A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Springer Science and Business Media LLC - 2024
Imogen J. Swift1,2, Rosa Rademakers3,4,5, NiCole Finch5, Matt Baker5, Roberta Ghidoni6, Luisa Benussi6, Giuliano Binetti7, Giacomina Rossi8, Matthis Synofzik9,10, Carlo Wilke9,10, David Mengel10,9, Caroline Graff11,12, Leonel T. Takada13, Raquel Sánchez-Valle14, Anna Antonell14, Daniela Galimberti15,16, Chiara Fenoglio16,15, Maria Serpente16, Marina Arcaro16, Stefanie Schreiber17, Stefan Vielhaber17, Philipp Arndt17, Isabel Santana18,19,20, Maria Rosario Almeida18, Fermín Moreno21,22, Myriam Barandiaran22,21, Alazne Gabilondo21,22, Johannes Stubert23, Estrella Gómez-Tortosa24, Pablo Agüero24, M. José Sainz24, Tomohito Gohda25, Maki Murakoshi25, Nozomu Kamei26,27, Sarah Kittel-Schneider28,29, Andreas Reif30, Johannes Weigl28,31, Jinlong Jian32, Chuanju Liu33, Ginette Serrero34,35, Thomas Greither36, Gerit Theil37, Ebba Lohmann38,39, Stefano Gazzina40, Silvia Bagnoli41, Giovanni Coppola42,43, Amalia Bruni44, Mirja Quante45, Wieland Kiess46,47,48, Andreas Hiemisch47,46, Anne Jurkutat47, Matthew S. Block49, Aaron M. Carlson50, Geir Bråthen51,52, Sigrid Botne Sando52,51, Gøril Rolfseng Grøntvedt51,52, Camilla Lauridsen53, Amanda Heslegrave2, Carolin Heller2,1, Emily Abel2, Alba Gómez-Núñez14, Roger Puey14, Andrea Arighi16, Enmanuela Rotondo16, Lize C. Jiskoot54, Lieke H. H. Meeter54, João Durães19, Marisa Lima19, Miguel Tábuas-Pereira18,19, João Lemos18, Bradley Boeve55, Ronald C. Petersen55, Dennis W. Dickson5, Neill R. Graff-Radford56, Isabelle LeBer57, Leila Sellami57,58, Foudil Lamari59, Fabienne Clot60, Barbara Borroni61, Valentina Cantoni61, Jasmine Rivolta61, Alberto Lleó62,63,64, Juan Fortea64,62,63, Daniel Alcolea64,62,63, Ignacio Illán-Gala64,62,63, Lucie Andres-Cerezo65, Philip Van Damme66, Jordi Clarimon67,68, Petra Steinacker69, Emily Feneberg70, Markus Otto69, Emma L. van der Ende54, John C. van Swieten54, Harro Seelaar54, Henrik Zetterberg2,71,72,73,74,75, Aitana Sogorb-Esteve2,1, Jonathan D. Rohrer1
1Department of Neurodegenerative Disease, Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK
2Department of Neurodegenerative Disease, Dementia Research Institute, UCL Institute of Neurology, Queen Square, London, UK
3VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
4Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
5Department of Neuroscience, Mayo Clinic, Jacksonville, USA
6Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
7MAC-Memory Clinic and Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni Di Dio Fatebenefratelli, Brescia, Italy
8Unit of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
9Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
10German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
11Unit for Hereditary Dementias, Theme Inflammation and Aging, Karolinska University Hospital, Solna, Sweden
12Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, BioclinicumKarolinska Institutet, Solna, Sweden
13Department of Neurology, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil
14Alzheimer’s Disease and Other Cognitive Disorders Unit, FRCB-IDIBAPS, Institut de Neurociències, Neurology Service, Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona, Spain
15Dept. of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
16Neurodegerative Diseases Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
17Department of Neurology, Otto-von-Guericke University, Magdeburg, Germany
18Faculty of Medicine, University of Coimbra, Coimbra, Portugal
19Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
20Center for Neuroscience and Cell Biology, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
21Neuroscience Area, Biodonostia Health Research Insitute, San Sebastian, Spain
22Cognitive Disorders Unit, Department of Neurology, Donostia University Hospital, San Sebastian, Spain
23Department of Obstetrics and Gynecology, Rostock University Medical Center, Rostock, Germany
24Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain
25Department of Nephrology, Faculty of Medicine, Juntendo University, Tokyo, Japan
26Institute for Clinical Research, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
27Department of Endocrinology and Metabolism, Hiroshima Red Cross Hospital & Atomicbomb Survivors Hospital, Hiroshima, Japan
28Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital Würzburg, Würzburg, Germany
29Department of Psychiatry, University College Cork, Cork, Ireland
30Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, University Hospital Frankfurt, Frankfurt, Germany
31Department of Psychiatry, Hospital in Tauberbischofsheim, Tauberbischofsheim, Germany
32University of Pennsylvania, Philadelphia, USA
33Department of Orthopaedics, Rehabilitation, Yale University School of Medicine, New Haven, USA
34A&G Pharmaceutical Inc., Columbia, USA
35Program in Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, USA
36Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, Halle, Germany
37Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany
38DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany
39Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
40Department of Neurological and Vision Sciences, Neurophysiology Unit, ASST SpedaliCivili, Brescia, Italy
41Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
42Department of Psychiatry Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, USA
43Department of Neurology, University of California, Los Angeles, USA
44Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy
45Department of Neonatology, Tuebingen University Hospital, Tuebingen, Germany
46Center of Pediatric Research (CPL), University of Leipzig, Leipzig, Germany
47Leipzig Research Center for Civilization Diseases - LIFE, University of Leipzig, Leipzig, Germany
48Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
49Department of Oncology, Mayo Clinic, Rochester, USA
50Department of Neurology, University of Colorado Anschutz Medical Campus, Denver, USA
51Department of Neurology and Clinical Neurophysiology, Trondheim University Hospital, Trondheim, Norway
52Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU, Trondheim, Norway
53Department of Research, Trondheim University Hospital, Trondheim, Norway
54Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, Netherlands
55Department of Neurology, Mayo Clinic, Rochester, USA
56Department of Neurology, Mayo Clinic, Jacksonville, USA
57Sorbonne UniversitéInserm U1127, CNRS UMR 7225, Institut du Cerveau Et La Moelle Épinière (ICM), AP-HP - Hôpital Pitié-Salpêtrière, Paris, France
58Centre de Référence Des Démences Rares Ou Précoces, IM2A, Département de Neurologie, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France
59UF de Biochimie des maladies neurométaboliques et neurodégénératives, Service de Biochimie Métabolique, AP-HP - Hôpital Pitié-Salpêtrière, Paris, France
60UF de Neurogénétique Moléculaire Et Cellulaire, Département de Génétique, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Paris, France
61Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
62Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
63Autonomous University of Barcelona, Barcelona, Spain
64Neurology Department. Hospital Sant Pau, Memory Unit, Barcelona, Spain
65Institute of Rheumatology, Prague, Czech Republic
66Laboratory of Neurobiology, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, Louvain, Belgium
67Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
68Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
69Department of Neurology, Martin-Luther University Halle-Wittenberg, University Clinic Halle, Halle (Saale), Germany
70Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
71UK Dementia Research Institute at University College London, UCL Queen Square Institute of Neurology, University College London, London, UK
72Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
73Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
74Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
75Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

Tóm tắt

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. 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. 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. 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.

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