sclerosis, frontotemporal dementia, Phrenic nerve, Young Adult, Progranulins, Pick Disease of the Brain, Respiratory tests, Mutation, C9orf72, MAPT, Humans, ddc:610, Neurology (clinical), Human medicine, GRN, Respiratory function
Abstract: © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved., While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period., This project was supported by Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and by Canadian Institutes of Health Research operating grants (327387; 452843; 70797). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC), and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Alzheimer’s Society grant (AS-PG-16-007), the Bluefield Project and the EU Joint Programme – Neurodegenerative Disease Research (GENFI-PROX grant 2019-02248). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a- 004-517). M.B.’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). J.B.R. is funded by the Wellcome Trust (103838) and the National Institute for Health Research Cambridge Biomedical Research Centre. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). It is also funded by the Ministry of Health, Italy (S.S.). R.V.’s work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. R.S.-V.’s work is supported by Instituto de Salud Carlos III (grant number 20/00448), cofunded by the EU. ANR-PRTS PrevdemALS study funding (I.L.B.). Several authors of this publication (J.C.vS., M.S., A.D., M.O., R.V., I.L.B., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510.
Published: 2023

34. Altered levels of CSF proteins in patients with FTD, presymptomatic mutation carriers and non-carriers

Author: Remnestål, Julia, Öijerstedt, Linn, Ullgren, Abbe, Olofsson, Jennie, Bergström, Sofia, Kultima, Kim, Ingelsson, Martin, Kilander, Lena, Uhlén, Mathias, Månberg, Anna, Graff, Caroline, and Nilsson, Peter
Published: 2020
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35. Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia

Author: Whiteside, David J, Malpetti, Maura, Jones, P Simon, Ghosh, Boyd CP, Coyle‐Gilchrist, Ian, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize, Borroni, Barbara, Sanchez‐Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R, Santana, Isabel, Ber, Isabelle Le, Gerhard, Alexander, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Pasquier, Florence, Bouzigues, Arabella, Russell, Lucy L, Rohrer, Jonathan D, Rowe, James B, Rittman, Timothy, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang‐Wai, David, Rogaeva, Ekaterina, Castelo‐Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego‐Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa‐Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl‐Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas‐Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Whiteside, David [0000-0002-5890-9220], Apollo - University of Cambridge Repository, GENFI Consortium, Repositório da Universidade de Lisboa, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, and Neurology
Subjects: Epidemiology, FEATURED ARTICLE, Medizin, Clinical Neurology, NETWORK CONNECTIVITY, frontotemporal dementia, disease progression, functional magnetic resonance imaging (fMRI), network dynamics, presymptomatic, DISEASE, Cellular and Molecular Neuroscience, Developmental Neuroscience, SDG 3 - Good Health and Well-being, Humans, Cognitive Dysfunction, ddc:610, BRAIN, BATTERY, Science & Technology, Health Policy, Brain, FUNCTIONAL CONNECTIVITY, Magnetic Resonance Imaging, STATE, TIME, Psychiatry and Mental health, COMPENSATION, Frontotemporal Dementia, Mutation, FEATURED ARTICLES, Neurology (clinical), Human medicine, Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine
Abstract: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Introduction: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). Methods: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. Results: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. Discussion: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. Highlights: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline., GENFI was funded by the Medical Research Council UK (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (by DLR/BMBF 2019-02248) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). The study was co-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge (BRC-1215-20014), the Cambridge Centre for Parkinson-plus (RG95450); the Wellcome Trust (220258); the Evelyn Trust (17/09) and Medical Research Council (SUAG/092 116768).
Published: 2022

36. Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort

Author: Foster, Phoebe H, Russell, Lucy L, Moreno, Fermin, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Sanchez-Valle, Raquel, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Laforce, Robert, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Graff, Caroline, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Masellis, Mario, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Tartaglia, Carmela, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Rowe, James B, Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Peakman, Georgia, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R, Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tagliavini, Fabrizio, Santana, Isabel, Pasquier, Florence, Convery, Rhian S, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D, Initiative, Genetic FTD, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Bouzigues, Arabella, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Greaves, Caroline V, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Bocchetta, Martina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Cash, David M, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, van Swieten, John C, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, Jiskoot, Lize C, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Repositório da Universidade de Lisboa
Subjects: Empathic concern, Cognitive Neuroscience, Medizin, Empathy, Frontotemporal dementia, Interpersonal Reactivity Index, Perspective taking, C9orf72 Protein, Humans, Mutation, Progranulins, tau Proteins, Frontotemporal Dementia, Pick Disease of the Brain, Experimental and Cognitive Psychology, genetics [Progranulins], diagnosis [Frontotemporal Dementia], mental disorders, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], genetics [tau Proteins], Neuropsychology and Physiological Psychology
Abstract: © 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)., Background: Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD. Methods: Empathy was examined using a modified version of the Interpersonal Reactivity Index (mIRI) in 676 participants from the Genetic FTD Initiative: 216 mutation-negative controls, 192 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. Using global scores from the CDR® plus NACC FTLD, mutation carriers were divided into three groups, asymptomatic (0), very mildly symptomatic/prodromal (.5), or fully symptomatic (1 or more). The mIRI Total score, as well as the subscores of Empathic Concern (EC) and Perspective Taking (PT) were assessed. Linear regression models with bootstrapping were used to assess empathy ratings across genetic groups, as well as across phenotypes in the symptomatic carriers. Neural correlates of empathy deficits were examined using a voxel-based morphometry (VBM) analysis. Results: All fully symptomatic groups scored lower on the mIRI Total, EC, and PT when compared to controls and their asymptomatic or prodromal counterparts (all p < .001). Prodromal C9orf72 expansion carriers also scored significantly lower than controls on the mIRI Total score (p = .046). In the phenotype analysis, all groups (behavioural variant FTD, primary progressive aphasia and FTD with amyotrophic lateral sclerosis) scored significantly lower than controls (all p < .007). VBM revealed an overlapping neural correlate of the mIRI Total score across genetic groups in the orbitofrontal lobe but with additional involvement in the temporal lobe, insula and basal ganglia in both the GRN and MAPT groups, and uniquely more posterior regions such as the parietal lobe and thalamus in the GRN group, and medial temporal structures in the MAPT group. Conclusions: Significant empathy deficits present in genetic FTD, particularly in symptomatic individuals and those with a bvFTD phenotype, while prodromal deficits are only seen using the mIRI in C9orf72 expansion carriers., This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. RC/CG are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517). MB's work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JCVS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organisation for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). RS-V is supported by an Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2), and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). CG received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. MM has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. JBR has received funding from the Wellcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). EF has received funding from a CIHR grant #327387. DG received support from the EU Joint Programme – Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. MO has received funding from BMBF (FTLDc).
Published: 2022

37. An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers

Author: Premi, Enrico, Costa, Tommaso, Moreno, Fermin, Panman, Jessica, Papma, Janne, Pievani, Michela, Pijnenburg, Yolande, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers As London Ontario Geneticist, Rosa, Redaelli, Veronica, Rittman, Tim, Santana, Isabel, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Laforce, Robert, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, L Thomas, David, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Ducharme, Simon, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Graff, Caroline, Galimberti, Daniela, Masellis, Mario, Tartaglia, Carmela, Rowe, James B, Finger, Elizabeth, Gazzina, Stefano, Tagliavini, Fabrizio, de Mendonça, Alexandre, Vandenberghe, Rik, Gerhard, Alexander, Butler, Chris R, Danek, Adrian, Synofzik, Matthis, Levin, Johannes, Otto, Markus, Ghidoni, Roberta, Benussi, Alberto, Frisoni, Giovanni B, Sorbi, Sandro, Peakman, Georgia, Todd, Emily, Bocchetta, Martina, Rohrer, Johnathan D, Borroni, Barbara, Members, GENFI Consortium, Afonso, Sónia, Rosario Almeida, Maria, Cauda, Franco, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Gasparotti, Roberto, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Archetti, Silvana, Cope, Thomas, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, B Ferreira, Catarina, Fox, Nick, Freedman, Morris, Alberici, Antonella, Fumagalli, Giorgio, Gabilondo, Alazne, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, van Swieten, John C, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans Otto, Keren, Ron, Langheinrich, Tobias, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Sanchez-Valle, Raquel, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, GENFI Consortium Members, Neurology, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: genetics [Granulins], Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic, Atrophy, Brain, Granulins, Humans, Magnetic Resonance Imaging, Mutation, Progranulins, Frontotemporal Dementia, Medizin, genetics [Mutation], diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, genetics [Progranulins], methods [Magnetic Resonance Imaging], SDG 3 - Good Health and Well-being, pathology [Brain], Settore BIO/13 - Biologia Applicata, ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], pathology [Atrophy], Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic, General Neuroscience, General Medicine, Psychiatry and Mental health, Clinical Psychology, pathology [Frontotemporal Dementia], Geriatrics and Gerontology
Abstract: Background:Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives:To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods:84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results:Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion:The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. Swedish Frontotemporal Dementia Initiative Schörling Foundation; Swedish Research Council: JPND Prefrontals, 2015-02926 ,2018-02754; Swedish Alzheimer foundation; Swedish Brain Foundation; Karolinska Institutet Doctoral Funding; KI StratNeuro; Swedish Dementia foundation and Stockholm County Council ALF/Region Stockholm.
Published: 2022

38. Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Author: Bouzigues, Arabella, Russell, Lucy L, Tiraboschi, Pietro, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Masellis, Mario, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Tartaglia, Maria Carmela, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Finger, Elizabeth, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, van Swieten, John C, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Seelaar, Harro, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Peakman, Georgia, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Bocchetta, Martina, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Esteve, Aitana Sogorb, Nelson, Annabel, Greaves, Caroline V, Heller, Carolin, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Convery, Rhian S, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Rowe, James B, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Keren, Ron, Black, Sandra, Mitchell, Sara, Borroni, Barbara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Galimberti, Daniela, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Bouzigues, Arabella [0000-0002-0267-8590], Russell, Lucy L [0000-0001-5023-5893], Peakman, Georgia [0000-0002-3319-138X], Bocchetta, Martina [0000-0003-1814-5024], Greaves, Caroline V [0000-0002-6446-1960], Convery, Rhian S [0000-0002-9477-1812], Rowe, James B [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], van Swieten, John C [0000-0001-6278-6844], Levin, Johannes [0000-0001-5092-4306], Otto, Markus [0000-0002-6647-5944], Apollo - University of Cambridge Repository, Esteve, Aitana Sogorb (Beitragende*r), Nelson, Annabel (Beitragende*r), Heller, Carolin (Beitragende*r), Cash, David (Beitragende*r), Thomas, David L (Beitragende*r), Benotmane, Hanya (Beitragende*r), Zetterberg, Henrik (Beitragende*r), Swift, Imogen J (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Samra, Kiran (Beitragende*r), Shafei, Rachelle (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Cope, Thomas (Beitragende*r), Rittman, Timothy (Beitragende*r), Benussi, Alberto (Beitragende*r), Premi, Enrico (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Archetti, Silvana (Beitragende*r), Gazzina, Stefano (Beitragende*r), Cantoni, Valentina (Beitragende*r), Arighi, Andrea (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Scarpini, Elio (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Borracci, Vittoria (Beitragende*r), Rossi, Giacomina (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Caroppo, Paola (Beitragende*r), Prioni, Sara (Beitragende*r), Redaelli, Veronica (Beitragende*r), Tang-Wai, David (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Keren, Ron (Beitragende*r), Black, Sandra (Beitragende*r), Mitchell, Sara (Beitragende*r), Shoesmith, Christen (Beitragende*r), Bartha, Robart (Beitragende*r), Rademakers, Rosa (Beitragende*r), Poos, Jackie (Beitragende*r), Papma, Janne M (Beitragende*r), Giannini, Lucia (Beitragende*r), Minkelen, Rick (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Ferrari, Camilla (Beitragende*r), Polito, Cristina (Beitragende*r), Lombardi, Gemma (Beitragende*r), Bessi, Valentina (Beitragende*r), Veldsman, Michele (Beitragende*r), Andersson, Christin (Beitragende*r), Thonberg, Hakan (Beitragende*r), Öijerstedt, Linn (Beitragende*r), Jelic, Vesna (Beitragende*r), Thompson, Paul (Beitragende*r), Lladó, Albert (Beitragende*r), Antonell, Anna (Beitragende*r), Olives, Jaume (Beitragende*r), Balasa, Mircea (Beitragende*r), Bargalló, Nuria (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Verdelho, Ana (Beitragende*r), Maruta, Carolina (Beitragende*r), Ferreira, Catarina B (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), do Couto, Frederico Simões (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gorostidi, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Cañada, Marta (Beitragende*r), Tainta, Mikel (Beitragende*r), Zulaica, Miren (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Alves, Patricia (Beitragende*r), Bender, Benjamin (Beitragende*r), Wilke, Carlo (Beitragende*r), Graf, Lisa (Beitragende*r), Vogels, Annick (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Van Damme, Philip (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Poesen, Koen (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Gauthier, Serge (Beitragende*r), Camuzat, Agnès (Beitragende*r), Brice, Alexis (Beitragende*r), Bertrand, Anne (Beitragende*r), Funkiewiez, Aurélie (Beitragende*r), Rinaldi, Daisy (Beitragende*r), Saracino, Dario (Beitragende*r), Colliot, Olivier (Beitragende*r), Sayah, Sabrina (Beitragende*r), Prix, Catharina (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Wagemann, Olivia (Beitragende*r), Loosli, Sandra (Beitragende*r), Schönecker, Sonja (Beitragende*r), Hoegen, Tobias (Beitragende*r), Lombardi, Jolina (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Rollin, Adeline (Beitragende*r), Kuchcinski, Gregory (Beitragende*r), Bertoux, Maxime (Beitragende*r), Lebouvier, Thibaud (Beitragende*r), Deramecourt, Vincent (Beitragende*r), Santiago, Beatriz (Beitragende*r), Duro, Diana (Beitragende*r), Leitão, Maria João (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Afonso, Sónia (Beitragende*r), Engel, Annerose (Beitragende*r), Polyakova, Maryna (Beitragende*r), Repositório da Universidade de Lisboa, Genetic FTD Initiative, GENFI, and Neurology
Subjects: Progranulin, Clinical Neurology, Medizin, Anomia, tau Proteins, Naming, IMPAIRMENTS, VARIANTS, diagnostic imaging [Frontotemporal Dementia], genetics [Progranulins], Cognition, Progranulins, Settore BIO/13 - Biologia Applicata, complications [Frontotemporal Dementia], mental disorders, C9orf72, Humans, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Science & Technology, C9orf72 Protein, MORPHOMETRIC ANALYSES, ANATOMY, ALZHEIMERS-DISEASE, genetics [tau Proteins], Neurology, Frontotemporal Dementia, Mutation, PATTERNS, Frontotemporal dementia, Tau, Human medicine, Neurosciences & Neurology, Neurology (clinical), complications [Anomia], Life Sciences & Biomedicine, MRI
Abstract: Funder: Alzheimer’s Research UK; doi: http://dx.doi.org/10.13039/501100002283, Funder: UCLH Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012317, Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265, Funder: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Funder: Bluefield Project, INTRODUCTION: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail. METHODS: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis. RESULTS: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions. CONCLUSION: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.
Published: 2022

39. Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia

Author: Sogorb-Esteve, Aitana, Nilsson, Johanna, Borroni, Barbara, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, de Mendonça, Alexandre, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Galimberti, Daniela, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Sanchez-Valle, Raquel, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Laforce, Robert, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Moreno, Fermin, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Synofzik, Matthis, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Swift, Imogen J, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, Santana, Isabel, Butler, Chris R, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Heller, Carolin, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Gobom, Johan, Brinkmalm, Ann, Blennow, Kaj, Zetterberg, Henrik, Rohrer, Jonathan D, Initiative, GENetic FTD, Nelson, Annabel, Bocchetta, Martina, Bouzigues, Arabella, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Russell, Lucy L, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Peakman, Georgia, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Convery, Rhian S, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van Swieten, John C, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Seelaar, Harro, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Neurology, Amsterdam Neuroscience - Neurodegeneration, Clinical Genetics, GENetic FTD Initiative, Poesen, Koen, Van Damme, Philip, Bruffaerts, rose, Vandenbulcke, Mathieu, Vogels, ann, Bocchetta, Martina [0000-0003-1814-5024], and Apollo - University of Cambridge Repository
Subjects: Synaptic dysfunction, Cognitive Neuroscience, cerebrospinal fluid [gamma-Synuclein], Medizin, cerebrospinal fluid [Syntaxin 1], Syntaxin 1, genetics [Mutation], tau Proteins, cerebrospinal fluid [Frontotemporal Dementia], frontotemporal dementia, beta-Synuclein, gamma-Synuclein, Settore BIO/13 - Biologia Applicata, Humans, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, genetics [beta-Synuclein], genetics [Syntaxin 1], C9orf72 Protein, synaptic dysfunction, cerebrospinal fluid [C9orf72 Protein], Research, Biomarkers, Frontotemporal dementia, Mutation, Neurogranin, Frontotemporal Dementia, biomarkers, genetics [Neurogranin], genetics [tau Proteins], Neurology, cerebrospinal fluid [Biomarkers], genetics [gamma-Synuclein], Neurology (clinical), Human medicine, cerebrospinal fluid [Neurogranin]
Abstract: Background Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN, and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants, so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials. Methods A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14–3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Results CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14–3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14–3-3 zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for the C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset. Conclusions Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.
Published: 2022

40. Data‐driven staging of genetic frontotemporal dementia using multi‐modal <scp>MRI</scp>

Author: McCarthy, Jillian, Borroni, Barbara, Tartaglia, Maria Carmela, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne, Peakman, Georgia, Piaceri, Irene, Finger, Elizabeth, Pievani, Michela, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Rogaeva, Ekaterina, Vandenberghe, Rik, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, de Mendonça, Alexandre, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Vandamme, Philip, Tagliavini, Fabrizio, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Santana, Isabel, Butler, Chris, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Sanchez-Valle, Raquel, Otto, Markus, Frisoni, Giovanni B, Ghidoni, Roberta, Sorbi, Sandro, Jiskoot, Lize C, Seelaar, Harro, van Swieten, John C, Rohrer, Jonathan D, Iturria-Medina, Yasser, Ducharme, Simon, Moreno, Fermin, Initiative, GENetic Frontotemporal Dementia, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Laforce, Robert, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Graff, Caroline, Bras, Jose, Bruffaerts, Rose, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Cosseddu, Maura, Synofzik, Matthis, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Carlos, Ferreira, Catarina B, Flanagan, Toby, Galimberti, Daniela, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Rowe, James B, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, Keren, Ron, Langheinrich, Tobias, Leitão, Maria João, Lladó, Albert, Masellis, Mario, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina M, Nacmias, Benedetta, Repositório da Universidade de Lisboa, Neurology, Amsterdam Neuroscience - Neurodegeneration, McCarthy, Jillian [0000-0002-9285-0023], Borroni, Barbara [0000-0001-9340-9814], Apollo - University of Cambridge Repository, GENetic Frontotemporal Dementia Initiative (GENFI), Clinical Genetics, and Clinical Psychology
Subjects: disease progression, frontotemporal dementia, magnetic resonance imaging, unsupervised machine learning, BIOMARKER, Heterozygote, Medizin, Neuroimaging, diagnostic imaging [Frontotemporal Dementia], Magnetic resonance imaging, SDG 3 - Good Health and Well-being, HARMONIZATION, Settore BIO/13 - Biologia Applicata, NEUROFILAMENT LIGHT-CHAIN, BEHAVIORAL VARIANT, CRITERIA, Humans, Radiology, Nuclear Medicine and imaging, ddc:610, Cross-Sectional Studies, Language, Magnetic Resonance Imaging, Frontotemporal Dementia, genetics [Frontotemporal Dementia], Unsupervised machine learning, Disease progression, Science & Technology, Radiological and Ultrasound Technology, Radiology, Nuclear Medicine & Medical Imaging, Neurosciences, DEGENERATION, DIFFUSION, psychology [Frontotemporal Dementia], Neurology, GRAY-MATTER ATROPHY, Neurosciences & Neurology, Neurology (clinical), Anatomy, Life Sciences & Biomedicine, GENFI, CLINICAL-TRIALS, Frontotemporal dementia
Abstract: Funder: Fondation Brain Canada; Id: http://dx.doi.org/10.13039/100009408, Funder: Fonds de Recherche du Québec ‐ Santé; Id: http://dx.doi.org/10.13039/501100000156, Funder: Health Canada; Id: http://dx.doi.org/10.13039/501100000008, Funder: Brain Canada Foundation; Id: http://dx.doi.org/10.13039/100009408, Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.
Published: 2022

41. Cognitive composites for genetic frontotemporal dementia: GENFI-Cog

Author: Poos, Jackie M, Moore, Katrina M, Seelaar, Harro, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B, Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Pijnenburg, Yolande A L, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Duro, Diana, Almeida, Maria Rosario, Castelo-Branco, Miguel, Leitão, Maria João, Tabuas-Pereira, Miguel, Santiago, Beatriz, Moreno, Fermin, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Thompson, Paul, Langheinrich, Tobias, Prix, Catharina, Hoegen, Tobias, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Sanchez-Valle, Raquel, Anderl-Straub, Sarah, Lombardi, Jolina, Bargalló, Nuria, Benussi, Alberto, Cantoni, Valentina, Bertoux, Maxime, Bertrand, Anne, Brice, Alexis, Camuzat, Agnès, Colliot, Olivier, Borroni, Barbara, Sayah, Sabrina, Funkiewiez, Aurélie, Rinaldi, Daisy, Lombardi, Gemma, Nacmias, Benedetta, Saracino, Dario, Bessi, Valentina, Ferrari, Camilla, Cañada, Marta, Deramecourt, Vincent, Laforce, Robert, Kuchcinski, Gregory, Lebouvier, Thibaud, Ourselin, Sebastien, Polito, Cristina, Rollin, Adeline, Masellis, Mario, Tartaglia, Carmela, Graff, Caroline, Galimberti, Daniela, Nicholas, Jennifer, Rowe, James B, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tiraboschi, Pietro, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alexander, Russell, Lucy L, Levin, Johannes, Danek, Adrian, Otto, Markus, Le Ber, Isabel, Pasquier, Florence, van Swieten, John C, Rohrer, Jonathan D, Initiative, Genetic FTD, Bouzigues, Arabella, Rossor, Martin N, Peakman, Georgia, Fox, Nick C, Warren, Jason D, Bocchetta, Martina, Swift, Imogen J, Shafei, Rachelle, Heller, Carolin, Todd, Emily, Cash, David, Woollacott, Ione, Zetterberg, Henrik, Convery, Rhian S, Nelson, Annabel, Guerreiro, Rita, Bras, Jose, Thomas, David L, Mead, Simon, Meeter, Lieke, Panman, Jessica, van Minkelen, Rick, Barandiaran, Myriam, Indakoetxea, Begoña, Jiskoot, Lize C, Gabilondo, Alazne, Tainta, Mikel, Gorostidi, Ana, Zulaica, Miren, Díez, Alina, Villanua, Jorge, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, van der Ende, Emma, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Gazzina, Stefano, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, van den Berg, Esther, Keren, Ron, Tang-Wai, David, Thonberg, Hakan, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Papma, Janne M, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnarth, Hans-Otto, Bender, Benjamin, Bruffaerts, Rose, Neurology, Amsterdam Neuroscience - Neurodegeneration, Medical Research Council, Clinical Genetics, Rowe, James [0000-0001-7216-8679], Rohrer, Jonathan D [0000-0002-6155-8417], and Apollo - University of Cambridge Repository
Subjects: PROGRESSION, Neuropsychological Tests, Composite score, Genetic FTD Initiative (GENFI), diagnosis [Frontotemporal Dementia], Cognition, CRITERIA, Attention, genetics [Frontotemporal Dementia], 11 Medical and Health Sciences, Language, Executive function, Frontotemporal dementia, Memory, Neuropsychology, Social cognition, Humans, Mutation, Prodromal Symptoms, Sample Size, tau Proteins, Frontotemporal Dementia, CARRIERS, Neurology, Psychology, Life Sciences & Biomedicine, CLINICAL-TRIALS, RC321-571, medicine.medical_specialty, Cognitive Neuroscience, Clinical Neurology, genetics [Mutation], Neurosciences. Biological psychiatry. Neuropsychiatry, Physical medicine and rehabilitation, Cog, mental disorders, medicine, ddc:610, RC346-429, Science & Technology, Research, Neurosciences, medicine.disease, genetics [tau Proteins], Neurosciences & Neurology, Neurology (clinical), Neurology. Diseases of the nervous system
Abstract: Funder: Alzheimer's Research UK, Funder: Alzheimer's Society, Funder: Brain Research UK, Funder: the Wolfson Foundation, Funder: NIHR UCL/H Biomedical Research Centre, Funder: Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: UK Dementia Research Institute, Funder: UK Medical Research Council, Funder: Bluefield project, Funder: the Association for Frontotemporal Dementias Research Grant 2009, BACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR�� plus NACC-FTLD �� 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR�� plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR�� plus NACC-FTLD �� 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR�� plus NACC-FTLD = 0.5 to �� 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR�� plus NACC-FTLD 0.5 to �� 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR�� plus NACC FTLD 0.5 to �� 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
Published: 2022

42. Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

Author: van der Ende, Emma L, Heller, Carolin, Papma, Janne M, Maruta, Carolina, Mead, Simon, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Meeter, Lieke H, Ourselin, Sebastien, Padovani, Alessandro, Peakman, Georgia, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Dopper, Elise G P, Rittman, Tim, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rosser, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Bocchetta, Martina, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Cash, David, Zulaica, Miren, Graff, Caroline, Synofzik, Matthis, Moreno, Fermin, Finger, Elizabeth, Sogorb-Esteve, Aitana, Sanchez-Valle, Raquel, Vandenberghe, Rik, Laforce, Robert, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Butler, Chris, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Swift, Imogen J, Levin, Johannes, Pijnenburg, Yolande A L, Otto, Markus, Borroni, Barbara, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Galimberti, Daniela, Sorbi, Sandro, Zetterberg, Henrik, McFall, David, Huang, Eric, van Swieten, John C, Rohrer, Jonathan D, Seelaar, Harro, Initiative, Genetic Frontotemporal Dementia, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Benussi, Luisa, Bessi, Valentina, Bouzigues, Arabella, Binetti, Giuliano, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Poos, Jackie M, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Jiskoot, Lize C, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Panman, Jessica L, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Langheinrich, Tobias, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Apollo - University of Cambridge Repository, Levin, Johannes [0000-0001-5092-4306], Repositório da Universidade de Lisboa, Genetic Frontotemporal Dementia Initiative (GENFI), Neurology, Erasmus MC other, Clinical Psychology, and Amsterdam Neuroscience - Neurodegeneration
Subjects: Biomarker, Complement, Frontotemporal dementia, Neuroinflammation, Immunology, Medizin, diagnostic imaging [Frontotemporal Dementia], Cohort Studies, Cellular and Molecular Neuroscience, CEREBROSPINAL-FLUID, Pick Disease of the Brain, Settore BIO/13 - Biologia Applicata, CRITERIA, Humans, ddc:610, C3, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Science & Technology, C9orf72 Protein, General Neuroscience, Complement C1q, Research, Neurosciences, Biomarkers, Complement System Proteins, Frontotemporal Dementia, ALZHEIMERS-DISEASE, Neurology, CHAIN, Neurosciences & Neurology, Human medicine, genetics [Complement System Proteins], Life Sciences & Biomedicine
Abstract: Funder: The Bluefield Project, Funder: UK Dementia Research Institute; doi: http://dx.doi.org/10.13039/501100017510, Funder: Alzheimer's Society; doi: http://dx.doi.org/10.13039/501100000320, Funder: schorling foundation, Funder: Swedish brain foundation, Funder: swedish alzheimer foundation, Funder: Stockholm Council ALF, Funder: Demensfonden; doi: http://dx.doi.org/10.13039/501100021594, Funder: Gun och Bertil Stohnes Stiftelse; doi: http://dx.doi.org/10.13039/100009673, Funder: Stiftelsen för Gamla Tjänarinnor; doi: http://dx.doi.org/10.13039/100010815, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Stratneuro, Funder: Mady Browaeys Fonds, Funder: Knut och Alice Wallenbergs Stiftelse; doi: http://dx.doi.org/10.13039/501100004063, BACKGROUND: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. METHODS: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). RESULTS: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. CONCLUSIONS: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.
Published: 2022

43. Confirmation of high frequency of C9orf72 mutations in patients with frontotemporal dementia from Sweden

Author: Öijerstedt, Linn, Chiang, Huei-Hsin, Björkström, Jenny, Forsell, Charlotte, Lilius, Lena, Lindström, Anna-Karin, Thonberg, Håkan, and Graff, Caroline
Published: 2019
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44. Practice effects in genetic frontotemporal dementia and at-risk individuals: a GENFI study

Author: Öijerstedt, Linn, Andersson, Christin, Synofzik, Matthis, Peakman, Georgia, Pievani, Michela, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Galimberti, Daniela, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Rowe, James Benedict, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Håkan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Masellis, Mario, Damme, Philip Van, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Tartaglia, Maria Carmela, Zulaica, Miren, Finger, Elizabeth, Vandenberghe, Rik, de Mendonca, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Jelic, Vesna, Ducharme, Simon, Butler, Christopher R, Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Frisoni, Giovanni B, Ghidoni, Roberta, Sorbi, Sandro, Rohrer, Jonathan Daniel, van Swieten, John Cornelis, Graff, Caroline, Initiative, Genetic Frontotemporal Dementia, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Jiskoot, Lize C, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Seelaar, Harro, Bras, Jose, Bruffaerts, Rose, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Fede, Giuseppe Di, Borroni, Barbara, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Sanchez-Valle, Raquel, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Karnath, Hans Otto, Moreno, Fermin, Keren, Ron, Langheinrich, Tobias, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Laforce, Robert, Minkelen, Rick van, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nicholas, Jennifer, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Öijerstedt, Linn [0000-0003-0635-6377], van Swieten, John Cornelis [0000-0001-6278-6844], Jiskoot, Lize C [0000-0002-1120-1858], Seelaar, Harro [0000-0003-1989-7527], Borroni, Barbara [0000-0001-9340-9814], Galimberti, Daniela [0000-0002-9284-5953], Rowe, James Benedict [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], Ducharme, Simon [0000-0002-7309-1113], Gerhard, Alexander [0000-0002-8071-6062], Danek, Adrian [0000-0001-8857-5383], Otto, Markus [0000-0002-6647-5944], Sorbi, Sandro [0000-0002-0380-6670], Rohrer, Jonathan Daniel [0000-0002-6155-8417], and Apollo - University of Cambridge Repository
Subjects: C9orf72 Protein, physiology [Cognition], Neuropsychological Tests, frontotemporal dementia, psychology [Frontotemporal Dementia], Cognition, Practice, Psychological, Frontotemporal Dementia, Mutation, Humans, ddc:610, C9ORF, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia]
Published: 2022

45. Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

Author: Gazzina, Stefano, primary, Grassi, Mario, additional, Premi, Enrico, additional, Alberici, Antonella, additional, Benussi, Alberto, additional, Archetti, Silvana, additional, Gasparotti, Roberto, additional, Bocchetta, Martina, additional, Cash, David M., additional, Todd, Emily G., additional, Peakman, Georgia, additional, Convery, Rhian S., additional, van Swieten, John C., additional, Jiskoot, Lize C., additional, Seelaar, Harro, additional, Sanchez-Valle, Raquel, additional, Moreno, Fermin, additional, Laforce, Robert, additional, Graff, Caroline, additional, Synofzik, Matthis, additional, Galimberti, Daniela, additional, Rowe, James B., additional, Masellis, Mario, additional, Tartaglia, Maria Carmela, additional, Finger, Elizabeth, additional, Vandenberghe, Rik, additional, de Mendonça, Alexandre, additional, Tagliavini, Fabrizio, additional, Butler, Chris R., additional, Santana, Isabel, additional, Gerhard, Alexander, additional, Ber, Isabelle Le, additional, Pasquier, Florence, additional, Ducharme, Simon, additional, Levin, Johannes, additional, Danek, Adrian, additional, Sorbi, Sandro, additional, Otto, Markus, additional, Rohrer, Jonathan D., additional, Borroni, Barbara, additional, Afonso, Sónia, additional, Almeida, Maria Rosario, additional, Andersson, Christin, additional, Antonell, Anna, additional, Arighi, Andrea, additional, Balasa, Mircea, additional, Barandiaran, Myriam, additional, Bargalló, Nuria, additional, Bartha, Robart, additional, Bender, Benjamin, additional, Bertoux, Maxime, additional, Bertrand, Anne, additional, Bessi, Valentina, additional, Black, Sandra, additional, Borrego-Ecija, Sergi, additional, Bouzigues, Arabella, additional, Bras, Jose, additional, Brice, Alexis, additional, Bruffaerts, Rose, additional, Camuzat, Agnès, additional, Cañada, Marta, additional, Cantoni, Valentina, additional, Caroppo, Paola, additional, Castelo-Branco, Miguel, additional, Colliot, Olivier, additional, Cope, Thomas, additional, Deramecourt, Vincent, additional, Fede, Giuseppe Di, additional, Díez, Alina, additional, Duro, Diana, additional, Fenoglio, Chiara, additional, Ferrari, Camilla, additional, Ferreira, Catarina B., additional, Fox, Nick, additional, Freedman, Morris, additional, Fumagalli, Giorgio, additional, Funkiewiez, Aurélie, additional, Gabilondo, Alazne, additional, Gauthier, Serge, additional, Giaccone, Giorgio, additional, Gorostidi, Ana, additional, Greaves, Caroline, additional, Guerreiro, Rita, additional, Heller, Carolin, additional, Hoegen, Tobias, additional, Indakoetxea, Begoña, additional, Jelic, Vesna, additional, Karnath, Hans-Otto, additional, Keren, Ron, additional, Kuchcinski, Gregory, additional, Langheinrich, Tobias, additional, Lebouvier, Thibaud, additional, Leitão, Maria João, additional, Lladó, Albert, additional, Lombardi, Gemma, additional, Lombardi, Jolina, additional, Loosli, Sandra, additional, Maruta, Carolina, additional, Mead, Simon, additional, Meeter, Lieke, additional, Miltenberger, Gabriel, additional, van Minkelen, Rick, additional, Mitchell, Sara, additional, Moore, Katrina, additional, Nacmias, Benedetta, additional, Nelson, Annabel, additional, Nicholas, Jennifer, additional, Öijerstedt, Linn, additional, Olives, Jaume, additional, Ourselin, Sebastien, additional, Panman, Jessica, additional, Papma, Janne M., additional, Pijnenburg, Yolande, additional, Polito, Cristina, additional, Prioni, Sara, additional, Prix, Catharina, additional, Rademakers, Rosa, additional, Redaelli, Veronica, additional, Rinaldi, Daisy, additional, Rittman, Tim, additional, Rogaeva, Ekaterina, additional, Rollin, Adeline, additional, Rosa-Neto, Pedro, additional, Rossi, Giacomina, additional, Rossor, Martin, additional, Santiago, Beatriz, additional, Saracino, Dario, additional, Sayah, Sabrina, additional, Scarpini, Elio, additional, Schönecker, Sonja, additional, Shafei, Rachelle, additional, Shoesmith, Christen, additional, Swift, Imogen, additional, Tábuas-Pereira, Miguel, additional, Tainta, Mikel, additional, Taipa, Ricardo, additional, Tang-Wai, David, additional, Thomas, David L, additional, Thompson, Paul, additional, Thonberg, Hakan, additional, Timberlake, Carolyn, additional, Tiraboschi, Pietro, additional, Van Damme, Philip, additional, Vandenbulcke, Mathieu, additional, Veldsman, Michele, additional, Verdelho, Ana, additional, Villanua, Jorge, additional, Warren, Jason, additional, Wilke, Carlo, additional, Woollacott, Ione, additional, Wlasich, Elisabeth, additional, Zetterberg, Henrik, additional, and Zulaica, Miren, additional
Published: 2022
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46. Comparison of arterial spin labeling registration strategies in the multi‐center GENetic frontotemporal dementia initiative (GENFI)

Author: Mutsaerts, Henri J.M.M., Petr, Jan, Thomas, David L., De Vita, Enrico, Cash, David M., van Osch, Matthias J.P., Golay, Xavier, Groot, Paul F.C., Ourselin, Sebastien, van Swieten, John, Laforce, Robert, Jr, Tagliavini, Fabrizio, Borroni, Barbara, Galimberti, Daniela, Rowe, James B., Graff, Caroline, Pizzini, Francesca B., Finger, Elizabeth, Sorbi, Sandro, Castelo Branco, Miguel, Rohrer, Jonathan D., Masellis, Mario, MacIntosh, Bradley J., Rossor, Martin, Fox, Nick, Warren, Jason, Bocchetta, Martina, Dick, Katrina, Pievani, Michela, Ghidoni, Roberta, Benussi, Luisa, Padovani, Alessandro, Cosseddu, Maura, Mendonça, Alexandre, Frisoni, Giovanni, Premi, Enrico, Archetti, Silvana, Scarpini, Elio, Fumagalli, Giorgio, Arighi, Andrea, Fenoglio, Chiara, Prioni, Sara, Redaelii, Veronica, Grisoli, Marina, Tiraboschi, Pietro, Black, Sandra, Rogaeva, Ekaterina, Freedman, Morris, Tartaglia, Maria Carmela, Tang‐Wai, David, Keren, Ron, Panman, Jessica, Meeter, Lieke, Jiskoot, Lize, van Minkelen, Rick, Lombardi, Gemma, Polito, Cristina, Nacmias, Benedetta, Jelic, Vesna, Andersson, Christin, Öijerstedt, Linn, Fallström, Marie, Thonberg, Hakan, Verdelho, Ana, and Maruta, Carolina
Published: 2018
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47. Corrigendum to “Dissemination in time and space in presymptomatic granulin mutation carriers: A spatial chronnectome study” [Neurobiology of Aging Volume 108, December 2021, Pages 155–167]

Author: Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bouzigues, Arabella, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Lombardi, Jolina, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Premi, Enrico, Giunta, Marcello, Iraji, Armin, Rachakonda, Srinivas, Calhoun, VinceD., Gazzina, Stefano, Benussi, Alberto, Gasparotti, Roberto, Archetti, Silvana, Bocchetta, Martina, Cash, Dave, Todd, Emily, Peakman, Georgia, Convery, Rhian, van Swieten, John C., Jiskoot, Lize, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, JamesB., Masellis, Mario, Tartaglia, Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R., Santana, Isabel, Gerhard, Alexander, Ber, Isabelle Le, Pasquier, Florence, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Sorbi, Sandro, Otto, Markus, Rohrer, Jonathan D., and Borroni, Barbara
Published: 2022
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48. The CBI-R detects early behavioural impairment in genetic frontotemporal dementia

Author: Nelson, Annabel, Russell, Lucy L., Moreno, Fermin, Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Sanchez-Valle, Raquel, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Laforce, Robert, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Graff, Caroline, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Masellis, Mario, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Tartaglia, Maria Carmela, Warren, Jason, Wilke, Carlo, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Peakman, Georgia, Galimberti, Daniela, Vandenberghe, Rik, Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Convery, Rhian S., Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Bouzigues, Arabella, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Greaves, Caroline V., Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Cash, David M., Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Swieten, John C., Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, Keren, Ron, Kuchcinski, Gregory, Jiskoot, Lize, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Neurology, Clinical Genetics, Genetic FTD Initiative (GENFI), Russell, Lucy L [0000-0001-5023-5893], Bocchetta, Martina [0000-0003-1814-5024], Sanchez-Valle, Raquel [0000-0001-7750-896X], Laforce, Robert [0000-0002-2031-490X], Borroni, Barbara [0000-0001-9340-9814], Finger, Elizabeth [0000-0003-4461-7427], Synofzik, Matthis [0000-0002-2280-7273], Galimberti, Daniela [0000-0002-9284-5953], Ducharme, Simon [0000-0002-7309-1113], Le Ber, Isabelle [0000-0002-2508-5181], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, and Amsterdam Neuroscience - Neurodegeneration
Subjects: FUNCTIONAL BRAIN CONNECTIVITY, Clinical Neurology, Medizin, PROGRESSION, tau Proteins, C9orf72 Protein, Humans, Progranulins, Frontotemporal Dementia, Pick Disease of the Brain, ATROPHY, genetics [Progranulins], diagnosis [Frontotemporal Dementia], mental disorders, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Research Articles, Science & Technology, HEXANUCLEOTIDE REPEAT, MUTATIONS, General Neuroscience, TEMPORAL VARIANT, Neurosciences, genetics [tau Proteins], Neurosciences & Neurology, Neurology (clinical), TAU, FTLD, Life Sciences & Biomedicine, Research Article
Abstract: Funder: UK Dementia Research Institute, Funder: NIHR UCL/H Biomedical Research Centre, Funder: The Wolfson Foundation, Funder: Brain Research UK; Id: http://dx.doi.org/10.13039/100013790, Funder: Alzheimer’s Research UK; Id: http://dx.doi.org/10.13039/501100002283, INTRODUCTION: Behavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present. METHODS: We assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI-R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non-mutation carriers (controls). All mutation carriers were stratified according to their global CDR plus NACC FTLD score into three groups: asymptomatic (CDR = 0), prodromal (CDR = 0.5) and symptomatic (CDR = 1+). Mixed-effects models adjusted for age, education, sex and family clustering were used to compare between the groups. Neuroanatomical correlates of the individual domains were assessed within each genetic group. RESULTS: CBI-R total scores were significantly higher in all CDR 1+ mutation carrier groups compared with controls [C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)] as well as their respective CDR 0.5 groups [C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)] and CDR 0 groups [C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)]. The C9orf72 and GRN 0.5 groups scored significantly higher than the controls. The greatest impairment was seen in the Motivation domain for the C9orf72 and GRN symptomatic groups, whilst in the symptomatic MAPTgroup, the highest-scoring domains were Stereotypic and Motor Behaviours and Memory and Orientation. Neural correlates of each CBI-R domain largely overlapped across the different mutation carrier groups. CONCLUSIONS: The CBI-R detects early behavioural change in genetic FTD, suggesting that it could be a useful measure within future clinical trials.
Published: 2022

49. Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Author: Wilson, Katherine M, Katona, Eszter, Knowles, Kathryn, Lebouvier, Thibaud, Leitão, Maria João, Levin, Johannes, Lladó, Albert, Lombardi, Gemma, Lombardi, Jolina, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Miltenberger, Gabriel, Patil, Saurabh, Minkelen, Rick van, Mitchell, Sara, Moreno, Fermin, Nacmias, Benedetta, Nelson, Annabel, Nicholas, Jennifer, Öijerstedt, Linn, Papma, Janne M, Pasquier, Florence, Peakman, Georgia, Mohapatra, Susovan, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Liu, Yuanjing, Rossi, Giacomina, Rossor, Martin, Santana, Isabel, Santiago, Beatriz, Saracino, Dario, Scarpini, Elio, Schönecker, Sonja, Shafei, Rachelle, Shoesmith, Christen, Sorbi, Sandro, Goyal, Jaya, Tábuas-Pereira, Miguel, Tagliavini, Fabrizio, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Sanchez-Valle, Raquel, Damme, Philip Van, Vandenbulcke, Mathieu, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Wlasich, Elisabeth, Zulaica, Miren, Laforce, Robert Jr, Synofzik, Matthis, Rowe, James B, Finger, Elizabeth, Glaria, Idoia, Vandenberghe, Rik, Butler, Christopher R, Gerhard, Alexander, Van Swieten, John C, Seelaar, Harro, Borroni, Barbara, Galimberti, Daniela, de Mendonça, Alexandre, Masellis, Mario, Tartaglia, M Carmela, Carcolé, Mireia, Otto, Markus, Graff, Caroline, Ducharme, Simon, Schott, Jonathan M, Malaspina, Andrea, Zetterberg, Henrik, Boyanapalli, Ramakrishna, Rohrer, Jonathan D, Isaacs, Adrian M, Initiative, Genetic FTD, Swift, Imogen J, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Sogorb-Esteve, Aitana, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Heller, Carolin, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Convery, Rhian, Bouzigues, Arabella, Cope, Thomas, Danek, Adrian, Deramecourt, Vincent, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Heslegrave, Amanda J, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Graf, Lisa, Keshavan, Ashvini, Greaves, Caroline, Guerreiro, Rita, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Ber, Isabelle Le, and Neurology
Subjects: Frontotemporal dementia, motor disease, Biomarkers, C9orf72 Protein, DNA Repeat Expansion, Humans, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia, C9ORF72 EXPANSION, PROTEINS, SENSE, Medizin, diagnosis [Amyotrophic Lateral Sclerosis], genetics [DNA Repeat Expansion], Clinical Neurology, FRONTOTEMPORAL DEMENTIA, MOTOR NEURON DISEASE, DIAGNOSIS, TOXICITY, diagnosis [Frontotemporal Dementia], SDG 3 - Good Health and Well-being, ddc:150, Settore BIO/13 - Biologia Applicata, CRITERIA, ddc:610, Motor neuron disease, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Frontotemporale Demenz, Psychiatry, Science & Technology, HEXANUCLEOTIDE REPEAT, DDC 150 / Psychology, ANTISENSE TRANSCRIPTS, Myatrophische Lateralsklerose, Biomarker, Motoneuron, genetics [Amyotrophic Lateral Sclerosis], Psychiatry and Mental health, Cerebrospinal fluid, cerebrospinal fluid [Biomarkers], RNA FOCI, metabolism [Frontotemporal Dementia], cerebrospinal fluid [Amyotrophic Lateral Sclerosis], Surgery, Neurosciences & Neurology, Neurology (clinical), ALS, Life Sciences & Biomedicine, DDC 610 / Medicine & health
Abstract: ObjectiveA GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay.MethodsWe used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS.Results and conclusionsWe show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze–thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts., publishedVersion
Published: 2022

50. Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia

Author: Shafiei, Golia, Bazinet, Vincent, Dadar, Mahsa, Manera, Ana L., Collins, D. Louis, Dagher, Alain, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B., Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Butler, Chris, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Jiskoot, Lize C., Seelaar, Harro, van Swieten, John C., Rohrer, Jonathan D., Misic, Bratislav, Ducharme, Simon, Rosen, Howard, Dickerson, Bradford C., Domoto-Reilly, Kimoko, Knopman, David, Boeve, Bradley F., Boxer, Adam L., Kornak, John, Miller, Bruce L., Seeley, William W., Gorno-Tempini, Maria-Luisa, McGinnis, Scott, Mandelli, Maria Luisa, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V., Cash, David, Thomas, David L., Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L., Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S., Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van Der Ende, Emma, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Fede, Giuseppe Di, do Couto, Frederico Simões, Shafiei, Golia [0000-0002-2036-5571], Dadar, Mahsa [0000-0003-4008-2672], Collins, D Louis [0000-0002-8432-7021], Dagher, Alain [0000-0002-0945-5779], Sanchez-Valle, Raquel [0000-0001-7750-896X], Graff, Caroline [0000-0002-9949-2951], Synofzik, Matthis [0000-0002-2280-7273], Masellis, Mario [0000-0002-6244-2096], Jiskoot, Lize C [0000-0002-8120-7366], Seelaar, Harro [0000-0003-1989-7527], Misic, Bratislav [0000-0003-0307-2862], Ducharme, Simon [0000-0002-7309-1113], and Apollo - University of Cambridge Repository
Subjects: Aging, connectome, disease epicentre, frontotemporal dementia, gene expression, network spreading, GENetic Frontotemporal dementia Initiative, Medizin, Neurodegenerative, Neuropsychological Tests, Alzheimer's Disease, diagnostic imaging [Frontotemporal Dementia], Medical and Health Sciences, Pick Disease of the Brain, Settore BIO/13 - Biologia Applicata, pathology [Brain], Frontotemporal Lobar Degeneration Neuroimaging Initiative, Acquired Cognitive Impairment, Connectome, 2.1 Biological and endogenous factors, Humans, ddc:610, Aetiology, genetics [Frontotemporal Dementia], pathology [Atrophy], Neurology & Neurosurgery, Psychology and Cognitive Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain, Magnetic Resonance Imaging, Brain Disorders, Frontotemporal Dementia (FTD), pathology [Pick Disease of the Brain], Neurological, pathology [Frontotemporal Dementia], Dementia, Neurology (clinical), Atrophy, Transcriptome
Abstract: Copyright © The Author(s) 2022. Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome. Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative. B.M. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant RGPIN #017-04265) and from the Canada Research Chairs Program. S.D. receives salary support from the Fonds de Recherche du Québec—Santé (FRQS). G.S. acknowledges support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Fonds de recherche du Québec—Nature et Technologies (FRQNT). V.B. acknowledges support from the Fonds de recherche du Québec—Nature et Technologies (FRQNT). FTLDNI data collection and sharing was funded by the Frontotemporal Lobar Degeneration Neuroimaging Initiative (National Institutes of Health Grant R01 AG032306) and is coordinated through the University of California, San Francisco, Memory and Aging Center. FTLDNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.
Published: 2022

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