Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

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

Research output: Contribution to journalArticle

Abstract

Background: Frontotemporal 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. Methods: In 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. Findings: Data 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. Interpretation: Our 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. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.

Original languageEnglish (US)
Pages (from-to)145-156
Number of pages12
JournalThe Lancet Neurology
Volume19
Issue number2
DOIs
StatePublished - Feb 2020

ASJC Scopus subject areas

  • Clinical Neurology

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    Moore, K. M., Nicholas, J., Grossman, M., McMillan, C. T., Irwin, D. J., Massimo, L., Van Deerlin, V. M., Warren, J. D., Fox, N. C., Rossor, M. N., Mead, S., Bocchetta, M., Boeve, B. F., Knopman, D. S., Graff-Radford, N. R., Forsberg, L. K., Rademakers, R., Wszolek, Z. K., van Swieten, J. C., ... Geschwind, D. (2020). Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. The Lancet Neurology, 19(2), 145-156. https://doi.org/10.1016/S1474-4422(19)30394-1