Ione O.C. Woollacott, UCL Queen Square Institute of Neurology
Imogen J. Swift, UCL Queen Square Institute of Neurology
Aitana Sogorb-Esteve, UCL Queen Square Institute of Neurology
Carolin Heller, UCL Queen Square Institute of Neurology
Kathryn Knowles, UCL Queen Square Institute of Neurology
Arabella Bouzigues, UCL Queen Square Institute of Neurology
Lucy L. Russell, UCL Queen Square Institute of Neurology
Georgia Peakman, UCL Queen Square Institute of Neurology
Caroline V. Greaves, UCL Queen Square Institute of Neurology
Rhian Convery, UCL Queen Square Institute of Neurology
Amanda Heslegrave, University College London
James B. Rowe, Cambridge University Hospitals NHS Foundation Trust
Barbara Borroni, Università degli Studi di Brescia
Daniela Galimberti, Università degli Studi di Milano
Pietro Tiraboschi, Foundation IRCCS Neurological Institute "C. Besta"
Mario Masellis, University of Toronto
Maria Carmela Tartaglia, Tanz Centre for Research in Neurodegenerative Diseases
Elizabeth Finger, Western UniversityFollow
John C. van Swieten, Erasmus MC
Harro Seelaar, Erasmus MC
Lize Jiskoot, Erasmus MC
Sandro Sorbi, Università degli Studi di Firenze
Chris R. Butler, University of Oxford Medical Sciences Division
Caroline Graff, Karolinska Institutet
Alexander Gerhard, The University of Manchester
Robert Laforce, CHU de Québec - Université Laval
Raquel Sanchez-Valle, Universitat de Barcelona
Alexandre de Mendonça, Faculdade de Medicina, Universidade de Lisboa
Fermin Moreno, Osakidetza, Donostia University Hospital
Matthis Synofzik, Hertie-Institut für klinische Hirnforschung

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Annals of Clinical and Translational Neurology

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Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.