1. Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study
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van der Ende, Emma L, Heller, Carolin, Papma, Janne M, Maruta, Carolina, Mead, Simon, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Meeter, Lieke H, Ourselin, Sebastien, Padovani, Alessandro, Peakman, Georgia, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Dopper, Elise G P, Rittman, Tim, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rosser, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Bocchetta, Martina, 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, Cash, David, Zulaica, Miren, Graff, Caroline, Synofzik, Matthis, Moreno, Fermin, Finger, Elizabeth, Sogorb-Esteve, Aitana, Sanchez-Valle, Raquel, Vandenberghe, Rik, Laforce, Robert, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Butler, Chris, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Swift, Imogen J, Levin, Johannes, Pijnenburg, Yolande A L, Otto, Markus, Borroni, Barbara, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Galimberti, Daniela, Sorbi, Sandro, Zetterberg, Henrik, McFall, David, Huang, Eric, van Swieten, John C, Rohrer, Jonathan D, Seelaar, Harro, Initiative, Genetic Frontotemporal Dementia, 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, Bouzigues, Arabella, Binetti, Giuliano, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Poos, Jackie M, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Jiskoot, Lize C, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Panman, Jessica L, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Langheinrich, Tobias, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Apollo - University of Cambridge Repository, Levin, Johannes [0000-0001-5092-4306], Repositório da Universidade de Lisboa, Genetic Frontotemporal Dementia Initiative (GENFI), Neurology, Erasmus MC other, Clinical Psychology, and Amsterdam Neuroscience - Neurodegeneration
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Biomarker ,Complement ,Frontotemporal dementia ,Neuroinflammation ,Immunology ,Medizin ,diagnostic imaging [Frontotemporal Dementia] ,Cohort Studies ,Cellular and Molecular Neuroscience ,CEREBROSPINAL-FLUID ,Pick Disease of the Brain ,Settore BIO/13 - Biologia Applicata ,CRITERIA ,Humans ,ddc:610 ,C3 ,genetics [C9orf72 Protein] ,genetics [Frontotemporal Dementia] ,Biology ,Science & Technology ,C9orf72 Protein ,General Neuroscience ,Complement C1q ,Research ,Neurosciences ,Biomarkers ,Complement System Proteins ,Frontotemporal Dementia ,ALZHEIMERS-DISEASE ,Neurology ,CHAIN ,Neurosciences & Neurology ,Human medicine ,genetics [Complement System Proteins] ,Life Sciences & Biomedicine - Abstract
Funder: The Bluefield Project, Funder: UK Dementia Research Institute; doi: http://dx.doi.org/10.13039/501100017510, Funder: Alzheimer's Society; doi: http://dx.doi.org/10.13039/501100000320, Funder: schorling foundation, Funder: Swedish brain foundation, Funder: swedish alzheimer foundation, Funder: Stockholm Council ALF, Funder: Demensfonden; doi: http://dx.doi.org/10.13039/501100021594, Funder: Gun och Bertil Stohnes Stiftelse; doi: http://dx.doi.org/10.13039/100009673, Funder: Stiftelsen för Gamla Tjänarinnor; doi: http://dx.doi.org/10.13039/100010815, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Stratneuro, Funder: Mady Browaeys Fonds, Funder: Knut och Alice Wallenbergs Stiftelse; doi: http://dx.doi.org/10.13039/501100004063, 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.
- Published
- 2022
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