Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study.
Biomarker
Complement
Frontotemporal dementia
Neuroinflammation
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
05 Sep 2022
05 Sep 2022
Historique:
received:
30
01
2022
accepted:
19
08
2022
entrez:
5
9
2022
pubmed:
6
9
2022
medline:
8
9
2022
Statut:
epublish
Résumé
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. 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). 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 36064709
doi: 10.1186/s12974-022-02573-0
pii: 10.1186/s12974-022-02573-0
pmc: PMC9446850
doi:
Substances chimiques
Biomarkers
0
C9orf72 Protein
0
Complement C1q
80295-33-6
Complement System Proteins
9007-36-7
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
217Subventions
Organisme : ZonMw
ID : 733050813, 733050103, 733050513
Pays : Netherlands
Organisme : Alzheimer Nederland
ID : 733050813, 733050103, 733050513
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008525/1
Pays : United Kingdom
Organisme : Stichting Dioraphte
ID : 14021300
Organisme : Deutsche Forschungsgemeinschaft
ID : 390857198
Organisme : Medical Research Council
ID : MR/M023664/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T046015/1
Pays : United Kingdom
Organisme : Horizon 2020 Framework Programme
ID : 779357
Organisme : fundacio marato de TV3
ID : 20143810
Organisme : Wellcome Trust
ID : 103838
Pays : United Kingdom
Organisme : NIHR Rare Disease Translational Research Collaboration
ID : BRC149/NS/MH
Organisme : EU Joint Programme - Neurodegenerative Disease Research
ID : 733051042, 733051024
Organisme : Vetenskapsrådet
ID : 529-2014-7504
Organisme : EU Joint Programme - Neurodegenerative Disease Research
ID : 2019-02248
Investigateurs
Sónia Afonso
(S)
Maria Rosario Almeida
(MR)
Sarah Anderl-Straub
(S)
Christin Andersson
(C)
Anna Antonell
(A)
Silvana Archetti
(S)
Andrea Arighi
(A)
Mircea Balasa
(M)
Myriam Barandiaran
(M)
Nuria Bargalló
(N)
Robart Bartha
(R)
Benjamin Bender
(B)
Alberto Benussi
(A)
Luisa Benussi
(L)
Valentina Bessi
(V)
Giuliano Binetti
(G)
Sandra Black
(S)
Martina Bocchetta
(M)
Sergi Borrego-Ecija
(S)
Jose Bras
(J)
Rose Bruffaerts
(R)
Marta Cañada
(M)
Valentina Cantoni
(V)
Paola Caroppo
(P)
David Cash
(D)
Miguel Castelo-Branco
(M)
Rhian Convery
(R)
Thomas Cope
(T)
Giuseppe Di Fede
(G)
Alina Díez
(A)
Diana Duro
(D)
Chiara Fenoglio
(C)
Camilla Ferrari
(C)
Catarina B Ferreira
(CB)
Nick Fox
(N)
Morris Freedman
(M)
Giorgio Fumagalli
(G)
Alazne Gabilondo
(A)
Roberto Gasparotti
(R)
Serge Gauthier
(S)
Stefano Gazzina
(S)
Giorgio Giaccone
(G)
Ana Gorostidi
(A)
Caroline Greaves
(C)
Rita Guerreiro
(R)
Tobias Hoegen
(T)
Begoña Indakoetxea
(B)
Vesna Jelic
(V)
Hans-Otto Karnath
(HO)
Ron Keren
(R)
Tobias Langheinrich
(T)
Maria João Leitão
(MJ)
Albert Lladó
(A)
Gemma Lombardi
(G)
Sandra Loosli
(S)
Carolina Maruta
(C)
Simon Mead
(S)
Gabriel Miltenberger
(G)
Rick van Minkelen
(R)
Sara Mitchell
(S)
Katrina Moore
(K)
Benedetta Nacmias
(B)
Jennifer Nicholas
(J)
Linn Öijerstedt
(L)
Jaume Olives
(J)
Sebastien Ourselin
(S)
Alessandro Padovani
(A)
Georgia Peakman
(G)
Michela Pievani
(M)
Cristina Polito
(C)
Enrico Premi
(E)
Sara Prioni
(S)
Catharina Prix
(C)
Rosa Rademakers
(R)
Veronica Redaelli
(V)
Tim Rittman
(T)
Ekaterina Rogaeva
(E)
Pedro Rosa-Neto
(P)
Giacomina Rossi
(G)
Martin Rosser
(M)
Beatriz Santiago
(B)
Elio Scarpini
(E)
Sonja Schönecker
(S)
Elisa Semler
(E)
Rachelle Shafei
(R)
Christen Shoesmith
(C)
Miguel Tábuas-Pereira
(M)
Mikel Tainta
(M)
Ricardo Taipa
(R)
David Tang-Wai
(D)
David L Thomas
(DL)
Paul Thompson
(P)
Hakan Thonberg
(H)
Carolyn Timberlake
(C)
Pietro Tiraboschi
(P)
Emily Todd
(E)
Philip Van Damme
(P)
Mathieu Vandenbulcke
(M)
Michele Veldsman
(M)
Ana Verdelho
(A)
Jorge Villanua
(J)
Jason Warren
(J)
Carlo Wilke
(C)
Ione Woollacott
(I)
Elisabeth Wlasich
(E)
Miren Zulaica
(M)
Informations de copyright
© 2022. The Author(s).
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