Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study

Henri J.M.M. Mutsaerts; Saira S. Mirza; Jan Petr; David L. Thomas; David M. Cash; Martina Bocchetta; Enrico De Vita; Arron W.S. Metcalfe; Zahra Shirzadi; Andrew D. Robertson; Maria Carmela Tartaglia; Sara B. Mitchell; Sandra E. Black; Morris Freedman; David Tang-Wai; Ron Keren; Ekaterina Rogaeva; John Van Swieten; Robert Laforce; Fabrizio Tagliavini; Barbara Borroni; Daniela Galimberti; James B. Rowe; Caroline Graff; Giovanni B. Frisoni; Elizabeth Finger; Sandro Sorbi; Alexandre De Mendonça; Jonathan D. Rohrer; Bradley J. MacIntosh; Mario Masellis; Christin Andersson; Silvana Archetti; Andrea Arighi; Luisa Benussi; Giuliano Binetti; Maura Cosseddu; Katrina M. Dick; Marie Fallström; Carlos Ferreira; Chiara Fenoglio; Nick C. Fox; Giorgio Fumagalli; Stefano Gazzina; Roberta Ghidoni; Marina Grisoli; Vesna Jelic; Lize Jiskoot; Gemma Lombardi; Carolina Maruta; Simon Mead; Lieke Meeter; Rick Van Minkelen; Benedetta Nacmias; Linn Öijerstedt; Sebastien Ourselin; Alessandro Padovani; Jessica Panman; Michela Pievani; Cristina Polito; Enrico Premi; Sara Prioni; Rosa Rademakers; Veronica Redaelli; Giacomina Rossi; Martin N. Rossor; Elio Scarpini; Hakan Thonberg; Pietro Tiraboschi; Ana Verdelho; Jason D. Warren

doi:10.1093/brain/awz039

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study

Henri J.M.M. Mutsaerts, Saira S. Mirza, Jan Petr, David L. Thomas, David M. Cash, Martina Bocchetta, Enrico De Vita, Arron W.S. Metcalfe, Zahra Shirzadi, Andrew D. Robertson, Maria Carmela Tartaglia, Sara B. Mitchell, Sandra E. Black, Morris Freedman, David Tang-Wai, Ron Keren, Ekaterina Rogaeva, John Van Swieten, Robert Laforce, Fabrizio TagliaviniBarbara Borroni, Daniela Galimberti, James B. Rowe, Caroline Graff, Giovanni B. Frisoni, Elizabeth Finger, Sandro Sorbi, Alexandre De Mendonça, Jonathan D. Rohrer, Bradley J. MacIntosh, Mario Masellis, Christin Andersson, Silvana Archetti, Andrea Arighi, Luisa Benussi, Giuliano Binetti, Maura Cosseddu, Katrina M. Dick, Marie Fallström, Carlos Ferreira, Chiara Fenoglio, Nick C. Fox, Giorgio Fumagalli, Stefano Gazzina, Roberta Ghidoni, Marina Grisoli, Vesna Jelic, Lize Jiskoot, Gemma Lombardi, Carolina Maruta, Simon Mead, Lieke Meeter, Rick Van Minkelen, Benedetta Nacmias, Linn Öijerstedt, Sebastien Ourselin, Alessandro Padovani, Jessica Panman, Michela Pievani, Cristina Polito, Enrico Premi, Sara Prioni, Rosa Rademakers, Veronica Redaelli, Giacomina Rossi, Martin N. Rossor, Elio Scarpini, Hakan Thonberg, Pietro Tiraboschi, Ana Verdelho, Jason D. Warren

Neuroscience

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

12 Scopus citations

Abstract

Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

Original language	English (US)
Pages (from-to)	1108-1120
Number of pages	13
Journal	Brain
Volume	142
Issue number	4
DOIs	https://doi.org/10.1093/brain/awz039
State	Published - Apr 1 2019

Keywords

Arterial spin labelling
Cerebral blood flow
Genetic frontotemporal dementia
Presymptomatic biomarker

ASJC Scopus subject areas

Medicine(all)

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10.1093/brain/awz039

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Mutsaerts, H. J. M. M., Mirza, S. S., Petr, J., Thomas, D. L., Cash, D. M., Bocchetta, M., De Vita, E., Metcalfe, A. W. S., Shirzadi, Z., Robertson, A. D., Tartaglia, M. C., Mitchell, S. B., Black, S. E., Freedman, M., Tang-Wai, D., Keren, R., Rogaeva, E., Van Swieten, J., Laforce, R., ... Warren, J. D. (2019). Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study. Brain, 142(4), 1108-1120. https://doi.org/10.1093/brain/awz039

Mutsaerts, HJMM, Mirza, SS, Petr, J, Thomas, DL, Cash, DM, Bocchetta, M, De Vita, E, Metcalfe, AWS, Shirzadi, Z, Robertson, AD, Tartaglia, MC, Mitchell, SB, Black, SE, Freedman, M, Tang-Wai, D, Keren, R, Rogaeva, E, Van Swieten, J, Laforce, R, Tagliavini, F, Borroni, B, Galimberti, D, Rowe, JB, Graff, C, Frisoni, GB, Finger, E, Sorbi, S, De Mendonça, A, Rohrer, JD, MacIntosh, BJ, Masellis, M, Andersson, C, Archetti, S, Arighi, A, Benussi, L, Binetti, G, Cosseddu, M, Dick, KM, Fallström, M, Ferreira, C, Fenoglio, C, Fox, NC, Fumagalli, G, Gazzina, S, Ghidoni, R, Grisoli, M, Jelic, V, Jiskoot, L, Lombardi, G, Maruta, C, Mead, S, Meeter, L, Van Minkelen, R, Nacmias, B, Öijerstedt, L, Ourselin, S, Padovani, A, Panman, J, Pievani, M, Polito, C, Premi, E, Prioni, S, Rademakers, R, Redaelli, V, Rossi, G, Rossor, MN, Scarpini, E, Thonberg, H, Tiraboschi, P, Verdelho, A & Warren, JD 2019, 'Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study', Brain, vol. 142, no. 4, pp. 1108-1120. https://doi.org/10.1093/brain/awz039

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title = "Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study",

abstract = "Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.",

keywords = "Arterial spin labelling, Cerebral blood flow, Genetic frontotemporal dementia, Presymptomatic biomarker",

author = "Mutsaerts, {Henri J.M.M.} and Mirza, {Saira S.} and Jan Petr and Thomas, {David L.} and Cash, {David M.} and Martina Bocchetta and {De Vita}, Enrico and Metcalfe, {Arron W.S.} and Zahra Shirzadi and Robertson, {Andrew D.} and Tartaglia, {Maria Carmela} and Mitchell, {Sara B.} and Black, {Sandra E.} and Morris Freedman and David Tang-Wai and Ron Keren and Ekaterina Rogaeva and {Van Swieten}, John and Robert Laforce and Fabrizio Tagliavini and Barbara Borroni and Daniela Galimberti and Rowe, {James B.} and Caroline Graff and Frisoni, {Giovanni B.} and Elizabeth Finger and Sandro Sorbi and {De Mendon{\c c}a}, Alexandre and Rohrer, {Jonathan D.} and MacIntosh, {Bradley J.} and Mario Masellis and Christin Andersson and Silvana Archetti and Andrea Arighi and Luisa Benussi and Giuliano Binetti and Maura Cosseddu and Dick, {Katrina M.} and Marie Fallstr{\"o}m and Carlos Ferreira and Chiara Fenoglio and Fox, {Nick C.} and Giorgio Fumagalli and Stefano Gazzina and Roberta Ghidoni and Marina Grisoli and Vesna Jelic and Lize Jiskoot and Gemma Lombardi and Carolina Maruta and Simon Mead and Lieke Meeter and {Van Minkelen}, Rick and Benedetta Nacmias and Linn {\"O}ijerstedt and Sebastien Ourselin and Alessandro Padovani and Jessica Panman and Michela Pievani and Cristina Polito and Enrico Premi and Sara Prioni and Rosa Rademakers and Veronica Redaelli and Giacomina Rossi and Rossor, {Martin N.} and Elio Scarpini and Hakan Thonberg and Pietro Tiraboschi and Ana Verdelho and Warren, {Jason D.}",

note = "Funding Information: This work was funded 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 to M.M. 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). This work was also supported by the MRC UK GENFI grant (MR/M023664/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

month = apr,

day = "1",

doi = "10.1093/brain/awz039",

language = "English (US)",

volume = "142",

pages = "1108--1120",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "4",

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TY - JOUR

T1 - Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia

T2 - A GENFI study

AU - Mutsaerts, Henri J.M.M.

AU - Mirza, Saira S.

AU - Petr, Jan

AU - Thomas, David L.

AU - Cash, David M.

AU - Bocchetta, Martina

AU - De Vita, Enrico

AU - Metcalfe, Arron W.S.

AU - Shirzadi, Zahra

AU - Robertson, Andrew D.

AU - Tartaglia, Maria Carmela

AU - Mitchell, Sara B.

AU - Black, Sandra E.

AU - Freedman, Morris

AU - Tang-Wai, David

AU - Keren, Ron

AU - Rogaeva, Ekaterina

AU - Van Swieten, John

AU - Laforce, Robert

AU - Tagliavini, Fabrizio

AU - Borroni, Barbara

AU - Galimberti, Daniela

AU - Rowe, James B.

AU - Graff, Caroline

AU - Frisoni, Giovanni B.

AU - Finger, Elizabeth

AU - Sorbi, Sandro

AU - De Mendonça, Alexandre

AU - Rohrer, Jonathan D.

AU - MacIntosh, Bradley J.

AU - Masellis, Mario

AU - Andersson, Christin

AU - Archetti, Silvana

AU - Arighi, Andrea

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Cosseddu, Maura

AU - Dick, Katrina M.

AU - Fallström, Marie

AU - Ferreira, Carlos

AU - Fenoglio, Chiara

AU - Fox, Nick C.

AU - Fumagalli, Giorgio

AU - Gazzina, Stefano

AU - Ghidoni, Roberta

AU - Grisoli, Marina

AU - Jelic, Vesna

AU - Jiskoot, Lize

AU - Lombardi, Gemma

AU - Maruta, Carolina

AU - Mead, Simon

AU - Meeter, Lieke

AU - Van Minkelen, Rick

AU - Nacmias, Benedetta

AU - Öijerstedt, Linn

AU - Ourselin, Sebastien

AU - Padovani, Alessandro

AU - Panman, Jessica

AU - Pievani, Michela

AU - Polito, Cristina

AU - Premi, Enrico

AU - Prioni, Sara

AU - Rademakers, Rosa

AU - Redaelli, Veronica

AU - Rossi, Giacomina

AU - Rossor, Martin N.

AU - Scarpini, Elio

AU - Thonberg, Hakan

AU - Tiraboschi, Pietro

AU - Verdelho, Ana

AU - Warren, Jason D.

N1 - Funding Information: This work was funded 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 to M.M. 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). This work was also supported by the MRC UK GENFI grant (MR/M023664/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2019 The Author(s).

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

AB - Genetic forms of frontotemporal dementia are most commonly due to mutations in three genes, C9orf72, GRN or MAPT, with presymptomatic carriers from families representing those at risk. While cerebral blood flow shows differences between frontotemporal dementia and other forms of dementia, there is limited evidence of its utility in presymptomatic stages of frontotemporal dementia. This study aimed to delineate the cerebral blood flow signature of presymptomatic, genetic frontotemporal dementia using a voxel-based approach. In the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study, we investigated cross-sectional differences in arterial spin labelling MRI-based cerebral blood flow between presymptomatic C9orf72, GRN or MAPT mutation carriers (n = 107) and non-carriers (n = 113), using general linear mixed-effects models and voxel-based analyses. Cerebral blood flow within regions of interest derived from this model was then explored to identify differences between individual gene carrier groups and to estimate a timeframe for the expression of these differences. The voxel-based analysis revealed a significant inverse association between cerebral blood flow and the expected age of symptom onset in carriers, but not non-carriers. Regions included the bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, and inferior parietal cortices, as well as the left middle temporal gyrus. For all bilateral regions, associations were greater on the right side. After correction for partial volume effects in a region of interest analysis, the results were found to be largely driven by the C9orf72 genetic subgroup. These cerebral blood flow differences first appeared approximately 12.5 years before the expected symptom onset determined on an individual basis. Cerebral blood flow was lower in presymptomatic mutation carriers closer to and beyond their expected age of symptom onset in key frontotemporal dementia signature regions. These results suggest that arterial spin labelling MRI may be a promising non-invasive imaging biomarker for the presymptomatic stages of genetic frontotemporal dementia.

KW - Arterial spin labelling

KW - Cerebral blood flow

KW - Genetic frontotemporal dementia

KW - Presymptomatic biomarker

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UR - http://www.scopus.com/inward/citedby.url?scp=85064287422&partnerID=8YFLogxK

U2 - 10.1093/brain/awz039

DO - 10.1093/brain/awz039

M3 - Article

C2 - 30847466

AN - SCOPUS:85064287422

SN - 0006-8950

VL - 142

SP - 1108

EP - 1120

JO - Brain

JF - Brain

IS - 4

ER -

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: A GENFI study

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