Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study

Enrico Premi, Marcello Giunta, on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), Armin Iraji, Srinivas Rachakonda, Vince D. Calhoun, Stefano Gazzina, Alberto Benussi, Roberto Gasparotti, Silvana Archetti, Martina Bocchetta, Dave Cash, Emily Todd, Georgia Peakman, Rhian Convery, John C. van Swieten, Lize Jiskoot, Raquel Sanchez-Valle, Fermin Moreno, Robert LaforceCaroline Graff, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Chris R. Butler, Isabel Santana, Alexander Gerhard, Isabelle Le Ber, Florence Pasquier, Simon Ducharme, Johannes Levin, Adrian Danek, Sandro Sorbi, Markus Otto, Jonathan D. Rohrer, Barbara Borroni*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

The presymptomatic brain changes of granulin (GRN) disease, preceding by years frontotemporal dementia, has not been fully characterized. New approaches focus on the spatial chronnectome can capture both spatial network configurations and their dynamic changes over time. To investigate the spatial dynamics in 141 presymptomatic GRN mutation carriers and 282 noncarriers from the Genetic Frontotemporal dementia research Initiative cohort. We considered time-varying patterns of the default mode network, the language network, and the salience network, each summarized into 4 distinct recurring spatial configurations. Dwell time (DT) (the time each individual spends in each spatial state of each network), fractional occupacy (FO) (the total percentage of time spent by each individual in a state of a specific network) and total transition number (the total number of transitions performed by each individual in a specifict state) were considered. Correlations between DT, FO, and transition number and estimated years from expected symptom onset (EYO) and clinical performances were assessed. Presymptomatic GRN mutation carriers spent significantly more time in those spatial states characterised by greater activation of the insula and the parietal cortices, as compared to noncarriers (p < 0.05, FDR-corrected). A significant correlation between DT and FO of these spatial states and EYO was found, the longer the time spent in the spatial states, the closer the EYO. DT and FO significantly correlated with performances at tests tapping processing speed, with worse scores associated with increased spatial states’ DT. Our results demonstrated that presymptomatic GRN disease presents a complex dynamic reorganization of brain connectivity. Change in both the spatial and temporal aspects of brain network connectivity could provide a unique glimpse into brain function and potentially allowing a more sophisticated evaluation of the earliest disease changes and the understanding of possible mechanisms in GRN disease.

Original languageEnglish
Pages (from-to)155-167
Number of pages13
JournalNeurobiology of Aging
Volume108
Early online date8 Sept 2021
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

on behalf of the Genetic Frontotemporal dementia Initiative (GENFI)

Funding Information:
Dr Graff reported receiving grants from the Swedish Research Council JointProgramme–Neurodegenerative Disease Research GENFI-prox domain registration no. 2019-02248, the SwedishResearch Council Joint Programme–Neurodegenerative Disease Research Prefrontals domain registration no.2015-02926, the Swedish Research Council Dnr 208-02754, the Schörling Foundation Swedish FTD Initiative, theSwedish Alzheimer Foundation, the Swedish Brain Foundation, the Region Stockholm ALF-project, the KarolinskaInstututet Doctoral and StratNeuro, and from the Swedish Dementia Foundation during the conduct of the study.Dr Masellis reported receiving grants from the Canadian Institutes of Health, the Cambridge Trust, the OntarioBrain Institute, the Weston Brain Institute, the Roche Clinical Trial, the Washington University Clinical Trial, and theAlector Clinical Trial; and personal fees from Arkuda Therapeutics Advisory Board, the Ionis Advisory Board, HenryStewart Talks Royalties, Alector Advisory Board, and Wave Life Sciences Advisory Board outside the submittedwork. Dr Rowe reported receiving grants from the National Institute for Health Research, Wellcome Trust, Janssen,AZ Medimmune, Lilly, and Medical Research Council; and personal fees from Biogen, Asceneuron, UCB, Althira,Astex, and SVHealth outside the submitted work. Dr Rowe also reported serving as Trustee for the ProgressiveSupranuclear Palsy Association, Darwin College, and Guarantor ofBrain; and reported serving as an editor ofBrain.Dr Le Ber reported receiving funding from the program “Investissements d'avenir” and from Agence Nationale dela Recherche/Direction Générale de l'Offre de Soins; serving as a member of the advisory board for PrevailTherapeutic; and receiving research grants from Agence Nationale de la Recherche, Direction Générale de l'Offrede Soins, Programme Hospitalier de Recherche Clinique, Vaincre Alzheimer Association, ARSla Association,Fondation Plan Alzheimer, and PRTS PrevDemALS; personal fees from Prevail Therapeutics; and grants from Programme Hospitalier de Recherche Clinique FTLD exome, Programme Hospitalier de Recherche Clinique PredictPGRN, and ANR-10-IAIHU-06 outside the submitted work. Dr Sanchez-Valle reported receiving grants fromFundació Marató de TV3 and personal fees from Wave Pharmaceuticals for participation in advisory boardmeetings and Ionis for participation in advisory board meetings outside the submitted work. Dr Moreno reportedreceiving grants from Tau Consortium outside the submitted work. Dr Synofzik reported receiving personal feesfrom Actelion Pharmaceuticals and Orphazyme outside the submitted work. Dr Santana reported receiving grantsfrom GENFI and personal fees and travel funds from commercial sponsors outside the submitted work. Dr Levinreported receiving grants from Munich Cluster of Systems Neurology (SyNergy) and personal fees from ModagGmbH, Bayer Vital, Roche, Axon Neuroscience, Thieme medical publishers, and W. Kohlhammer GmbH medicalpublishers; and nonfinancial support from Abbvie outside the submitted work. Dr Otto reported receiving grantsfrom BMBF during the conduct of the study. Dr Ghidoni reported receiving grants from the Italian Ministry ofHealth during the conduct of the study. Dr Rohrer reported performing medical advisory board work for Alector,Wave Life Sciences, and Prevail Therapeutics outside the submitted work. No other disclosures were reported.

Funding Information:
This work is supported by JPND grant “GENFI-prox” (to MS, JvS, MO, CG, JR, and BB), the Centre d'Investigation Clinique (ICM, France), the Centre pour l'Acquisition et le Traitement des Images platform

(CATI, France), the UK Medical Research Council, 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, Fundació Marató de TV3, Spain.

Funding Information:
We thank our participant volunteers and their families for their participation; the radiographers/technologists and research nurses from all centers involved in this study for their invaluable support in data acquisition. This work is supported by JPND grant ?GENFI-prox? (to MS, JvS, MO, CG, JR, and BB), the Centre d'Investigation Clinique (ICM, France), the Centre pour l'Acquisition et le Traitement des Images platform (CATI, France), the UK Medical Research Council, 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, Fundaci? Marat? de TV3, Spain.

Publisher Copyright:
© 2021

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