Background There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker.
Methods Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman’s correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures.
Results Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, –61.3 to 54.6), MAPT mutations (12.7, –33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe.
Conclusions Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.
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Collaborators Martin N Rossor, Jason D Warren (Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK); Nick C Fox (Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Dementia Research Institute, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK); Rita Guerreiro, Jose Bras (Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA); Jennifer Nicholas (Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK); Simon Mead (MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK); Lize Jiskoot, Lieke Meeter, Jessica Panman, Janne Papma (Department of Neurology, Erasmus Medical Centre, Rotterdam, Netherlands); Rick van Minkelen (Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, Netherlands); Yolanda Pijnenburg (Amsterdam University Medical Centre, Amsterdam VUmc, Amsterdam, Netherlands); Myriam Barandiaran, Begoña Indakoetxea (Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Gipuzkoa, Spain; Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain); Alazne Gabilondo, Mikel Tainta, Maria de Arriba, Ana Gorostidi, Miren Zulaica (Neuroscience Area, Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain); Jorge Villanua (OSATEK, University of Donostia, San Sebastian, Gipuzkoa, Spain); Zigor Diaz (1CITA Alzheimer, San Sebastian, Gipuzkoa, Spain); Sergi Borrego-Ecija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell (Alzheimer’s disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain); Nuria Bargallo (Imaging Diagnostic Center, Hospital Clínic, Barcelona, Spain), Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani (Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy); Roberto Gasparotti (Neuroradiology Unit, University of Brescia, Brescia, Italy); Silvana Archetti (Biotechnology Laboratory, Department of Diagnostics, Spedali Civili Hospital, Brescia, Italy), Sandra Black, Sara Mitchell (Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada); Ekaterina Rogaeva (Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada); Morris Freedman (Baycrest Health Sciences, Rotman Research Institute, University of Toronto, Toronto, Canada), Ron Keren (The University Health Network, Toronto Rehabilitation Institute, Toronto, Canada); David Tang-Wai (The University Health Network, Krembil Research Institute, Toronto, Canada); Linn Öijerstedt (Department of Geriatric Medicine, Karolinska University Hospital-Huddinge, Stockholm, Sweden); Christin Andersson (Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden); Vesna Jelic (Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden); Hakan Thonberg (Center for Alzheimer Research, Divison of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden); Andrea Arighi, Chiara Fenoglio, Elio Scarpini (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy); Giorgio Fumagalli (Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy; University of Milan, Centro Dino Ferrari, Milan, Italy; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy); Thomas Cope, Carolyn Timberlake, Timothy Rittman (Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK); Christen Shoesmith (Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario Canada); 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); Rosa Rademakers (Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA); 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), Hans-Otto Karnarth (Division of Neuropsychology, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany); Benjamin Bender (Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany), Rose Bruffaerts (Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Leuven, Belgium); Philip Vandamme (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); Catarina B Ferreira (Laboratory of Neurosciences, Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal); Gabriel Miltenberger (45Faculty of Medicine, University of Lisbon, Lisbon, Portugal); Carolina Maruta (Laboratory of Language Research, Centro de Estudos Egas Moniz, Faculty of Medicine, University of Lisbon, Lisbon, Portugal); Ana Verdelho (Department of Neurosciences and Mental Health, Centro Hospitalar Lisboa Norte - Hospital de Santa Maria & Faculty of Medicine, University of Lisbon, Lisbon, Portugal); Sónia Afonso (Instituto Ciencias Nucleares Aplicadas a Saude, Universidade de Coimbra, Coimbra, Portugal); Ricardo Taipa (Neuropathology Unit and Department of Neurology, Centro Hospitalar do Porto - Hospital de Santo António, Oporto, Portugal); Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi (Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy); Diana Duro, Maria Rosario Almeida, Miguel Castelo-Branco (Faculty of Medicine, University of Coimbra, Coimbra, Portugal), Maria João Leitão (Centre of Neurosciences and Cell biology, Universidade de Coimbra, Coimbra, Portugal), Miguel Tabuas-Pereira, Beatriz Santiago (Neurology Department, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal); Serge Gauthier (Alzheimer Disease Research Unit, McGill Centre for Studies in Aging, Department of Neurology & Neurosurgery, McGill University, Montreal, Québec, Canada), Pedro Rosa-Neto (Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, Québec, Canada), Michele Veldsman (Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, UK); Toby Flanagan (Faculty of Biology, Medicine and Health, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, UK); Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schonecker (Neurologische Klinik, Ludwig-Maximilians-Universität München, Munich, Germany); Elisa Semler, Sarah Anderl-Straub (Department of Neurology, University of Ulm, Ulm); Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Michela Pievani (Instituto di Recovero e Cura a Carattere Scientifico Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy); Gemma Lombardi, Benedetta Nacmias, Camilla Ferrari, Valentina Bessi (Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Florence, Italy).
Contributors CH and JR contributed to the study design, acquisition, analysis and interpretation of the data as well as drafting and revising the manuscript. All other authors (MSF, AJH, HZ, KM, RC, MB, MN, DMC, DT, CVG, IOCW, RS, JCVS, FM, RS-V, BB, RJrL, MM, MCT, CG, DG, JBR, EF, MS, RV, AdeM, FT, IS, SD, CRB, AG, JL, AD, GF, SS, MO) contributed to the acquisition of data and study coordination as well as helping to critically review and revise the manuscript.
Funding The GENFI study has been supported by the Medical Research Council UK (MR/M023664/1), the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation as well as an Alzheimer's Society grant (AS-PG-16-007). The biomarker measurements were funded in part by the UK Dementia Research Institute at UCL and by a Wellcome Trust Multi-User Equipment Grant. KM has received funding from an Alzheimer’s Society PhD studentship. IOCW is supported by a MRC Clinical Research Training Fellowship (MR/M018288/1). RS-V is supported by an Alzheimer's Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2). JCVS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG received support from the EU Joint Programme—Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. RS-V has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). JBR has received funding from the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MO has received funding from BMBF (FTLDc). MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. HZ is a Wallenberg Academy Fellow. JR is a MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Local ethics committees at each site approved the study and all participants provided written informed consent at enrolment.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. Some GENFI data is available on reasonable request through application to the GENFI Data Access Committee.
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