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

TY - JOUR

T1 - Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

AU - Moore, Katrina M

AU - Nicholas, Jennifer

AU - Grossman, Murray

AU - McMillan, Corey T

AU - Irwin, David J

AU - Massimo, Lauren

AU - Van Deerlin, Vivianna M

AU - Warren, Jason D

AU - Fox, Nick C

AU - Rossor, Martin N

AU - Mead, Simon

AU - Bocchetta, Martina

AU - Boeve, Bradley F

AU - Knopman, David S

AU - Graff-Radford, Neill R

AU - Forsberg, Leah K

AU - Rademakers, Rosa

AU - Wszolek, Zbigniew K

AU - van Swieten, John C

AU - Jiskoot, Lize C

AU - Meeter, Lieke H

AU - Dopper, Elise Gp

AU - Papma, Janne M

AU - Snowden, Julie S

AU - Saxon, Jennifer

AU - Jones, Matthew

AU - Pickering-Brown, Stuart

AU - Le Ber, Isabelle

AU - Camuzat, Agnès

AU - Brice, Alexis

AU - Caroppo, Paola

AU - Ghidoni, Roberta

AU - Pievani, Michela

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Dickerson, Bradford C

AU - Lucente, Diane

AU - Krivensky, Samantha

AU - Graff, Caroline

AU - Öijerstedt, Linn

AU - Fallström, Marie

AU - Thonberg, Håkan

AU - Ghoshal, Nupur

AU - Morris, John C

AU - Borroni, Barbara

AU - Benussi, Alberto

AU - Padovani, Alessandro

AU - Galimberti, Daniela

AU - Scarpini, Elio

AU - Fumagalli, Giorgio G

AU - Mackenzie, Ian R

AU - Hsiung, Ging-Yuek R

AU - Sengdy, Pheth

AU - Boxer, Adam L

AU - Rosen, Howie

AU - Taylor, Joanne B

AU - Synofzik, Matthis

AU - Wilke, Carlo

AU - Sulzer, Patricia

AU - Hodges, John R

AU - Halliday, Glenda

AU - Kwok, John

AU - Sanchez-Valle, Raquel

AU - Lladó, Albert

AU - Borrego-Ecija, Sergi

AU - Santana, Isabel

AU - Almeida, Maria Rosário

AU - Tábuas-Pereira, Miguel

AU - Moreno, Fermin

AU - Barandiaran, Myriam

AU - Indakoetxea, Begoña

AU - Levin, Johannes

AU - Danek, Adrian

AU - Rowe, James B

AU - Cope, Thomas E

AU - Otto, Markus

AU - Anderl-Straub, Sarah

AU - de Mendonça, Alexandre

AU - Maruta, Carolina

AU - Masellis, Mario

AU - Black, Sandra E

AU - Couratier, Philippe

AU - Lautrette, Geraldine

AU - Huey, Edward D

AU - Sorbi, Sandro

AU - Nacmias, Benedetta

AU - Laforce, Robert

AU - Tremblay, Marie-Pier L

AU - Vandenberghe, Rik

AU - Damme, Philip Van

AU - Rogalski, Emily J

AU - Weintraub, Sandra

AU - Gerhard, Alexander

AU - Onyike, Chiadi U

AU - Ducharme, Simon

AU - Papageorgiou, Sokratis G

AU - Lyn, Adeline Su

AU - Brodtmann, Amy

AU - Finger, Elizabeth

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Rohrer, Jonathan D

AU - FTD Prevention Initiative

AU - Volk, Alexander E

N1 - Copyright © 2020 Elsevier Ltd. All rights reserved.

PY - 2020/2

Y1 - 2020/2

N2 - 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.

AB - 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.

KW - Adult

KW - Age of Onset

KW - Aged

KW - Aged, 80 and over

KW - C9orf72 Protein/genetics

KW - Cohort Studies

KW - Disease Progression

KW - Family

KW - Female

KW - Frontotemporal Dementia/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phenotype

KW - Progranulins/genetics

KW - Retrospective Studies

KW - tau Proteins/genetics

U2 - 10.1016/S1474-4422(19)30394-1

DO - 10.1016/S1474-4422(19)30394-1

M3 - SCORING: Journal article

C2 - 31810826

VL - 19

SP - 145

EP - 156

JO - LANCET NEUROL

JF - LANCET NEUROL

SN - 1474-4422

IS - 2

ER -