Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

Maura Malpetti; P. Simon Jones; Genetic Frontotemporal Initiative (GENFI); Kamen A. Tsvetanov; Timothy Rittman; John C. van Swieten; Barbara Borroni; Raquel Sanchez-Valle; Fermin Moreno; Robert Laforce; Caroline Graff; Matthis Synofzik; Daniela Galimberti; Mario Masellis; Maria Carmela Tartaglia; Elizabeth Finger; Rik Vandenberghe; Alexandre de Mendonça; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Chris R. Butler; Alexander Gerhard; Johannes Levin; Adrian Danek; Markus Otto; Giovanni B. Frisoni; Roberta Ghidoni; Sandro Sorbi; Carolin Heller; Emily G. Todd; Martina Bocchetta; David M. Cash; Rhian S. Convery; Georgia Peakman; Katrina M. Moore; Jonathan D. Rohrer; Rogier A. Kievit; James B. Rowe

doi:10.1002/alz.12252

Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

Maura Malpetti
, P. Simon Jones
, Genetic Frontotemporal Initiative (GENFI)
, Kamen A. Tsvetanov
, Timothy Rittman
, John C. van Swieten
, Barbara Borroni
, Raquel Sanchez-Valle
, Fermin Moreno
, Robert Laforce
, Caroline Graff
, Matthis Synofzik
, Daniela Galimberti
, Mario Masellis
, Maria Carmela Tartaglia
, Elizabeth Finger
, Rik Vandenberghe
, Alexandre de Mendonça
, Fabrizio Tagliavini
, Isabel Santana

Simon Ducharme, Chris R. Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Giovanni B. Frisoni, Roberta Ghidoni, Sandro Sorbi, Carolin Heller, Emily G. Todd, Martina Bocchetta, David M. Cash, Rhian S. Convery, Georgia Peakman, Katrina M. Moore, Jonathan D. Rohrer, Rogier A. Kievit, James B. Rowe^*

^*Corresponding author for this work

Neurology

Cambridge University Hospitals NHS Foundation Trust
University of Brescia
University of Barcelona
Hospital Universitario Donostia
Instituto de Investigación Sanitaria Biodonostia
Centre Hospitalier Universitaire de Québec
Karolinska Institutet
Karolinska University Hospital
University of Tübingen
German Center for Neurodegenerative Diseases
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
University of Milan
University of Toronto
University of Western Ontario
KU Leuven
University Hospitals Leuven
Leuven Brain Institute
Faculdade de Medicina de Lisboa
IRCCS Fondazione Istituto Neurologico Carlo Besta - Milano
Centro Hospitalar e Universitário de Coimbra
University of Coimbra
McGill University
McConnell Brain Imaging Centre
University of Oxford
University of Manchester
University of Duisburg-Essen
Ludwig-Maximilians-Universität München
Munich Cluster of Systems Neurology (SyNergy)
Ulm University
IRCCS Centro San Giovanni di Dio Fatebenefratelli - Brescia
University of Florence
IRCCS Fondazione Don Carlo Gnocchi - Milano
University College London
MRC Cognition and Brain Sciences Unit
Donders Institute for Brain, Cognition and Behaviour

Research output: Contribution to journal › Article › Academic › peer-review

52 Citations (Scopus)

77 Downloads (Pure)

Abstract

Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

Original language	English
Pages (from-to)	969-983
Number of pages	15
Journal	Alzheimer's and Dementia
Volume	17
Issue number	6
Early online date	14 Dec 2020
DOIs	https://doi.org/10.1002/alz.12252
Publication status	Published - Jun 2021

Bibliographical note

Funding Information:
We thank our participant volunteers and their families for their participation, and the radiographers/technologists and research nurses from all centers involved in this study for their invaluable support in data acquisition. This work is co-funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant ?GENFI-prox? (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517), and 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.

Funding Information:
This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517), and 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.

Publisher Copyright:
© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association

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Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changesFinal published version, 1.19 MBLicence: CC BY

Cite this

Malpetti, M., Jones, P. S., Genetic Frontotemporal Initiative (GENFI), Tsvetanov, K. A., Rittman, T., van Swieten, J. C., Borroni, B., Sanchez-Valle, R., Moreno, F., Laforce, R., Graff, C., Synofzik, M., Galimberti, D., Masellis, M., Tartaglia, M. C., Finger, E., Vandenberghe, R., de Mendonça, A., Tagliavini, F., ... Rowe, J. B. (2021). Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes. Alzheimer's and Dementia, 17(6), 969-983. https://doi.org/10.1002/alz.12252

@article{988c75ed7f7748e7b451c9a78f111196,

title = "Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes",

abstract = "Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.",

author = "Maura Malpetti and Jones, \{P. Simon\} and \{Genetic Frontotemporal Initiative (GENFI)\} and Tsvetanov, \{Kamen A.\} and Timothy Rittman and \{van Swieten\}, \{John C.\} and Barbara Borroni and Raquel Sanchez-Valle and Fermin Moreno and Robert Laforce and Caroline Graff and Matthis Synofzik and Daniela Galimberti and Mario Masellis and Tartaglia, \{Maria Carmela\} and Elizabeth Finger and Rik Vandenberghe and \{de Mendon{\c c}a\}, Alexandre and Fabrizio Tagliavini and Isabel Santana and Simon Ducharme and Butler, \{Chris R.\} and Alexander Gerhard and Johannes Levin and Adrian Danek and Markus Otto and Frisoni, \{Giovanni B.\} and Roberta Ghidoni and Sandro Sorbi and Carolin Heller and Todd, \{Emily G.\} and Martina Bocchetta and Cash, \{David M.\} and Convery, \{Rhian S.\} and Georgia Peakman and Moore, \{Katrina M.\} and Rohrer, \{Jonathan D.\} and Kievit, \{Rogier A.\} and Rowe, \{James B.\}",

note = "Funding Information: We thank our participant volunteers and their families for their participation, and the radiographers/technologists and research nurses from all centers involved in this study for their invaluable support in data acquisition. This work is co-funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant ?GENFI-prox? (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust \& Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517), and 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. Funding Information: This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust \& Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517), and 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. Publisher Copyright: {\textcopyright} 2020 The Authors. Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association",

year = "2021",

month = jun,

doi = "10.1002/alz.12252",

language = "English",

volume = "17",

pages = "969--983",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley \& Sons Inc.",

number = "6",

}

Malpetti, M, Jones, PS, Genetic Frontotemporal Initiative (GENFI), Tsvetanov, KA, Rittman, T, van Swieten, JC, Borroni, B, Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Masellis, M, Tartaglia, MC, Finger, E, Vandenberghe, R, de Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Frisoni, GB, Ghidoni, R, Sorbi, S, Heller, C, Todd, EG, Bocchetta, M, Cash, DM, Convery, RS, Peakman, G, Moore, KM, Rohrer, JD, Kievit, RA & Rowe, JB 2021, 'Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes', Alzheimer's and Dementia, vol. 17, no. 6, pp. 969-983. https://doi.org/10.1002/alz.12252

TY - JOUR

T1 - Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

AU - Malpetti, Maura

AU - Jones, P. Simon

AU - Genetic Frontotemporal Initiative (GENFI)

AU - Tsvetanov, Kamen A.

AU - Rittman, Timothy

AU - van Swieten, John C.

AU - Borroni, Barbara

AU - Sanchez-Valle, Raquel

AU - Moreno, Fermin

AU - Laforce, Robert

AU - Graff, Caroline

AU - Synofzik, Matthis

AU - Galimberti, Daniela

AU - Masellis, Mario

AU - Tartaglia, Maria Carmela

AU - Finger, Elizabeth

AU - Vandenberghe, Rik

AU - de Mendonça, Alexandre

AU - Tagliavini, Fabrizio

AU - Santana, Isabel

AU - Ducharme, Simon

AU - Butler, Chris R.

AU - Gerhard, Alexander

AU - Levin, Johannes

AU - Danek, Adrian

AU - Otto, Markus

AU - Frisoni, Giovanni B.

AU - Ghidoni, Roberta

AU - Sorbi, Sandro

AU - Heller, Carolin

AU - Todd, Emily G.

AU - Bocchetta, Martina

AU - Cash, David M.

AU - Convery, Rhian S.

AU - Peakman, Georgia

AU - Moore, Katrina M.

AU - Rohrer, Jonathan D.

AU - Kievit, Rogier A.

AU - Rowe, James B.

N1 - Funding Information: We thank our participant volunteers and their families for their participation, and the radiographers/technologists and research nurses from all centers involved in this study for their invaluable support in data acquisition. This work is co-funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant ?GENFI-prox? (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517), and 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. Funding Information: This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health 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 Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outside the submitted work. 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). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517), and 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. Publisher Copyright: © 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association

PY - 2021/6

Y1 - 2021/6

N2 - Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

AB - Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

UR - https://www.scopus.com/pages/publications/85097622754

U2 - 10.1002/alz.12252

DO - 10.1002/alz.12252

M3 - Article

C2 - 33316852

AN - SCOPUS:85097622754

SN - 1552-5260

VL - 17

SP - 969

EP - 983

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 6

ER -

Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

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