Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

Carolin Heller, Martha S. Foiani, Katrina Moore, Rhian Convery, Martina Bocchetta, Mollie Neason, David M. Cash, David Thomas, Caroline V. Greaves, Ione O.C. Woollacott, Rachelle Shafei, John C. van Swieten, Fermin Moreno, Raquel Sanchez-Valle, Barbara Borroni, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela GalimbertiJames B. Rowe, Elizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonca, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Christopher R. Butler, Alex Gerhard, Johannes Levin, Adrian Danek, Giovanni Frisoni, Sandra Sorbi, Markus Otto, Amanda J. Heslegrave, Henrik Zetterberg, Jonathan D. Rohrer*, Martin N. Rossor, Jason D. Warren, Nick C. Fox, Rita Guerreiro, Jose Bras, Jennifer Nicholas, Simon Mead, Lize Jiskoot, Lieke Meeter, Jessica Panman, Janne Papma, Rick van Minkelen, Yolanda Pijnenburg, Myriam Barandiaran, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, Maria de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanua, Zigor Diaz, Sergi Borrego-Ecija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Nuria Bargallo, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David Tang-Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelic, Hakan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, Hans Otto Karnarth, Benjamin Bender, Rose Bruffaerts, Philip Vandamme, Mathieu Vandenbulcke, Catarina B. Ferreira, Gabriel Miltenberger, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Dura, Maria Rosario Almeida, Miguel Castelo-Branco, Maria João Leitão, Miguel Tabuas-Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa-Neto, Michele Veldsman, Toby Flanagan, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schonecker, Elisa Semler, Sarah Anderl-Straub, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Michela Pievani, Gemma Lombardi, Benedetta Nacmias, Camilla Ferrari, Valentina Bessi, GENFI

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: There are fewvalidated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. Methods: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. Results: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% Cl 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. Conclusions: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials.

Original languageEnglish
Article number2019321954
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume91
Issue number3
DOIs
Publication statusPublished - 1 Jan 2020

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