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

Kamen A. Tsvetanov*, Stefano Gazzina, Genetic FTD 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

Research output: Contribution to journalArticleAcademicpeer-review

19 Citations (Scopus)
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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 languageEnglish
Pages (from-to)500-514
Number of pages15
JournalAlzheimer's and Dementia
Volume17
Issue number3
DOIs
Publication statusPublished - 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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