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

Swift IJ, Rademakers R, Finch NC, Baker M, Ghidoni R, Benussi L, Binetti G, Rossi G, Synofzik M, Wilke C, Mengel D, Graff C, Takada LT, Sánchez-Valle R, Antonell A, Galimberti D, Fenoglio C, Serpente M, Arcaro M, Schreiber S, Vielhaber S, Arndt P, Santana I, Almeida MR, Moreno F, Barandiaran M, Gabilondo A, Stubert J, Gómez-Tortosa E, Agüero P, Sainz MJ, Gohda T, Murakoshi M, Kamei N, Kittel-Schneider S, Reif A, Weigl J, Jian J, Liu C, Serrero G, Greither T, Theil G, Lohmann E, Gazzina S, Bagnoli S, Coppola G, Bruni A, Quante M, Kiess W, Hiemisch A, Jurkutat A, Block MS, Carlson AM, Bråthen G, Sando SB, Grøntvedt GR, Lauridsen C, Heslegrave A, Heller C, Abel E, Gómez-Núñez A, Puey R, Arighi A, Rotondo E, Jiskoot LC, Meeter LH, Durães J, Lima M, Tábuas-Pereira M, Lemos J, Boeve B, Petersen RC, Dickson DW, Graff-Radford NR, LeBer I, Sellami L, Lamari F, Clot F, Borroni B, Cantoni V, Rivolta J, Lleó A, Fortea J, Alcolea D, Illán-Gala I, Andres-Cerezo L, Van Damme P, Clarimon J, Steinacker P, Feneberg E, Otto M, van der Ende EL, van Swieten JC, Seelaar H, Zetterberg H, Sogorb-Esteve A, Rohrer JD (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 16

Article Number: 66

Journal Issue: 1

DOI: 10.1186/s13195-024-01420-z

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.

Involved external institutions

University College London (UCL) United Kingdom (GB) Mayo Clinic College of Medicine and Science (MCCMS) United States (USA) (US) IRCCS Fatebenefratelli - Brescia Italy (IT) Otto-von-Guericke-Universität Magdeburg Germany (DE) Centro Hospitalar e Universitário de Coimbra (CHUC) Portugal (PT) Foundation of the Carlo Besta Neurological Institute (IRCCS) Italy (IT) Universidade de Coimbra Portugal (PT) Donostia University Hospital / Donostia Unibertsitate Ospitalea Spain (ES) Hertie-Institut für klinische Hirnforschung Germany (DE) Universitätsmedizin Rostock Germany (DE) Fundación Jiménez Díaz Spain (ES) Universitat de Barcelona (UB) / University of Barcelona Spain (ES) Università degli studi di Milano Italy (IT) Juntendo University Japan (JP) University College Cork (UCC) Ireland (IE) Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital / 認可法人日本赤十字社広島赤十字・原爆病院 Japan (JP) Universitätsklinikum Würzburg Germany (DE) Universitätsklinikum Frankfurt am Main (KGU) Germany (DE) Mayo Clinic United States (USA) (US) University of Pennsylvania (UPenn) United States (USA) (US) Yale University United States (USA) (US) University of Colorado Anschutz Medical Campus United States (USA) (US) A&G Pharmaceutical United States (USA) (US) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) Martin-Luther-Universität Halle-Wittenberg (MLU) Germany (DE) Università degli Studi di Brescia Italy (IT) Hospital de la Santa Creu i Sant Pau Spain (ES) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia Italy (IT) Università degli Studi di Firenze / University of Florence Italy (IT) University of California Los Angeles (UCLA) United States (USA) (US) Azienda Sanitaria Provinciale (ASP) Catanzaro Italy (IT) Universitätsklinikum Tübingen Germany (DE) Universität Leipzig Germany (DE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Biomedical Research Networking Center on Neurodegenerative Diseases / Centro de Investigación Biomédica en Red Enfermedades neurodegenerativas (CIBERNED) Spain (ES) Universitätsklinikum Halle (Saale) Germany (DE) Klinikum rechts der Isar Germany (DE) Karolinska Institute Sweden (SE) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico Italy (IT) University of São Paulo / Universidade de São Paulo (USP) Brazil (BR) Erasmus University Medical Center (MC) Netherlands (NL) Mayo Clinic Hospital United States (USA) (US) Institut du Cerveau et de la Moelle Epinière (ICM) France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR)

How to cite

APA:

Swift, I.J., Rademakers, R., Finch, N.C., Baker, M., Ghidoni, R., Benussi, L.,... Rohrer, J.D. (2024). A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors. Alzheimer's Research and Therapy, 16(1). https://doi.org/10.1186/s13195-024-01420-z

MLA:

Swift, Imogen J., et al. "A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors." Alzheimer's Research and Therapy 16.1 (2024).

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