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Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

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dc.contributor.authorvan der Ende, Emma L.
dc.contributor.authorHeller, Carolin
dc.contributor.authorSogorb-Esteve, Aitana
dc.contributor.authorSwift, Imogen J.
dc.contributor.authorMcFall, David
dc.contributor.authorPeakman, Georgia
dc.contributor.authorBouzigues, Arabella
dc.contributor.authorPoos, Jackie M.
dc.contributor.authorJiskoot, Lize C.
dc.contributor.authorPanman, Jessica L.
dc.contributor.authorPapma, Janne M.
dc.contributor.authorBargalló, Nuria
dc.contributor.authorRohrer, Jonathan D.
dc.contributor.authorSeelaar, Harro
dc.contributor.authorAfonso, Sónia
dc.contributor.authorAlmeida, Maria Rosario
dc.contributor.authorAnderl-Straub, Sarah
dc.contributor.authorAndersson, Christin
dc.contributor.authorAntonell, Anna
dc.contributor.authorArchetti, Silvana
dc.contributor.authorBartha, Robart
dc.contributor.authorIndakoetxea, Begoña
dc.contributor.authorBender, Benjamin
dc.contributor.authorBenussi, Alberto
dc.contributor.authorBenussi, Luisa
dc.contributor.authorBessi, Valentina
dc.contributor.authorBinetti, Giuliano
dc.contributor.authorMead, Simon
dc.contributor.authorBlack, Sandra
dc.contributor.authorBorrego-Ecija, Sergi
dc.contributor.authorBras, Jose
dc.contributor.authorBruffaerts, Rose
dc.contributor.authorMitchell, Sara
dc.contributor.authorCañada, Marta
dc.contributor.authorCantoni, Valentina
dc.contributor.authorCaroppo, Paola
dc.contributor.authorCastelo-Branco, Miguel
dc.contributor.authorConvery, Rhian
dc.contributor.authorMiltenberger-Miltenyi, Gabriel
dc.contributor.authorCope, Thomas
dc.contributor.authorDi Fede, Giuseppe
dc.contributor.authorDíez, Alina
dc.contributor.authorDuro, Diana
dc.contributor.authorJelic, Vesna
dc.contributor.authorFenoglio, Chiara
dc.contributor.authorFerrari, Camilla
dc.contributor.authorFerreira, Catarina B.
dc.contributor.authorFox, Nick
dc.contributor.authorFreedman, Morris
dc.contributor.authorFumagalli, Giorgio
dc.contributor.authorvan Minkelen, Rick
dc.contributor.authorGabilondo, Alazne
dc.contributor.authorGasparotti, Roberto
dc.contributor.authorGauthier, Serge
dc.contributor.authorKarnath, Hans-Otto
dc.contributor.authorGazzina, Stefano
dc.contributor.authorGiaccone, Giorgio
dc.contributor.authorGorostidi, Ana
dc.contributor.authorGreaves, Caroline
dc.contributor.authorGuerreiro, Rita
dc.contributor.authorHoegen, Tobias
dc.contributor.authorKeren, Ron
dc.contributor.authorLangheinrich, Tobias
dc.contributor.authorLeitão, Maria João
dc.contributor.authorLladó, Albert
dc.contributor.authorLombardi, Gemma
dc.contributor.authorLoosli, Sandra
dc.contributor.authorTiraboschi, Pietro
dc.contributor.authorMaruta, Carolina
dc.contributor.authorMoore, Katrina
dc.contributor.authorNacmias, Benedetta
dc.contributor.authorNicholas, Jennifer
dc.contributor.authorÖijerstedt, Linn
dc.contributor.authorOlives, Jaume
dc.contributor.authorOurselin, Sebastien
dc.contributor.authorMeeter, Lieke H.
dc.contributor.authorPadovani, Alessandro
dc.contributor.authorPievani, Michela
dc.contributor.authorTodd, Emily
dc.contributor.authorPolito, Cristina
dc.contributor.authorPremi, Enrico
dc.contributor.authorPrioni, Sara
dc.contributor.authorPrix, Catharina
dc.contributor.authorRademakers, Rosa
dc.contributor.authorRedaelli, Veronica
dc.contributor.authorRittman, Tim
dc.contributor.authorDopper, Elise G. P.
dc.contributor.authorRogaeva, Ekaterina
dc.contributor.authorRosa-Neto, Pedro
dc.contributor.authorRossi, Giacomina
dc.contributor.authorRosser, Martin
dc.contributor.authorSantiago, Beatriz
dc.contributor.authorScarpini, Elio
dc.contributor.authorSchönecker, Sonja
dc.contributor.authorSemler, Elisa
dc.contributor.authorShafei, Rachelle
dc.contributor.authorShoesmith, Christen
dc.contributor.authorBocchetta, Martina
dc.contributor.authorTábuas-Pereira, Miguel
dc.contributor.authorVan Damme, Philip
dc.contributor.authorTainta, Mikel
dc.contributor.authorTaipa, Ricardo
dc.contributor.authorTang-Wai, David
dc.contributor.authorThomas, David L.
dc.contributor.authorThompson, Paul
dc.contributor.authorThonberg, Hakan
dc.contributor.authorTimberlake, Carolyn
dc.contributor.authorVandenbulcke, Mathieu
dc.contributor.authorVeldsman, Michele
dc.contributor.authorVerdelho, Ana
dc.contributor.authorVillanua, Jorge
dc.contributor.authorWarren, Jason
dc.contributor.authorWilke, Carlo
dc.contributor.authorArighi, Andrea
dc.contributor.authorWoollacott, Ione
dc.contributor.authorWlasich, Elisabeth
dc.contributor.authorZulaica, Miren
dc.contributor.authorCash, David
dc.contributor.authorGraff, Caroline
dc.contributor.authorSynofzik, Matthis
dc.contributor.authorMoreno, Fermin
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorSanchez-Valle, Raquel
dc.contributor.authorVandenberghe, Rik
dc.contributor.authorBalasa, Mircea
dc.contributor.authorLaforce, Robert
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, Maria Carmela
dc.contributor.authorRowe, James B.
dc.contributor.authorButler, Chris
dc.contributor.authorDucharme, Simon
dc.contributor.authorGerhard, Alexander
dc.contributor.authorDanek, Adrian
dc.contributor.authorLevin, Johannes
dc.contributor.authorPijnenburg, Yolande A. L.
dc.contributor.authorBarandiaran, Myriam
dc.contributor.authorOtto, Markus
dc.contributor.authorBorroni, Barbara
dc.contributor.authorTagliavini, Fabrizio
dc.contributor.authorDe Mendonça, Alexandre
dc.contributor.authorSantana, Isabel
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorSorbi, Sandro
dc.contributor.authorZetterberg, Henrik
dc.contributor.authorHuang, Eric
dc.contributor.authorvan Swieten, John C.
dc.date.accessioned2022-09-09T14:42:57Z
dc.date.available2022-09-09T14:42:57Z
dc.date.issued2022
dc.description© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.pt_PT
dc.description.abstractBackground: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. Methods: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Results: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. Conclusions: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.pt_PT
dc.description.sponsorshipThis study was supported in the Netherlands by Memorabel grants from Deltaplan Dementie (ZonMw and Alzheimer Nederland; grant numbers 733050813, 733050103, 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), and the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248); JDR 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); ASE supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; IJS is supported by the Alzheimer’s Association; JBR is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to RSV); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 “Solve-RD” from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding, and StratNeuro. HZ is a Wallenberg Scholar.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1186/s12974-022-02573-0pt_PT
dc.identifier.eissn1742-2094
dc.identifier.urihttp://hdl.handle.net/10451/54421
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relation.publisherversionhttps://jneuroinflammation.biomedcentral.com/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectBiomarkerpt_PT
dc.subjectComplementpt_PT
dc.subjectFrontotemporal dementiapt_PT
dc.subjectNeuroinflammationpt_PT
dc.titleElevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI studypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue1pt_PT
oaire.citation.titleJournal of Neuroinflammationpt_PT
oaire.citation.volume19pt_PT
person.familyNameCastelo-Branco
person.familyNameMiltenberger-Miltenyi
person.familyNameMaruta
person.familyNameVerdelho
person.familyNamede Mendonça
person.givenNameMiguel
person.givenNameGabriel
person.givenNameCarolina
person.givenNameAna
person.givenNameAlexandre
person.identifier351267
person.identifier.ciencia-id7A12-48FE-7B56
person.identifier.ciencia-idAE16-3A8D-0392
person.identifier.ciencia-id4B1D-5F59-6221
person.identifier.ciencia-idFC14-938F-EBBD
person.identifier.ciencia-id1615-41B4-0848
person.identifier.orcid0000-0003-4364-6373
person.identifier.orcid0000-0003-0224-1281
person.identifier.orcid0000-0003-3359-379X
person.identifier.orcid0000-0003-4945-4946
person.identifier.orcid0000-0002-0488-1453
person.identifier.ridF-3866-2019
person.identifier.scopus-author-id6701423628
person.identifier.scopus-author-id35327513800
person.identifier.scopus-author-id6602902026
person.identifier.scopus-author-id7003320823
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication16245106-f8db-49a9-be95-8806aa05dfad
relation.isAuthorOfPublication58c7f5b7-9f9d-42b6-9b39-c53dd40a79c7
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relation.isAuthorOfPublication53ca3547-99ce-4b68-9330-7879a54c47b7
relation.isAuthorOfPublication.latestForDiscovery53ca3547-99ce-4b68-9330-7879a54c47b7

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