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

Katrina Moore Jennifer Nicholas 1 Murray Grossman 2 Corey Mcmillan 2 David Irwin 2 Lauren Massimo 2 Vivianna van Deerlin 2 Jason Warren 3 Nick Fox Martin Rossor 3 Simon Mead Martina Bocchetta Bradley Boeve David Knopman 4 Neill Graff-Radford 5 Leah Forsberg Rosa Rademakers 5 Zbigniew Wszolek 6 John van Swieten 7 Lize Jiskoot 7 Lieke Meeter 7 Elise Gp Dopper Janne Papma Julie Snowden 8 Jennifer Saxon Matthew Jones Stuart Pickering-Brown Isabelle Le Ber 9 Agnès Camuzat 9 Alexis Brice 10 Paola Caroppo 11 Roberta Ghidoni Michela Pievani 12 Luisa Benussi Giuliano Binetti Bradford Dickerson Diane Lucente Samantha Krivensky Caroline Graff 13 Linn Öijerstedt Marie Fallström Hakan Thonberg 13 Nupur Ghoshal John Morris Barbara Borroni 14 Alberto Benussi Alessandro Padovani 15 Daniela Galimberti 16 Elio Scarpini 17 Giorgio Fumagalli 17 Ian Mackenzie Ging-Yuek Hsiung Pheth Sengdy Adam Boxer Howie Rosen Joanne Taylor Matthis Synofzik 18 Carlo Wilke Patricia Sulzer John Hodges Glenda Halliday 19 John Kwok Raquel Sanchez-Valle Albert Lladó Sergi Borrego-Ecija Isabel Santana Maria Rosário Almeida 20 Miguel Tábuas-Pereira Fermin Moreno Myriam Barandiaran Begoña Indakoetxea Johannes Levin Adrian Danek 21 James Rowe 22 Thomas Cope Markus Otto 23 Sarah Anderl-Straub Alexandre de Mendonça 24 Carolina Maruta 24 Mario Masellis 25 Sandra Black Philippe Couratier 26, 27 Géraldine Lautrette 27 Edward Huey Sandro Sorbi 28 Benedetta Nacmias 28 Robert Laforce 29 Marie-Pier Tremblay Rik Vandenberghe 30 Philip Van Damme Emily Rogalski Sandra Weintraub Alexander Gerhard 31 Chiadi Onyike Simon Ducharme Sokratis Papageorgiou Adeline Su Lyn Amy Brodtmann Elizabeth Finger Rita Guerreiro 32 Jose Bras 32 Jonathan Rohrer 33
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.
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https://hal-unilim.archives-ouvertes.fr/hal-02409114
Contributeur : Elisabeth Grelier <>
Soumis le : vendredi 13 décembre 2019 - 12:02:32
Dernière modification le : jeudi 20 août 2020 - 03:05:00

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Katrina Moore, Jennifer Nicholas, Murray Grossman, Corey Mcmillan, David Irwin, et al.. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. The Lancet Neurology, Elsevier, 2019, ⟨10.1016/S1474-4422(19)30394-1⟩. ⟨hal-02409114⟩

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