A systematic review of progranulin concentrations in biofluids in over 7,000 people : assessing the pathogenicity of GRN mutations and other influencing factors
Creators: name: Swift, Imogen J.
name: Rademakers, Rosa
name: Finch, NiCole
name: Baker, Matt
name: Ghidoni, Roberta
name: Benussi, Luisa
name: Binetti, Giuliano
name: Rossi, Giacomina
name: Synofzik, Matthis
name: Wilke, Carlo
name: Mengel, David
name: Graff, Caroline
name: Takada, Leonel T.
name: Sánchez-Valle, Raquel
name: Antonell, Anna
name: Galimberti, Daniela
name: Fenoglio, Chiara
name: Serpente, Maria
name: Arcaro, Marina
name: Schreiber, Stefanie
name: Vielhaber, Stefan
name: Arndt, Philipp
name: Santana, Isabel
name: Almeida, Maria Rosario
name: Moreno, Fermín
name: Barandiaran, Myriam
name: Gabilondo, Alazne
name: Stubert, Johannes
name: Gómez-Tortosa, Estrella
name: Agüero, Pablo
name: Sainz, M. José
name: Gohda, Tomohito
name: Murakoshi, Maki
name: Kamei, Nozomu
name: Kittel-Schneider, Sarah
name: Reif, Andreas
name: Weigl, Johannes
name: Jian, Jinlong
name: Liu, Chuanju
name: Serrero, Ginette
name: Greither, Thomas
name: Theil, Gerit
name: Lohmann, Ebba
name: Gazzina, Stefano
name: Bagnoli, Silvia
name: Coppola, Giovanni
name: Bruni, Amalia
name: Quante, Mirja
name: Kiess, Wieland
name: Hiemisch, Andreas
name: Jurkutat, Anne
name: Block, Matthew S.
name: Carlson, Aaron M.
name: Bråthen, Geir
name: Sando, Sigrid Botne
name: Grøntvedt, Gøril Rolfseng
name: Lauridsen, Camilla
name: Heslegrave, Amanda
name: Heller, Carolin
name: Abel, Emily
name: Gómez-Núñez, Alba
name: Puey, Roger
name: Arighi, Andrea
name: Rotondo, Enmanuela
name: Jiskoot, Lize C.
name: Meeter, Lieke H. H.
name: Durães, João
name: Lima, Marisa
name: Tábuas-Pereira, Miguel
name: Lemos, João
name: Boeve, Bradley
name: Petersen, Ronald
name: Dickson, Dennis W.
name: Graff-Radford, Neill R.
name: LeBer, Isabelle
name: Sellami, Leila
name: Lamari, Foudil
name: Clot, Fabienne
name: Borroni, Barbara
name: Cantoni, Valentina
name: Rivolta, Jasmine
name: Lleó, Alberto
name: Fortea, Juan
name: Alcolea, Daniel
name: Illán-Gala, Ignacio
name: Andres-Cerezo, Lucie
name: Damme, Philip
name: Clarimon, Jordi
name: Steinacker, Petra
name: Feneberg, Emily
name: Otto, Markus
name: Ende, Emma L.
name: Swieten, John C.
name: Seelaar, Harro
name: Zetterberg, Henrik
name: Sogorb-Esteve, Aitana
name: Rohrer, Jonathan D.
Publisher: name: Universitäts- und Landesbibliothek Sachsen-Anhalt
Year: 2024
Subjects: subject: 610

description: 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.