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

Journal of Neuroinflammation, ISSN: 1742-2094, Vol: 19, Issue: 1, Page: 217
2022
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Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study.

J Neuroinflammation. 2022 Sep 5;19(1):217. 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 EG, Bocchetta M, Todd E, Cash D, Graff C, Synofzik M, Moreno F, Finger E, Sanchez-Valle R, Vandenberghe R, Laforce R Jr, Masellis M, Tartaglia MC, Rowe JB, Butler C, Ducharme S, Gerhard A, Danek A, Le

Article Description

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.

Bibliographic Details

Emma L. van der Ende; Carolin Heller; Aitana Sogorb-Esteve; Imogen J. Swift; David McFall; Georgia Peakman; Arabella Bouzigues; Jackie M. Poos; Lize C. Jiskoot; Jessica L. Panman; Janne M. Papma; Lieke H. Meeter; Elise G. P. Dopper; Martina Bocchetta; Emily Todd; David Cash; Caroline Graff; Matthis Synofzik; Fermin Moreno; Elizabeth Finger; Raquel Sanchez-Valle; Rik Vandenberghe; Robert Laforce Jr; Mario Masellis; Maria Carmela Tartaglia; James B. Rowe; Chris Butler; Simon Ducharme; Alexander Gerhard; Adrian Danek; Johannes Levin; Yolande A. L. Pijnenburg; Markus Otto; Barbara Borroni; Fabrizio Tagliavini; Alexandre de Mendonça; Isabel Santana; Daniela Galimberti; Sandro Sorbi; Henrik Zetterberg; Eric Huang; John C. van Swieten; Jonathan D. Rohrer; Harro Seelaar; Sónia Afonso; Maria Rosario Almeida; 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; Sergi Borrego-Ecija; Jose Bras; Rose Bruffaerts; Marta Cañada; Valentina Cantoni; Paola Caroppo; Miguel Castelo-Branco; Rhian Convery; Thomas Cope; Giuseppe Di Fede; Alina Díez; Diana Duro; Chiara Fenoglio; Camilla Ferrari; Catarina B. Ferreira; Nick Fox; Morris Freedman; Giorgio Fumagalli; Alazne Gabilondo; Roberto Gasparotti; Serge Gauthier; Stefano Gazzina; Giorgio Giaccone; Ana Gorostidi; Caroline Greaves; Rita Guerreiro; Tobias Hoegen; Begoña Indakoetxea; Vesna Jelic; Hans-Otto Karnath; Ron Keren; Tobias Langheinrich; Maria João Leitão; Albert Lladó; Gemma Lombardi; Sandra Loosli; Carolina Maruta; Simon Mead; Gabriel Miltenberger; Rick van Minkelen; Sara Mitchell; Katrina Moore; Benedetta Nacmias; Jennifer Nicholas; Linn Öijerstedt; Jaume Olives; Sebastien Ourselin; Alessandro Padovani; Michela Pievani; Cristina Polito; Enrico Premi; Sara Prioni; Catharina Prix; Rosa Rademakers; Veronica Redaelli; Tim Rittman; Ekaterina Rogaeva; Pedro Rosa-Neto; Giacomina Rossi; Martin Rosser; Beatriz Santiago; Elio Scarpini; Sonja Schönecker; Elisa Semler; Rachelle Shafei; Christen Shoesmith; Miguel Tábuas-Pereira; Mikel Tainta; Ricardo Taipa; David Tang-Wai; David L. Thomas; Paul Thompson; Hakan Thonberg; Carolyn Timberlake; Pietro Tiraboschi; Philip Van Damme; Mathieu Vandenbulcke; Michele Veldsman; Ana Verdelho; Jorge Villanua; Jason Warren; Carlo Wilke; Ione Woollacott; Elisabeth Wlasich; Miren Zulaica

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Neuroscience; Immunology and Microbiology

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