A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors
Year: 2024
Type: review
Abstract: BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
Source: Alzheimer s Research & Therapy
Authors: Imogen J. Swift, Rosa Rademakers, NiCole Finch, Matt Baker, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Giacomina Rossi, Matthis Synofzik, Carlo Wilke, David Mengel, Caroline Graff, Leonel T. Takada, Raquel Sánchez-Valle, Anna Antonell, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Stefanie Schreiber, Stefan Vielhaber, Philipp Arndt, Isabel Santana, Maria Rosario Almeida, Fermín Moreno, Myriam Barandiaran, Alazne Gabilondo, Johannes Stubert, Estrella Gómez-Tortosa, Pablo Agüero, M. José Sainz, Tomohito Gohda, Maki Murakoshi, Nozomu Kamei, Sarah Kittel-Schneider, Andreas Reif, Johannes Weigl, Jinlong Jian, Chuanju Liu, Ginette Serrero, Thomas Greither, Gerit Theil, Ebba Lohmann, Stefano Gazzina, Silvia Bagnoli, Giovanni Coppola, Amalia Bruni, Mirja Quante, Wieland Kiess, Andreas Hiemisch, Anne Jurkutat, Matthew S. Block, Aaron M. Carlson, Geir Bråthen, Sigrid Botne Sando, Gøril Rolfseng Grøntvedt, Camilla Lauridsen, Amanda Heslegrave, Carolin Heller, Emily Abel, Alba Gómez-Núñez, Roger Puey, Andrea Arighi, Enmanuela Rotondo, Lize C. Jiskoot, Lieke H. H. Meeter, João Durães, Marisa Lima, Miguel Tábuas-Pereira, João Lemos, Bradley Boeve, Ronald C. Petersen, Dennis W. Dickson, Neill R. Graff-Radford, Isabelle LeBer, Leila Sellami, Foudil Lamari, Fabienne Clot, Barbara Borroni, Valentina Cantoni, Jasmine Rivolta, Alberto Lleó, Juan Fortea, Daniel Alcolea, Ignacio Illán-Gala, Lucie Andres-Cerezo, Philip Van Damme, Jordi Clarimon, Petra Steinacker, Emily Feneberg, Markus Otto, Emma L. van der Ende, John C. van Swieten, Harro Seelaar, Henrik Zetterberg, Aitana Sogorb-Esteve, Jonathan D. Rohrer
Institutions: National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, University of Antwerp, VIB-UAntwerp Center for Molecular Neurology, Mayo Clinic in Florida, Centro San Giovanni di Dio Fatebenefratelli, Fondazione IRCCS Istituto Neurologico Carlo Besta, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Karolinska University Hospital, Karolinska Institutet, Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Hospital Clínic de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Otto-von-Guericke-Universität Magdeburg, Unidade Local de Saúde de Coimbra, Centro de Neurociências e Biologia Celular, Centro de Inovação em Biomedicina e Biotecnologia, University of Coimbra, Biogipuzkoa Health Research Institute, Donostiako Unibertsitate Ospitalea, Universitätsmedizin Rostock, Hospital Universitario Fundación Jiménez Díaz, Juntendo University, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, National Hospital Organization, Kure Medical Center, University College Cork, Universitätsklinikum Würzburg, University Hospital Frankfurt, University of Pennsylvania, Yale University, A&G Pharmaceutical (United States), University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Martin Luther University Halle-Wittenberg, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, University of Florence, University of California, Los Angeles, Presidio Ospedaliero Lamezia Terme, Universitätsklinikum Tübingen, University Hospital Leipzig, Leipzig University, Mayo Clinic, University of Colorado Anschutz, University of Colorado Denver, Norwegian University of Science and Technology, St Olav's University Hospital, Erasmus MC, Centre National de la Recherche Scientifique, Inserm, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Institut du Cerveau, University of Brescia, Universitat Autònoma de Barcelona, Hospital de Sant Pau, Biomedical Research Networking Center on Neurodegenerative Diseases, Institute of Rheumatology, KU Leuven, TUM Klinikum, Technical University of Munich, Sahlgrenska University Hospital, UK Dementia Research Institute, University of Gothenburg
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,990
Funders: Alzheimer's Association, EU Joint Programme – Neurodegenerative Disease Research, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Else Kröner-Fresenius-Stiftung, Ministero della Salute, Vetenskapsrådet, UK Dementia Research Institute, National Institutes of Health, Medical Research Council, National Institute on Aging
OpenAlex ID: W4393272997