CSF sTREM2 is elevated in a subset in GRN-related frontotemporal dementia

Emma L Van Der Ende,Estrella Morenas-Rodriguez,Corey Mcmillan,Murray Grossman,David Irwin,Raquel Sanchez-Valle,Caroline Graff,Rik Vandenberghe,Yolande A.L Pijnenburg,Robert Laforce,Isabelle Le Ber,Alberto Lleo,Christian Haass,Marc Suarez-Calvet,John C Van Swieten,Harro Seelaar

doi:10.1016/j.neurobiolaging.2021.02.024

Abstract

Excessive microglial activation might be a central pathological process in GRN-related frontotemporal dementia (FTD-GRN). We measured soluble triggering receptor expressed on myeloid cells 2 (sTREM2), which is shed from disease-associated microglia following cleavage of TREM2, in cerebrospinal fluid of 34 presymptomatic and 35 symptomatic GRN mutation carriers, 6 presymptomatic and 32 symptomatic C9orf72 mutation carriers and 67 healthy noncarriers by ELISA. Although no group differences in sTREM2 levels were observed (GRN: symptomatic (median 5.2 ng/mL, interquartile range [3.9–9.2]) vs. presymptomatic (4.3 ng/mL [2.6–6.1]) vs. noncarriers (4.2 ng/mL [2.6–5.5]): p = 0.059; C9orf72: symptomatic (4.3 [2.9–7.0]) vs. presymptomatic (3.2 [2.2–4.2]) vs. noncarriers: p = 0.294), high levels were seen in a subset of GRN, but not C9orf72, mutation carriers, which might reflect differential TREM2-related microglial activation. Interestingly, 2 presymptomatic carriers with low sTREM2 levels developed symptoms after 1 year, whereas 2 with high levels became symptomatic after >5 years. While sTREM2 is not a promising diagnostic biomarker for FTD-GRN or FTD-C9orf72, further research might elucidate its potential to monitor microglial activity and predict disease progression.

Highlights

Frontotemporal dementia (FTD) is frequently caused by autosomal dominant genetic mutations in granulin (GRN). the exact mechanisms by which GRN mutations lead to FTD are poorly understood, accumulating evidence suggests a role for dysregulation of microglial homeostasis (Bright et al, 2019; Chitramuthu et al, 2017)
In both genetic groups (GRN and C9orf72), symptomatic mutation carriers were older at cerebrospinal fluid (CSF) collection than presymptomatic carriers and noncarriers (p < 0.001). sTREM2 levels were positively correlated with age across the entire cohort and in noncarriers alone but not in symptomatic GRN or C9orf72 mutation carriers (GRN: rs = 0.020, p = 0.911; C9orf72: rs = 0.206, p = 0.258)
No significant differences in sTREM2 levels were seen in symptomatic GRN mutation carriers compared to presymptomatic carriers (4.3 ng/mL [2.6–6.1]) and noncarriers (4.2 ng/mL [2.6–5.5]) (p = 0.059 by Kruskal-Wallis test; p = 0.513 by ANCOVA) (Fig. 1). sTREM2 levels did not correlate with disease duration or Mini Mental State Examination (MMSE) score among symptomatic carriers

Summary

Introduction

Frontotemporal dementia (FTD) is frequently caused by autosomal dominant genetic mutations in granulin (GRN). The exact mechanisms by which GRN mutations lead to FTD are poorly understood, accumulating evidence suggests a role for dysregulation of microglial homeostasis (Bright et al, 2019; Chitramuthu et al, 2017). GRN−/− mice display excessive microglial activation with subsequent release of proinflammatory factors and neuronal loss (Lui et al, 2016; Martens et al, 2012; Tanaka et al, 2013), and suppression of genes characteristic for homeostatic microglia. Biomarkers that accurately reflect microglial activity in vivo are currently lacking and might provide more insight into disease pathogenesis, as well as measure treatment effect in clinical trials aiming to restore immune dysregulation

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