Journal of Neuroinflammation (Sep 2022)
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 L. Panman,
- Janne M. Papma,
- Lieke H. Meeter,
- Elise G. P. Dopper,
- Martina Bocchetta,
- Emily Todd,
- David Cash,
- Caroline Graff,
- Matthis Synofzik,
- Fermin Moreno,
- Elizabeth 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,
- the Genetic Frontotemporal Dementia Initiative (GENFI)
Affiliations
- Emma L. van der Ende
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Carolin Heller
- UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology
- Aitana Sogorb-Esteve
- UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology
- Imogen J. Swift
- UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology
- David McFall
- Department of Pathology, University of California San Francisco
- Georgia Peakman
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- Arabella Bouzigues
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- Jackie M. Poos
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Lize C. Jiskoot
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Jessica L. Panman
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Janne M. Papma
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Lieke H. Meeter
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Elise G. P. Dopper
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Martina Bocchetta
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- Emily Todd
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- David Cash
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- Caroline Graff
- Center for Alzheimer Research, Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Bioclinicum, Karolinska Institutet
- Matthis Synofzik
- German Center for Neurodegenerative Diseases (DZNE)
- Fermin Moreno
- Cognitive Disorders Unit, Department of Neurology, Hospital Universitario Donostia
- Elizabeth Finger
- Department of Clinical Neurological Sciences, University of Western Ontario
- Raquel Sanchez-Valle
- Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clinic, IDIBAPS, University of Barcelona
- Rik Vandenberghe
- Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, KU Leuven
- Robert Laforce
- Clinique Interdisciplinaire de Mémoire, Département Des Sciences Neurologiques, CHU de Québec, Université Laval
- Mario Masellis
- Sunnybrook Research Institute
- Maria Carmela Tartaglia
- Tanz Centre for Research in Neurodegenerative Disease, University of Toronto
- James B. Rowe
- Cambridge University Centre for Frontotemporal Dementia, University of Cambridge
- Chris Butler
- Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford
- Simon Ducharme
- McConnell Brain Imaging Centre, Montreal Neurological Institute and McGill University Health Centre, McGill University
- Alexander Gerhard
- Department of Nuclear Medicine and Geriatric Medicine, University Hospital Essen
- Adrian Danek
- Neurologische Klinik Und Poliklinik, Ludwig-Maximilians-Universität München
- Johannes Levin
- Neurologische Klinik Und Poliklinik, Ludwig-Maximilians-Universität München
- Yolande A. L. Pijnenburg
- Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC
- Markus Otto
- Department of Neurology, Universität Ulm
- Barbara Borroni
- Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia
- Fabrizio Tagliavini
- Fondazione IRCCS Istituto Neurologico Carlo Besta
- Alexandre de Mendonça
- Faculdade de Medicina da Universidade de Lisboa
- Isabel Santana
- Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra
- Daniela Galimberti
- Fondazione IRCCS, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit
- Sandro Sorbi
- Department of Neurofarba, University of Florence
- Henrik Zetterberg
- UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology
- Eric Huang
- Department of Pathology, University of California San Francisco
- John C. van Swieten
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- Jonathan D. Rohrer
- Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London
- Harro Seelaar
- Alzheimer Center Rotterdam and Department of Neurology, Erasmus University Medical Center
- the Genetic Frontotemporal Dementia Initiative (GENFI)
- DOI
- https://doi.org/10.1186/s12974-022-02573-0
- Journal volume & issue
-
Vol. 19,
no. 1
pp. 1 – 13
Abstract
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.
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