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

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.