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Title: Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study
Authors: van der Ende, EL
Heller, C
Sogorb-Esteve, A
Swift, IJ
McFall, D
Peakman, G
Bouzigues, A
Poos, JM
Jiskoot, LC
Panman, JL
Papma, JM
Meeter, LH
Dopper, EGP
Bocchetta, M
Todd, E
Cash, D
Graff, C
Synofzik, M
Moreno, F
Finger, E
Sanchez-Valle, R
Vandenberghe, R
Laforce, R
Masellis, M
Tartaglia, MC
Rowe, JB
Butler, C
Ducharme, S
Gerhard, A
Danek, A
Levin, J
Pijnenburg, YAL
Otto, M
Borroni, B
Tagliavini, F
de Mendonça, A
Santana, I
Galimberti, D
Sorbi, S
Zetterberg, H
Huang, E
van Swieten, JC
Rohrer, JD
Seelaar, H
Afonso, S
Almeida, MR
Anderl-Straub, S
Andersson, C
Antonell, A
Archetti, S
Arighi, A
Balasa, M
Barandiaran, M
Bargalló, N
Bartha, R
Bender, B
Benussi, A
Benussi, L
Bessi, V
Binetti, G
Black, S
Borrego-Ecija, S
Bras, J
Bruffaerts, R
Cañada, M
Cantoni, V
Caroppo, P
Cash, D
Castelo-Branco, M
Convery, R
Cope, T
Di Fede, G
Díez, A
Duro, D
Fenoglio, C
Ferrari, C
Ferreira, CB
Fox, N
Freedman, M
Fumagalli, G
Gabilondo, A
Gasparotti, R
Gauthier, S
Gazzina, S
Giaccone, G
Gorostidi, A
Greaves, C
Guerreiro, R
Hoegen, T
Indakoetxea, B
Jelic, V
Karnath, HO
Keren, R
Langheinrich, T
Leitão, MJ
Lladó, A
Lombardi, G
Loosli, S
Maruta, C
Mead, S
Keywords: biomarker;complement;frontotemporal dementia;neuroinflammation
Issue Date: 5-Sep-2022
Publisher: BioMed Central (part of Springer Nature)
Citation: van der Ende, E.L. et al. (2022) 'Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study', Journal of Neuroinflammation, 19 (1), 217 , pp. 1 - 13. doi: 10.1186/s12974-022-02573-0.
Abstract: Copyright © The Author(s) 2022. 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.
Description: Availability of data and materials: The raw data of this project are part of GENFI. De-identified patient data can be accessed upon reasonable request to
Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID no. 739510.
Supplementary Information: Additional file 1 of Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study. Available at: Additional file 1: Table S1. Number of samples for each of the analytes in CSF and plasma. Table S2. Correlations between complement proteins and age. Table S3. Correlations between grey matter volume and (a) CSF and (b) plasma complement protein concentration. Table S4. Correlations between clinical measures of disease severity and (a) CSF and (b) plasma complement proteins. Table S5. Correlations between plasma complement factors. Table S6. Correlations between plasma complement proteins, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Table S7. Complement protein levels of seven presymptomatic carriers who became symptomatic during follow-up (‘converters’). Figure S1. Correlations between CSF C1q, C3b and disease duration. P-values were derived from Spearman’s rho.
Other Identifiers: ORCID iD: Martina Bocchetta
Appears in Collections:Dept of Life Sciences Research Papers

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