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

GENetic Frontotemporal dementia Initiative (GENFI); Enrico Premi; Marcello Giunta; 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 Laforce; Caroline 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

doi:10.1016/j.neurobiolaging.2021.09.001

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

GENetic Frontotemporal dementia Initiative (GENFI), Enrico Premi, Marcello Giunta, 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

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

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 language	English
Pages (from-to)	155-167
Number of pages	13
Journal	Neurobiol. Aging
Volume	108
DOIs	https://doi.org/10.1016/j.neurobiolaging.2021.09.001
Publication status	Published - Dec 2021

Keywords

dynamic functional network connectivity
Frontotemporal Dementia
GRN mutation
resting-state functional MRI
spatial chronnectome

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10.1016/j.neurobiolaging.2021.09.001

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(GENFI), GEN. F. D. I., Premi, E., Giunta, M., Iraji, A., Rachakonda, S., Calhoun, V. D., Gazzina, S., Benussi, A., Gasparotti, R., Archetti, S., Bocchetta, M., Cash, D., Todd, E., Peakman, G., Convery, R., van Swieten, J. C., Jiskoot, L., Sanchez-Valle, R., Moreno, F., ... Borroni, B. (2021). Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study. Neurobiol. Aging, 108, 155-167. https://doi.org/10.1016/j.neurobiolaging.2021.09.001

(GENFI), GENFDI, Premi, E, Giunta, M, Iraji, A, Rachakonda, S, Calhoun, VD, Gazzina, S, Benussi, A, Gasparotti, R, Archetti, S, Bocchetta, M, Cash, D, Todd, E, Peakman, G, Convery, R, van Swieten, JC, Jiskoot, L, Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Rowe, JB, Masellis, M, Tartaglia, C, Finger, E, Vandenberghe, R, de Mendonça, A, Tagliavini, F, Butler, CR, Santana, I, Gerhard, A, Le Ber, I, Pasquier, F, Ducharme, S, Levin, J, Danek, A, Sorbi, S, Otto, M, Rohrer, JD & Borroni, B 2021, 'Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study', Neurobiol. Aging, vol. 108, pp. 155-167. https://doi.org/10.1016/j.neurobiolaging.2021.09.001

@article{692acbfdb081418784024f7d11b210e0,

title = "Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study",

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{\textquoteright} 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.",

keywords = "dynamic functional network connectivity, Frontotemporal Dementia, GRN mutation, resting-state functional MRI, spatial chronnectome",

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

note = "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 Sch{\"o}rling 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 G{\'e}n{\'e}rale 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 G{\'e}n{\'e}rale 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 fromFundaci{\'o} Marat{\'o} 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, Fundaci{\'o} Marat{\'o} 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: {\textcopyright} 2021",

year = "2021",

month = dec,

doi = "10.1016/j.neurobiolaging.2021.09.001",

language = "English",

volume = "108",

pages = "155--167",

journal = "Neurobiol. Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Dissemination in time and space in presymptomatic granulin mutation carriers: a GENFI spatial chronnectome study

AU - (GENFI), GENetic Frontotemporal dementia Initiative

AU - Premi, Enrico

AU - Giunta, Marcello

AU - Iraji, Armin

AU - Rachakonda, Srinivas

AU - Calhoun, Vince D.

AU - Gazzina, Stefano

AU - Benussi, Alberto

AU - Gasparotti, Roberto

AU - Archetti, Silvana

AU - Bocchetta, Martina

AU - Cash, Dave

AU - Todd, Emily

AU - Peakman, Georgia

AU - Convery, Rhian

AU - van Swieten, John C.

AU - Jiskoot, Lize

AU - Sanchez-Valle, Raquel

AU - Moreno, Fermin

AU - Laforce, Robert

AU - Graff, Caroline

AU - Synofzik, Matthis

AU - Galimberti, Daniela

AU - Rowe, James B.

AU - Masellis, Mario

AU - Tartaglia, Carmela

AU - Finger, Elizabeth

AU - Vandenberghe, Rik

AU - de Mendonça, Alexandre

AU - Tagliavini, Fabrizio

AU - Butler, Chris R.

AU - Santana, Isabel

AU - Gerhard, Alexander

AU - Le Ber, Isabelle

AU - Pasquier, Florence

AU - Ducharme, Simon

AU - Levin, Johannes

AU - Danek, Adrian

AU - Sorbi, Sandro

AU - Otto, Markus

AU - Rohrer, Jonathan D.

AU - Borroni, Barbara

N1 - 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

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

KW - dynamic functional network connectivity

KW - Frontotemporal Dementia

KW - GRN mutation

KW - resting-state functional MRI

KW - spatial chronnectome

U2 - 10.1016/j.neurobiolaging.2021.09.001

DO - 10.1016/j.neurobiolaging.2021.09.001

M3 - Article

SN - 0197-4580

VL - 108

SP - 155

EP - 167

JO - Neurobiol. Aging

JF - Neurobiol. Aging

ER -

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

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