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 & 12 others 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, GENetic Frontotemporal dementia Initiative (GENFI)

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)1108-1120
JournalBrain
Volume142
Issue number4
DOIs
Publication statusPublished - 2019

Cite this

Mutsaerts, H. J. M. M., Mirza, S. S., Petr, J., Thomas, D. L., Cash, D. M., Bocchetta, M., ... GENetic Frontotemporal dementia Initiative (GENFI) (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, Henri J. M. M. ; Mirza, Saira S. ; Petr, Jan ; Thomas, David L. ; Cash, David M. ; Bocchetta, Martina ; de Vita, Enrico ; Metcalfe, Arron W. S. ; Shirzadi, Zahra ; Robertson, Andrew D. ; Tartaglia, Maria Carmela ; Mitchell, Sara B. ; Black, Sandra E. ; Freedman, Morris ; Tang-Wai, David ; Keren, Ron ; Rogaeva, Ekaterina ; van Swieten, John ; Laforce, Robert ; Tagliavini, Fabrizio ; Borroni, Barbara ; Galimberti, Daniela ; Rowe, James B. ; Graff, Caroline ; Frisoni, Giovanni B. ; Finger, Elizabeth ; Sorbi, Sandro ; de Mendonça, Alexandre ; Rohrer, Jonathan D. ; MacIntosh, Bradley J. ; Masellis, Mario ; GENetic Frontotemporal dementia Initiative (GENFI). / Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study. In: Brain. 2019 ; Vol. 142, No. 4. pp. 1108-1120.
@article{c2d002f3c2b44397b9320fd9a46e400a,
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.",
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{\cc}a}, Alexandre and Rohrer, {Jonathan D.} and MacIntosh, {Bradley J.} and Mario Masellis and {GENetic Frontotemporal dementia Initiative (GENFI)}",
year = "2019",
doi = "10.1093/brain/awz039",
language = "English",
volume = "142",
pages = "1108--1120",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "4",

}

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 & GENetic Frontotemporal dementia Initiative (GENFI) 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

Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study. / Mutsaerts, Henri J. M. M.; Mirza, Saira S.; Petr, Jan; Thomas, David L.; Cash, David M.; Bocchetta, Martina; de Vita, Enrico; Metcalfe, Arron W. S.; Shirzadi, Zahra; Robertson, Andrew D.; Tartaglia, Maria Carmela; Mitchell, Sara B.; Black, Sandra E.; Freedman, Morris; Tang-Wai, David; Keren, Ron; Rogaeva, Ekaterina; van Swieten, John; Laforce, Robert; Tagliavini, Fabrizio; Borroni, Barbara; Galimberti, Daniela; Rowe, James B.; Graff, Caroline; Frisoni, Giovanni B.; Finger, Elizabeth; Sorbi, Sandro; de Mendonça, Alexandre; Rohrer, Jonathan D.; MacIntosh, Bradley J.; Masellis, Mario; GENetic Frontotemporal dementia Initiative (GENFI).

In: Brain, Vol. 142, No. 4, 2019, p. 1108-1120.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: 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 - GENetic Frontotemporal dementia Initiative (GENFI)

PY - 2019

Y1 - 2019

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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85064287422&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30847466

U2 - 10.1093/brain/awz039

DO - 10.1093/brain/awz039

M3 - Article

VL - 142

SP - 1108

EP - 1120

JO - Brain

JF - Brain

SN - 0006-8950

IS - 4

ER -