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Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study
Authors
Sónia Afonso
Maria Rosario Almeida
+144 more
Sarah Anderl-Straub
Christin Andersson
Anna Antonell
Silvana Archetti
Andrea Arighi
Mircea Balasa
Myriam Barandiaran
Nuria Bargalló
Robart Bartha
Benjamin Bender
Alberto Benussi
Luisa Benussi
Valentina Bessi
Giuliano Binetti
Sandra Black
Martina Bocchetta
Sergi Borrego-Ecija
Barbara Borroni
Arabella Bouzigues
Jose Bras
Rose Bruffaerts
Chris Butler
Valentina Cantoni
Paola Caroppo
David Cash
Miguel Castelo-Branco
Marta Cañada
Rhian Convery
Thomas Cope
Adrian Danek
Alexandre De Mendonça
Giuseppe Di Fede
Elise G. P. Dopper
Simon Ducharme
Diana Duro
Alina Díez
Chiara Fenoglio
Camilla Ferrari
Catarina B. Ferreira
Elizabeth Finger
Nick Fox
Morris Freedman
Giorgio Fumagalli
Alazne Gabilondo
Daniela Galimberti
Roberto Gasparotti
Serge Gauthier
Stefano Gazzina
Alexander Gerhard
Giorgio Giaccone
Ana Gorostidi
Caroline Graff
Caroline Greaves
Rita Guerreiro
Carolin Heller
Tobias Hoegen
Eric Huang
Begoña Indakoetxea
Vesna Jelic
Lize C. Jiskoot
Hans-Otto Karnath
Ron Keren
Robert Laforce
Tobias Langheinrich
Maria João Leitão
Johannes Levin
Albert Lladó
Gemma Lombardi
Sandra Loosli
Carolina Maruta
Mario Masellis
David McFall
Simon Mead
Lieke H. Meeter
Gabriel Miltenberger-Miltenyi
Sara Mitchell
Katrina Moore
Fermin Moreno
Benedetta Nacmias
Jennifer Nicholas
Jaume Olives
Markus Otto
Sebastien Ourselin
Alessandro Padovani
Jessica L. Panman
Janne M. Papma
Georgia Peakman
Michela Pievani
Yolande A. L. Pijnenburg
Cristina Polito
Jackie M. Poos
Enrico Premi
Sara Prioni
Catharina Prix
Rosa Rademakers
Veronica Redaelli
Tim Rittman
Ekaterina Rogaeva
Jonathan D. Rohrer
Pedro Rosa-Neto
Martin Rosser
Giacomina Rossi
James B. Rowe
Raquel Sanchez-Valle
Isabel Santana
Beatriz Santiago
Elio Scarpini
Sonja Schönecker
Harro Seelaar
Elisa Semler
Rachelle Shafei
Christen Shoesmith
Aitana Sogorb-Esteve
Sandro Sorbi
Imogen J. Swift
Matthis Synofzik
Fabrizio Tagliavini
Mikel Tainta
Ricardo Taipa
David Tang-Wai
Maria Carmela Tartaglia
David L. Thomas
Paul Thompson
Hakan Thonberg
Carolyn Timberlake
Pietro Tiraboschi
Emily Todd
Miguel Tábuas-Pereira
Philip Van Damme
Emma L. van der Ende
Rick van Minkelen
John C. van Swieten
Rik Vandenberghe
Mathieu Vandenbulcke
Michele Veldsman
Ana Verdelho
Jorge Villanua
Jason Warren
Carlo Wilke
Elisabeth Wlasich
Ione Woollacott
Henrik Zetterberg
Miren Zulaica
Linn Öijerstedt
Publication date
1 January 2022
Publisher
'Springer Science and Business Media LLC'
Doi
Cite
Abstract
© 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.Background: 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.This 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.info:eu-repo/semantics/publishedVersio
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Last time updated on 06/10/2022