Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Kamen A. Tsvetanov; Stefano Gazzina; on behalf of the Genetic Frontotemporal dementia Initiative (GENFI); P. Simon Jones; John 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 Butler; Alexander Gerhard; Adrian Danek; Johannes Levin; Markus Otto; Giovanni Frisoni; Roberta Ghidoni; Sandro Sorbi; Jonathan D. Rohrer; James B. Rowe; Sónia Afonso; Maria Rosario Almeida; Sarah Anderl-Straub; Christin Andersson; Anna Antonell; Silvana Archetti; Andrea Arighi; Mircea Balasa; Myriam Barandiaran; Nuria Bargalló; Robart Bartha; Benjamin Bender; Luisa Benussi; Valentina Bessi; Giuliano Binetti; Sandra Black; Lize Jiskoot; Lieke Meeter; Rick van Minkelen; Jessica Panman; Janne Papma

doi:10.1002/alz.12209

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Kamen A. Tsvetanov^*, Stefano Gazzina, on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), P. Simon Jones, John 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 DucharmeChris Butler, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Giovanni Frisoni, Roberta Ghidoni, Sandro Sorbi, Jonathan D. Rohrer, James B. Rowe, Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Luisa Benussi, Valentina Bessi, Giuliano Binetti, Sandra Black, Lize Jiskoot, Lieke Meeter, Rick van Minkelen, Jessica Panman, Janne Papma

^*Corresponding author for this work

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Abstract

Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

Original language	English
Pages (from-to)	500-514
Number of pages	15
Journal	Alzheimer's and Dementia
Volume	17
Issue number	3
DOIs	https://doi.org/10.1002/alz.12209
Publication status	Published - Mar 2021

Bibliographical note

Funding Information:
K.A.T. is supported by the British Academy Postdoctoral Fellowship (PF160048) and the Guarantors of Brain (101149). J.B.R. is supported by the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400), and the Cambridge NIHR Biomedical Research Centre. R. S.-V. is supported by the Instituto de Salud Carlos III and the JPND network PreFrontAls (01ED1512/AC14/0013) and the Fundaci? Marat? de TV3 (20143810). M.M and E.F are supported by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also a Canadian Institutes of Health Research operating grant (MOP 327387) and funding from the Weston Brain Institute. J.D.R., D.C., and K.M.M. are supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. 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), the MRC UK GENFI grant (MR/ M023664/1), and The Bluefield Project. F.T. is supported by the Italian Ministry of Health (Grant NET-2011-02346784). L.C.J. and J.V.S. are supported by the Association for Frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project number 733050103 and 733050813, and the Bluefield project. R.G. is supported by Italian Ministry of Health, Ricerca Corrente. J.L. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145; SyNergy - ID 390857198). The Swedish contributors C.G., L.O., and C.A. were supported by grants from JPND Prefrontals Swedish Research Council (VR) 529-2014-7504, JPND GENFI-PROX Swedish Research Council (VR) 2019-02248, Swedish Research Council (VR) 2015- 02926, Swedish Research Council (VR) 2018-02754, Swedish FTD Initiative-Schorling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding, and StratNeuro, Swedish Demensfonden, during the conduct of the study.

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

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Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementiaFinal published version, 5.32 MBLicence: CC BY

Cite this

Tsvetanov, K. A., Gazzina, S., on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), Jones, P. S., van Swieten, J., 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., Santana, I., ... Papma, J. (2021). Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia. Alzheimer's and Dementia, 17(3), 500-514. https://doi.org/10.1002/alz.12209

@article{c9933b054c014b258a430e26465d0fa6,

title = "Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia",

abstract = "Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.",

author = "Tsvetanov, {Kamen A.} and Stefano Gazzina and {on behalf of the Genetic Frontotemporal dementia Initiative (GENFI)} and Jones, {P. Simon} and {van Swieten}, John 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 Chris Butler and Alexander Gerhard and Adrian Danek and Johannes Levin and Markus Otto and Giovanni Frisoni and Roberta Ghidoni and Sandro Sorbi and Rohrer, {Jonathan D.} and Rowe, {James B.} and S{\'o}nia Afonso and Almeida, {Maria Rosario} and Sarah Anderl-Straub and Christin Andersson and Anna Antonell and Silvana Archetti and Andrea Arighi and Mircea Balasa and Myriam Barandiaran and Nuria Bargall{\'o} and Robart Bartha and Benjamin Bender and Luisa Benussi and Valentina Bessi and Giuliano Binetti and Sandra Black and Lize Jiskoot and Lieke Meeter and {van Minkelen}, Rick and Jessica Panman and Janne Papma",

note = "Funding Information: K.A.T. is supported by the British Academy Postdoctoral Fellowship (PF160048) and the Guarantors of Brain (101149). J.B.R. is supported by the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400), and the Cambridge NIHR Biomedical Research Centre. R. S.-V. is supported by the Instituto de Salud Carlos III and the JPND network PreFrontAls (01ED1512/AC14/0013) and the Fundaci? Marat? de TV3 (20143810). M.M and E.F are supported by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also a Canadian Institutes of Health Research operating grant (MOP 327387) and funding from the Weston Brain Institute. J.D.R., D.C., and K.M.M. are supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. 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), the MRC UK GENFI grant (MR/ M023664/1), and The Bluefield Project. F.T. is supported by the Italian Ministry of Health (Grant NET-2011-02346784). L.C.J. and J.V.S. are supported by the Association for Frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project number 733050103 and 733050813, and the Bluefield project. R.G. is supported by Italian Ministry of Health, Ricerca Corrente. J.L. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145; SyNergy - ID 390857198). The Swedish contributors C.G., L.O., and C.A. were supported by grants from JPND Prefrontals Swedish Research Council (VR) 529-2014-7504, JPND GENFI-PROX Swedish Research Council (VR) 2019-02248, Swedish Research Council (VR) 2015- 02926, Swedish Research Council (VR) 2018-02754, Swedish FTD Initiative-Schorling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding, and StratNeuro, Swedish Demensfonden, during the conduct of the study. Publisher Copyright: {\textcopyright} 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association",

year = "2021",

month = mar,

doi = "10.1002/alz.12209",

language = "English",

volume = "17",

pages = "500--514",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "Elsevier Inc.",

number = "3",

}

Tsvetanov, KA, Gazzina, S, on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), Jones, PS, van Swieten, J, 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, C, Gerhard, A, Danek, A, Levin, J, Otto, M, Frisoni, G, Ghidoni, R, Sorbi, S, Rohrer, JD, Rowe, JB, Afonso, S, Almeida, MR, Anderl-Straub, S, Andersson, C, Antonell, A, Archetti, S, Arighi, A, Balasa, M, Barandiaran, M, Bargalló, N, Bartha, R, Bender, B, Benussi, L, Bessi, V, Binetti, G, Black, S, Jiskoot, L , Meeter, L , van Minkelen, R, Panman, J & Papma, J 2021, 'Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia', Alzheimer's and Dementia, vol. 17, no. 3, pp. 500-514. https://doi.org/10.1002/alz.12209

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia. / Tsvetanov, Kamen A.; Gazzina, Stefano; on behalf of the Genetic Frontotemporal dementia Initiative (GENFI) et al.
In: Alzheimer's and Dementia, Vol. 17, No. 3, 03.2021, p. 500-514.

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

TY - JOUR

T1 - Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

AU - Tsvetanov, Kamen A.

AU - Gazzina, Stefano

AU - on behalf of the Genetic Frontotemporal dementia Initiative (GENFI)

AU - Jones, P. Simon

AU - van Swieten, John

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

AU - Gerhard, Alexander

AU - Danek, Adrian

AU - Levin, Johannes

AU - Otto, Markus

AU - Frisoni, Giovanni

AU - Ghidoni, Roberta

AU - Sorbi, Sandro

AU - Rohrer, Jonathan D.

AU - Rowe, James B.

AU - Afonso, Sónia

AU - Almeida, Maria Rosario

AU - Anderl-Straub, Sarah

AU - Andersson, Christin

AU - Antonell, Anna

AU - Archetti, Silvana

AU - Arighi, Andrea

AU - Balasa, Mircea

AU - Barandiaran, Myriam

AU - Bargalló, Nuria

AU - Bartha, Robart

AU - Bender, Benjamin

AU - Benussi, Luisa

AU - Bessi, Valentina

AU - Binetti, Giuliano

AU - Black, Sandra

AU - Jiskoot, Lize

AU - Meeter, Lieke

AU - van Minkelen, Rick

AU - Panman, Jessica

AU - Papma, Janne

N1 - Funding Information: K.A.T. is supported by the British Academy Postdoctoral Fellowship (PF160048) and the Guarantors of Brain (101149). J.B.R. is supported by the Wellcome Trust (103838), the Medical Research Council (SUAG/051 G101400), and the Cambridge NIHR Biomedical Research Centre. R. S.-V. is supported by the Instituto de Salud Carlos III and the JPND network PreFrontAls (01ED1512/AC14/0013) and the Fundaci? Marat? de TV3 (20143810). M.M and E.F are supported by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also a Canadian Institutes of Health Research operating grant (MOP 327387) and funding from the Weston Brain Institute. J.D.R., D.C., and K.M.M. are supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre, and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility. J.D.R. 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), the MRC UK GENFI grant (MR/ M023664/1), and The Bluefield Project. F.T. is supported by the Italian Ministry of Health (Grant NET-2011-02346784). L.C.J. and J.V.S. are supported by the Association for Frontotemporal Dementias Research Grant 2009, ZonMw Memorabel project number 733050103 and 733050813, and the Bluefield project. R.G. is supported by Italian Ministry of Health, Ricerca Corrente. J.L. was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145; SyNergy - ID 390857198). The Swedish contributors C.G., L.O., and C.A. were supported by grants from JPND Prefrontals Swedish Research Council (VR) 529-2014-7504, JPND GENFI-PROX Swedish Research Council (VR) 2019-02248, Swedish Research Council (VR) 2015- 02926, Swedish Research Council (VR) 2018-02754, Swedish FTD Initiative-Schorling Foundation, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Karolinska Institutet Doctoral Funding, and StratNeuro, Swedish Demensfonden, during the conduct of the study. Publisher Copyright: © 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association

PY - 2021/3

Y1 - 2021/3

N2 - Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

AB - Introduction: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). Methods: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. Results: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. Discussion: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

UR - http://www.scopus.com/inward/record.url?scp=85112783312&partnerID=8YFLogxK

U2 - 10.1002/alz.12209

DO - 10.1002/alz.12209

M3 - Article

C2 - 33215845

AN - SCOPUS:85112783312

SN - 1552-5260

VL - 17

SP - 500

EP - 514

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 3

ER -

Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

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Bibliographical note

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