CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia
Authors: Woollacott Ione O. C. , Swift Imogen J. , Sogorb‐Esteve Aitana , Heller Carolin , Knowles Kathryn , Bouzigues Arabella , Russell Lucy L. , Peakman Georgia , Greaves Caroline V. , Convery Rhian , Heslegrave Amanda , Rowe James B. , Borroni Barbara , Galimberti Daniela , Tiraboschi Pietro , Masellis Mario , Tartaglia Maria Carmela , Finger Elizabeth , van Swieten John C. , Seelaar Harro , Jiskoot Lize , Sorbi Sandro , Butler Chris R. , Graff Caroline , Gerhard Alexander , Laforce Robert , Sanchez‐Valle Raquel , de Mendonça Alexandre , Moreno Fermin , Synofzik Matthis , Vandenberghe Rik , Ducharme Simon , Ber Isabelle Le , Levin Johannes , Otto Markus , Pasquier Florence , Santana Isabel , Zetterberg Henrik , Rohrer Jonathan D. ,   the Genetic FTD Initiative, GENFI
Published: October 2022

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.