CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

• Published in: Annals of clinical and translational neurology 2022-11, Vol.9 (11), p.1764-1777
• Main Authors: Swift, Imogen J., Heller, Carolin, Knowles, Kathryn, Bouzigues, Arabella, Russell, Lucy L., Greaves, Caroline V., Convery, Rhian, Heslegrave, Amanda, Rowe, James B., Borroni, Barbara, Galimberti, Daniela, Tartaglia, Maria Carmela, Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R., Graff, Caroline, Gerhard, Alexander, Mendonça, Alexandre, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Ber, Isabelle Le, Levin, Johannes, Otto, Markus, Pasquier, Florence, Santana, Isabel, Zetterberg, Henrik, Rohrer, Jonathan D., Nelson, Annabel, Cash, David, Thomas, David L., Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang‐Wai, David, Rogaeva, Ekaterina, Castelo‐Branco, Miguel, Keren, Ron, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Poos, Jackie, Papma, Janne M., Giannini, Lucia, Nacmias, Benedetta, Polito, Cristina, Lombardi, Gemma, Andersson, Christin, Thonberg, Hakan, Jelic, Vesna, Langheinrich, Tobias, Balasa, Mircea, Borrego‐Ecija, Sergi, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Barandiaran, Myriam, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Camuzat, Agnès, Funkiewiez, Aurélie, Rinaldi, Daisy, Colliot, Olivier, Prix, Catharina, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Bertoux, Maxime, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Almeida, Maria Rosario, Afonso, Sónia
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Amyotrophic lateral sclerosis; Asymptomatic; Biomarkers; Biomarkers - cerebrospinal fluid; C9orf72 Protein - genetics; Chitinase; Chitinase-3-Like Protein 1 - genetics; Confidence intervals; Dementia; Frontotemporal Dementia - diagnosis; Human health and pathology; Humans; Immunoassay; Life Sciences; Medicin och hälsovetenskap; Mutation; Neurobiology; Neuroglia; Neurons and Cognition; Pick Disease of the Brain; Psychiatrics and mental health
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.51672

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.