Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study.
Creators: name: Van Der Ende, Emma L
name: Heller, Carolin
name: Sogorb-Esteve, Aitana
name: Swift, Imogen J
name: McFall, David
name: Peakman, Georgia
name: Bouzigues, Arabella
name: Poos, Jackie M
name: Jiskoot, Lize C
name: Panman, Jessica L
name: Papma, Janne M
name: Meeter, Lieke H
name: Dopper, Elise GP
name: Bocchetta, Martina
name: Todd, Emily
name: Cash, David
name: Graff, Caroline
name: Synofzik, Matthis
name: Moreno, Fermin
name: Finger, Elizabeth
name: Sanchez-Valle, Raquel
name: Vandenberghe, Rik
name: Laforce, Robert
name: Masellis, Mario
name: Tartaglia, Maria Carmela
name: Rowe, James B
name: Butler, Chris
name: Ducharme, Simon
name: Gerhard, Alexander
name: Danek, Adrian
name: Levin, Johannes
name: Pijnenburg, Yolande AL
name: Otto, Markus
name: Borroni, Barbara
name: Tagliavini, Fabrizio
name: De Mendonça, Alexandre
name: Santana, Isabel
name: Galimberti, Daniela
name: Sorbi, Sandro
name: Zetterberg, Henrik
name: Huang, Eric
name: Van Swieten, John C
name: Rohrer, Jonathan D
name: Seelaar, Harro
name: Genetic Frontotemporal Dementia Initiative (GENFI)
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: Research
Biomarker
Complement
Frontotemporal dementia
Neuroinflammation

description: Funder: The Bluefield Project
description: Funder: UK Dementia Research Institute; doi: http://dx.doi.org/10.13039/501100017510
description: Funder: Alzheimer's Society; doi: http://dx.doi.org/10.13039/501100000320
description: Funder: schorling foundation
description: Funder: Swedish brain foundation
description: Funder: swedish alzheimer foundation
description: Funder: Stockholm Council ALF
description: Funder: Demensfonden; doi: http://dx.doi.org/10.13039/501100021594
description: Funder: Gun och Bertil Stohnes Stiftelse; doi: http://dx.doi.org/10.13039/100009673
description: Funder: Stiftelsen för Gamla Tjänarinnor; doi: http://dx.doi.org/10.13039/100010815
description: Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047
description: Funder: Stratneuro
description: Funder: Mady Browaeys Fonds
description: Funder: Knut och Alice Wallenbergs Stiftelse; doi: http://dx.doi.org/10.13039/501100004063
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.