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

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.