CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.14/40953 |
Resumo: | Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementiaBackground: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.Veritati - Repositório Institucional da Universidade Católica Portuguesathe Genetic FTD Initiative, GENFIWoollacott, Ione O.C.Swift, Imogen J.Sogorb-Esteve, AitanaHeller, CarolinKnowles, KathrynBouzigues, ArabellaRussell, Lucy L.Peakman, GeorgiaGreaves, Caroline V.Convery, RhianHeslegrave, AmandaRowe, James B.Borroni, BarbaraGalimberti, DanielaTiraboschi, PietroMasellis, MarioTartaglia, Maria CarmelaFinger, Elizabethvan Swieten, John C.Seelaar, HarroJiskoot, LizeSorbi, SandroButler, Chris R.Graff, CarolineGerhard, AlexanderLaforce, RobertSanchez-Valle, Raquelde Mendonça, AlexandreMoreno, FerminSynofzik, MatthisVandenberghe, RikDucharme, SimonBer, Isabelle LeLevin, JohannesOtto, MarkusPasquier, FlorenceSantana, IsabelZetterberg, HenrikRohrer, Jonathan D.Nelson, AnnabelBocchetta, MartinaCash, DavidThomas, David L.Todd, EmilyBenotmane, HanyaNicholas, JenniferSamra, KiranMaruta, Carolinado Couto, Frederico SimõesAlmeida, Maria Rosário2023-04-26T08:50:18Z2022-112022-11-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.14/40953eng2328-950310.1002/acn3.5167285139878909PMC963963536245297000868509300001info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-14T01:36:35Zoai:repositorio.ucp.pt:10400.14/40953Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T18:33:37.911929Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
title |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
spellingShingle |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia the Genetic FTD Initiative, GENFI |
title_short |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
title_full |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
title_fullStr |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
title_full_unstemmed |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
title_sort |
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia |
author |
the Genetic FTD Initiative, GENFI |
author_facet |
the Genetic FTD Initiative, GENFI Woollacott, Ione O.C. Swift, Imogen J. Sogorb-Esteve, Aitana Heller, Carolin Knowles, Kathryn Bouzigues, Arabella Russell, Lucy L. Peakman, Georgia Greaves, Caroline V. Convery, Rhian Heslegrave, Amanda Rowe, James B. Borroni, Barbara Galimberti, Daniela Tiraboschi, Pietro Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth van Swieten, John C. Seelaar, Harro Jiskoot, Lize Sorbi, Sandro Butler, Chris R. Graff, Caroline Gerhard, Alexander Laforce, Robert Sanchez-Valle, Raquel de Mendonça, Alexandre Moreno, Fermin Synofzik, Matthis Vandenberghe, Rik Ducharme, Simon Ber, Isabelle Le Levin, Johannes Otto, Markus Pasquier, Florence Santana, Isabel Zetterberg, Henrik Rohrer, Jonathan D. Nelson, Annabel Bocchetta, Martina Cash, David Thomas, David L. Todd, Emily Benotmane, Hanya Nicholas, Jennifer Samra, Kiran Maruta, Carolina do Couto, Frederico Simões Almeida, Maria Rosário |
author_role |
author |
author2 |
Woollacott, Ione O.C. Swift, Imogen J. Sogorb-Esteve, Aitana Heller, Carolin Knowles, Kathryn Bouzigues, Arabella Russell, Lucy L. Peakman, Georgia Greaves, Caroline V. Convery, Rhian Heslegrave, Amanda Rowe, James B. Borroni, Barbara Galimberti, Daniela Tiraboschi, Pietro Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth van Swieten, John C. Seelaar, Harro Jiskoot, Lize Sorbi, Sandro Butler, Chris R. Graff, Caroline Gerhard, Alexander Laforce, Robert Sanchez-Valle, Raquel de Mendonça, Alexandre Moreno, Fermin Synofzik, Matthis Vandenberghe, Rik Ducharme, Simon Ber, Isabelle Le Levin, Johannes Otto, Markus Pasquier, Florence Santana, Isabel Zetterberg, Henrik Rohrer, Jonathan D. Nelson, Annabel Bocchetta, Martina Cash, David Thomas, David L. Todd, Emily Benotmane, Hanya Nicholas, Jennifer Samra, Kiran Maruta, Carolina do Couto, Frederico Simões Almeida, Maria Rosário |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Veritati - Repositório Institucional da Universidade Católica Portuguesa |
dc.contributor.author.fl_str_mv |
the Genetic FTD Initiative, GENFI Woollacott, Ione O.C. Swift, Imogen J. Sogorb-Esteve, Aitana Heller, Carolin Knowles, Kathryn Bouzigues, Arabella Russell, Lucy L. Peakman, Georgia Greaves, Caroline V. Convery, Rhian Heslegrave, Amanda Rowe, James B. Borroni, Barbara Galimberti, Daniela Tiraboschi, Pietro Masellis, Mario Tartaglia, Maria Carmela Finger, Elizabeth van Swieten, John C. Seelaar, Harro Jiskoot, Lize Sorbi, Sandro Butler, Chris R. Graff, Caroline Gerhard, Alexander Laforce, Robert Sanchez-Valle, Raquel de Mendonça, Alexandre Moreno, Fermin Synofzik, Matthis Vandenberghe, Rik Ducharme, Simon Ber, Isabelle Le Levin, Johannes Otto, Markus Pasquier, Florence Santana, Isabel Zetterberg, Henrik Rohrer, Jonathan D. Nelson, Annabel Bocchetta, Martina Cash, David Thomas, David L. Todd, Emily Benotmane, Hanya Nicholas, Jennifer Samra, Kiran Maruta, Carolina do Couto, Frederico Simões Almeida, Maria Rosário |
description |
Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-11 2022-11-01T00:00:00Z 2023-04-26T08:50:18Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.14/40953 |
url |
http://hdl.handle.net/10400.14/40953 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2328-9503 10.1002/acn3.51672 85139878909 PMC9639635 36245297 000868509300001 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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