Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study
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 Panman, Janne M. Papma, Lieke Meeter, Elise G.P. Dopper, Martina Bocchetta, Emily Todd, David M. Cash, Caroline Graff, Matthis Synofzik, Fermín Moreno, Elizabeth Finger, Raquel Sánchez‐Valle, Rik Vandenberghe, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Christopher 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 J. Huang, John C. van Swieten, Jonathan D. Rohrer, Harro Seelaar, the Genetic Frontotemporal Dementia Initiative (GENFI), Sónia Afonso, Maria Rosário Almeida, Sarah Anderl‐Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiarán, Núria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Luisa Benussi, Valentina Bessi, Giuliano Binetti, Sandra E. Black, Martina Bocchetta, Sergi Borrego‐Écija, José Brás, Rose Bruffaerts, Marta Cañada, Valentina Cantoni, Paola Caroppo, David Cash, Miguel Castelo‐Branco, Rhian S. Convery, Thomas Cope, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick C. 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 Jelić, Hans‐Otto Karnath, Ron Keren, Tobias Langheinrich, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli
Abstract
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.