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

Emma L. van der Ende, Carolin Heller, on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), 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 MorenoElizabeth Finger, Raquel Sanchez-Valle, Rik Vandenberghe, Robert Laforce, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number217
JournalJournal of Neuroinflammation
Volume19
Issue number1
DOIs
Publication statusPublished - 1 Dec 2022

Bibliographical note

Funding Information:
We thank all participants and their family members for taking part in this study. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID no. 739510. GENFI consortium author list: Sónia Afonso, Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal; Maria Rosario Almeida, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Sarah Anderl-Straub, Department of Neurology, University of Ulm, Ulm, Germany; Christin Andersson, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Anna Antonell, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Silvana Archetti, Biotechnology Laboratory, Department of Diagnostics, ASST Brescia Hospital, Brescia, Italy; Andrea Arighi, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Mircea Balasa, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Myriam Barandiaran, Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Nuria Bargalló, Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain; Robart Bartha, Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada; Centre for Functional and Metabolic Mapping, Robarts Research Institute, The University of Western Ontario, London, Ontario, Canada; Benjamin Bender, Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany; Alberto Benussi, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Luisa Benussi, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Valentina Bessi, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy ; Giuliano Binetti, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sandra Black, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; Martina Bocchetta, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Sergi Borrego-Ecija, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Jose Bras, Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USA; Rose Bruffaerts, Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium; Marta Cañada, CITA Alzheimer, San Sebastian, Gipuzkoa, Spain; Valentina Cantoni, Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy; Paola Caroppo, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; David Cash, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Miguel Castelo-Branco, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Rhian Convery, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Thomas Cope, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK; Giuseppe Di Fede, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Alina Díez, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Diana Duro, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Chiara Fenoglio, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Camilla Ferrari, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Catarina B. Ferreira, Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Nick Fox, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Morris Freedman, Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada; Giorgio Fumagalli, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Alazne Gabilondo, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Roberto Gasparotti, Neuroradiology Unit, University of Brescia, Brescia, Italy; Serge Gauthier, Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada; Stefano Gazzina, Neurology, ASST Brescia Hospital, Brescia, Italy; Giorgio Giaccone, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Ana Gorostidi, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Caroline Greaves, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Rita Guerreiro, Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USA; Tobias Hoegen, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Begoña Indakoetxea, Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Vesna Jelic, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden; Hans-Otto Karnath, Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; Ron Keren, The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada; Tobias Langheinrich, Manchester Centre for Clinical Neurosciences, Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK;; Manchester Centre for Clinical Neurosciences, Department of Neurology, Salford Royal NHS Foundation Trust, Manchester, UK; Maria João Leitão, Centre of Neurosciences and Cell Biology, Universidade de Coimbra, Coimbra, Portugal; Albert Lladó, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Gemma Lombardi, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Sandra Loosli, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Carolina Maruta, Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Simon Mead, MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK; Gabriel Miltenberger, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Rick van Minkelen, Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands; Sara Mitchell, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada; Katrina Moore, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Benedetta Nacmias, Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; Jennifer Nicholas, Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK; Linn Öijerstedt, Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet, Solna, Sweden; Unit for Hereditary Dementias, Theme Aging, Karolinska University Hospital, Solna, Sweden ; Jaume Olives, Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain; Sebastien Ourselin, School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK; Alessandro Padovani, Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Georgia Peakman, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Michela Pievani, Istituto di Ricovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Cristina Polito, Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Nuclear Medicine Unit, University of Florence, Florence, Italy; Enrico Premi, Stroke Unit, ASST Brescia Hospital, Brescia, Italy; Sara Prioni, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Catharina Prix, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Rosa Rademakers, Department of Neurosciences, Mayo Clinic, Jacksonville, Florida, USA; Veronica Redaelli, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Tim Rittman, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Ekaterina Rogaeva, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada; Pedro Rosa-Neto, Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada; Giacomina Rossi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Martin Rosser, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Beatriz Santiago, Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Elio Scarpini, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Sonja Schönecker, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Elisa Semler, Department of Neurology, University of Ulm, Ulm; Rachelle Shafei, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Christen Shoesmith, Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada; Miguel Tábuas-Pereira, Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal; Mikel Tainta, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain; Ricardo Taipa, Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto—Hospital de Santo António, Oporto, Portugal; David Tang-Wai, The University Health Network, Krembil Research Institute, Toronto, Canada; David L Thomas, Neuroimaging Analysis Centre, Department of Brain Repair and Rehabilitation, UCL Institute of Neurology, Queen Square, London, UK; Paul Thompson, Division of Neuroscience and Experimental Psychology, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK; Hakan Thonberg, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden; Carolyn Timberlake, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Pietro Tiraboschi, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Emily Todd, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Philip Van Damme, Neurology Service, University Hospitals Leuven, Belgium; Laboratory for Neurobiology, VIB-KU Leuven Centre for Brain Research, Leuven, Belgium; Mathieu Vandenbulcke, Geriatric Psychiatry Service, University Hospitals Leuven, Belgium; Neuropsychiatry, Department of Neurosciences, KU Leuven, Leuven, Belgium; Michele Veldsman, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK; Ana Verdelho, Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte—Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Jorge Villanua, OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain; Jason Warren, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Carlo Wilke, Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany; Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Ione Woollacott, Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK; Elisabeth Wlasich, Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany; Miren Zulaica, Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Gipuzkoa, Spain

Funding Information:
This study was supported in the Netherlands by Memorabel grants from Deltaplan Dementie (ZonMw and Alzheimer Nederland; grant numbers 733050813, 733050103, 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), and the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248); JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); ASE supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; IJS is supported by the Alzheimer’s Association; JBR is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to RSV); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 “Solve-RD” from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding, and StratNeuro. HZ is a Wallenberg Scholar.

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© 2022, The Author(s).

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