Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

Stefano Gazzina; Mario Grassi; Genetic FTD Initiative (GENFI); Enrico Premi; Antonella Alberici; Alberto Benussi; Silvana Archetti; Roberto Gasparotti; Martina Bocchetta; David M. Cash; Emily G. Todd; Georgia Peakman; Rhian S. Convery; John C. van Swieten; Lize C. Jiskoot; Harro Seelaar; Raquel Sanchez-Valle; Fermin Moreno; Robert Laforce; Caroline Graff; Matthis Synofzik; Daniela Galimberti; James B. Rowe; Mario Masellis; Maria 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.2022.02.009

Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

Stefano Gazzina, Mario Grassi, Genetic FTD Initiative (GENFI), Enrico Premi, Antonella Alberici, Alberto Benussi, Silvana Archetti, Roberto Gasparotti, Martina Bocchetta, David M. Cash, Emily G. Todd, Georgia Peakman, Rhian S. Convery, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Caroline GraffMatthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Maria 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 journal › Article › Academic › peer-review

Abstract

Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.

Original language	English
Pages (from-to)	94-104
Number of pages	11
Journal	Neurobiology of Aging
Volume	114
DOIs	https://doi.org/10.1016/j.neurobiolaging.2022.02.009
Publication status	Published - Jun 2022

Bibliographical note

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. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

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? Marat? de TV3, Spain. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors 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.

Publisher Copyright:
© 2022

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Gazzina, S., Grassi, M., Genetic FTD Initiative (GENFI), Premi, E., Alberici, A., Benussi, A., Archetti, S., Gasparotti, R., Bocchetta, M., Cash, D. M., Todd, E. G., Peakman, G., Convery, R. S., van Swieten, J. C., Jiskoot, L. C., Seelaar, H., Sanchez-Valle, R., Moreno, F., Laforce, R., ... Borroni, B. (2022). Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia. Neurobiology of Aging, 114, 94-104. https://doi.org/10.1016/j.neurobiolaging.2022.02.009

@article{24e1c7762bf94883989be9a9ca16d40a,

title = "Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia",

abstract = "Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.",

author = "Stefano Gazzina and Mario Grassi and {Genetic FTD Initiative (GENFI)} and Enrico Premi and Antonella Alberici and Alberto Benussi and Silvana Archetti and Roberto Gasparotti and Martina Bocchetta and Cash, {David M.} and Todd, {Emily G.} and Georgia Peakman and Convery, {Rhian S.} and {van Swieten}, {John C.} and Jiskoot, {Lize C.} and Harro Seelaar 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 Tartaglia, {Maria Carmela} 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 Ber, {Isabelle Le} 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 and Lieke Meeter and {van Minkelen}, Rick and Jessica Panman and Papma, {Janne M.}",

note = "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. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. 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? Marat? de TV3, Spain. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors 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. Publisher Copyright: {\textcopyright} 2022",

year = "2022",

month = jun,

doi = "10.1016/j.neurobiolaging.2022.02.009",

language = "English",

volume = "114",

pages = "94--104",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

}

Gazzina, S, Grassi, M, Genetic FTD Initiative (GENFI), Premi, E, Alberici, A, Benussi, A, Archetti, S, Gasparotti, R, Bocchetta, M, Cash, DM, Todd, EG, Peakman, G, Convery, RS, van Swieten, JC, Jiskoot, LC, Seelaar, H, Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Rowe, JB, Masellis, M, Tartaglia, MC, Finger, E, Vandenberghe, R, de Mendonça, A, Tagliavini, F, Butler, CR, Santana, I, Gerhard, A, Ber, IL, Pasquier, F, Ducharme, S, Levin, J, Danek, A, Sorbi, S, Otto, M, Rohrer, JD & Borroni, B 2022, 'Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia', Neurobiology of Aging, vol. 114, pp. 94-104. https://doi.org/10.1016/j.neurobiolaging.2022.02.009

TY - JOUR

T1 - Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

AU - Gazzina, Stefano

AU - Grassi, Mario

AU - Genetic FTD Initiative (GENFI)

AU - Premi, Enrico

AU - Alberici, Antonella

AU - Benussi, Alberto

AU - Archetti, Silvana

AU - Gasparotti, Roberto

AU - Bocchetta, Martina

AU - Cash, David M.

AU - Todd, Emily G.

AU - Peakman, Georgia

AU - Convery, Rhian S.

AU - van Swieten, John C.

AU - Jiskoot, Lize C.

AU - Seelaar, Harro

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, Maria 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 - Ber, Isabelle Le

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

AU - Meeter, Lieke

AU - van Minkelen, Rick

AU - Panman, Jessica

AU - Papma, Janne M.

N1 - 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. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. 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? Marat? de TV3, Spain. JBR is supported by the Medical Research Council (SUAG/051 101400) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The authors 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. Publisher Copyright: © 2022

PY - 2022/6

Y1 - 2022/6

N2 - Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.

AB - Frontotemporal dementia associated with granulin (GRN) mutations presents asymmetric brain atrophy. We applied a Minimum Spanning Tree plus an Efficiency Cost Optimization approach to cortical thickness data in order to test whether graph theory measures could identify global or local impairment of connectivity in the presymptomatic phase of pathology, where other techniques failed in demonstrating changes. We included 52 symptomatic GRN mutation carriers (SC), 161 presymptomatic GRN mutation carriers (PSC) and 341 non-carriers relatives from the Genetic Frontotemporal dementia research Initiative cohort. Group differences of global, nodal and edge connectivity in (Minimum Spanning Tree plus an Efficiency Cost Optimization) graph were tested via Structural Equation Models. Global graph perturbation was selectively impaired in SC compared to non-carriers, with no changes in PSC. At the local level, only SC exhibited perturbation of frontotemporal nodes, but edge connectivity revealed a characteristic pattern of interhemispheric disconnection, involving homologous parietal regions, in PSC. Our results suggest that GRN-related frontotemporal dementia resembles a disconnection syndrome, with interhemispheric disconnection between parietal regions in presymptomatic phases that progresses to frontotemporal areas as symptoms emerge.

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U2 - 10.1016/j.neurobiolaging.2022.02.009

DO - 10.1016/j.neurobiolaging.2022.02.009

M3 - Article

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AN - SCOPUS:85127511026

VL - 114

SP - 94

EP - 104

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -

Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

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