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Article Dans Une Revue The Lancet Neurology Année : 2019

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

Katrina Moore , Jennifer M 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 C. 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 M. 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)
1 DRC - Dementia Research Centre [London]
2 Perelman School of Medicine
3 UCL Queen Square Institute of Neurology
4 Mayo Clinic [Rochester]
5 Mayo Clinic [Jacksonville]
6 Centre for Molecular Medicine and Therapeutics
7 Erasmus MC - Erasmus University Medical Center [Rotterdam]
8 Division of Neuroscience and Experimental Psychology [Salford, UK]
9 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
10 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
11 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
12 LENITEM - Neuroimaging and Telemedicine
13 Karolinska Institutet [Stockholm]
14 UniBs - Università degli Studi di Brescia = University of Brescia
15 Dipartimento di Scienze Neurologiche
16 Centro Dino Ferrari [Milano]
17 Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
18 Hertie Institute for Clinical Brain Research and Center for Neurology, University of Tübingen
19 NeuRA - Neuroscience Research Australia
20 Instituto de Biologia Molecular e Celular - IBMC
21 Neurology department
22 MRC CBU - Cognition and Brain Sciences Unit
23 Universität Ulm - Ulm University [Ulm, Allemagne]
24 Faculdade de Medicina [Lisboa]
25 SRI - Sunnybrook Research Institute [Toronto]
26 NET - Neuroépidémiologie Tropicale
27 Service de Neurologie [CHU Limoges]
28 UniFI - Università degli Studi di Firenze = University of Florence
29 ULaval - Université Laval [Québec]
30 Department of Neurology
31 WMIC - Wolfson Molecular Imaging Centre
32 Department of Molecular Neurosciences
33 Institute of Neurology [London]
Katrina Moore
  • Fonction : Auteur
Nick Fox
  • Fonction : Auteur
Simon Mead
  • Fonction : Auteur
Martina Bocchetta
  • Fonction : Auteur
Bradley Boeve
  • Fonction : Auteur
Leah Forsberg
  • Fonction : Auteur
Elise Gp Dopper
  • Fonction : Auteur
Janne Papma
  • Fonction : Auteur
Jennifer Saxon
  • Fonction : Auteur
Matthew Jones
  • Fonction : Auteur
Stuart Pickering-Brown
  • Fonction : Auteur
Roberta Ghidoni
  • Fonction : Auteur
Michela Pievani
Luisa Benussi
  • Fonction : Auteur
Giuliano Binetti
  • Fonction : Auteur
Bradford Dickerson
  • Fonction : Auteur
Diane Lucente
  • Fonction : Auteur
Samantha Krivensky
  • Fonction : Auteur
Caroline Graff
  • Fonction : Auteur
  • PersonId : 889097
Linn Öijerstedt
  • Fonction : Auteur
Marie Fallström
  • Fonction : Auteur
Nupur Ghoshal
John Morris
Alberto Benussi
  • Fonction : Auteur
Ian Mackenzie
  • Fonction : Auteur
Ging-Yuek Hsiung
  • Fonction : Auteur
Pheth Sengdy
  • Fonction : Auteur
Adam Boxer
  • Fonction : Auteur
Howie Rosen
  • Fonction : Auteur
Joanne Taylor
  • Fonction : Auteur
Carlo Wilke
  • Fonction : Auteur
Patricia Sulzer
  • Fonction : Auteur
John Hodges
  • Fonction : Auteur
John Kwok
  • Fonction : Auteur
Raquel Sanchez-Valle
  • Fonction : Auteur
Albert Lladó
  • Fonction : Auteur
Sergi Borrego-Ecija
  • Fonction : Auteur
Isabel Santana
  • Fonction : Auteur
Miguel Tábuas-Pereira
  • Fonction : Auteur
Fermin Moreno
  • Fonction : Auteur
Myriam Barandiaran
  • Fonction : Auteur
Begoña Indakoetxea
  • Fonction : Auteur
Johannes Levin
  • Fonction : Auteur
James Rowe
  • Fonction : Auteur
  • PersonId : 887931
Thomas Cope
  • Fonction : Auteur
Sarah Anderl-Straub
  • Fonction : Auteur
Sandra Black
  • Fonction : Auteur
Géraldine Lautrette
  • Fonction : Auteur
  • PersonId : 956310
Edward Huey
  • Fonction : Auteur
Marie-Pier Tremblay
  • Fonction : Auteur
Rik Vandenberghe
  • Fonction : Auteur
  • PersonId : 921848
Philip Van Damme
  • Fonction : Auteur
Emily Rogalski
  • Fonction : Auteur
Sandra Weintraub
  • Fonction : Auteur
Alexander Gerhard
  • Fonction : Auteur
  • PersonId : 887831
Chiadi Onyike
  • Fonction : Auteur
Simon Ducharme
  • Fonction : Auteur
Sokratis Papageorgiou
  • Fonction : Auteur
Adeline Su Lyn
  • Fonction : Auteur
Amy Brodtmann
  • Fonction : Auteur
Elizabeth Finger
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-02409114 , version 1 (13-12-2019)

Identifiants

Citer

Katrina Moore, Jennifer M 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, 2019, ⟨10.1016/S1474-4422(19)30394-1⟩. ⟨hal-02409114⟩
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