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


Carolin Heller, University College London
Martha S. Foiani, University College London
Katrina Moore, UCL Queen Square Institute of Neurology
Rhian Convery, UCL Queen Square Institute of Neurology
Martina Bocchetta, UCL Queen Square Institute of Neurology
Mollie Neason, UCL Queen Square Institute of Neurology
David M. Cash, UCL Queen Square Institute of Neurology
David Thomas, UCL Queen Square Institute of Neurology
Caroline V. Greaves, UCL Queen Square Institute of Neurology
Ione O.C. Woollacott, UCL Queen Square Institute of Neurology
Rachelle Shafei, UCL Queen Square Institute of Neurology
John C. van Swieten, Erasmus MC
Fermin Moreno, Osakidetza, Donostia University Hospital
Raquel Sanchez-Valle, Hospital Clinic Barcelona
Barbara Borroni, Università degli Studi di Brescia
Robert Laforce, CHU de Québec - Université Laval
Mario Masellis, University of Toronto
Maria Carmela Tartaglia, Tanz Centre for Research in Neurodegenerative Diseases
Caroline Graff, Karolinska Universitetssjukhuset
Daniela Galimberti, Università degli Studi di Milano
James B. Rowe, University of Cambridge
Elizabeth Finger, The University of Western Ontario
Matthis Synofzik, Hertie-Institut für klinische Hirnforschung
Rik Vandenberghe, KU Leuven
Alexandre de Mendonca, Universidade de Lisboa
Fabrizio Tagliavini, Foundation IRCCS Neurological Institute "C. Besta"
Isabel Santana, Universidade de Coimbra, Faculdade de Medicina
Simon Ducharme, Université McGill
Christopher R. Butler, University of Oxford
Alex Gerhard, Faculty of Biology, Medicine and Health
Johannes Levin, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V.
Adrian Danek, Ludwig-Maximilians-Universität München

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Journal of Neurology, Neurosurgery and Psychiatry





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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.

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