Cerebrospinal fluid sTREM2 in Alzheimer’s disease: comparisons between clinical presentation and AT classification

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…Furthermore, its ectodomain is cleaved in the cell surface and shed at the plasma membrane, thus releasing a soluble fragment (sTREM2) which can be measured in the CSF as an indicator of microglial activity [78][79][80]. As it is involved in the regulation of microglia dynamics, and the subsequent amyloid plaque formation and synaptic plasticity, increased levels of sTREM2 within the CSF have been related to a protective response against AD pathology, thus serving as a potential biomarker [80][81][82][83]. On the other hand, YKL-40, the inflammation-related glycoprotein known as chitinase-3-like protein 1, breast regression protein 39, human cartilage glycoprotein 39 or chondrex, belongs to the family of chitinase-like proteins, but lacks the enzymatic activity of chitinases [84,85].…”

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes

“…Presence of mixed pathology and the differences in recruitment biases to atypical AD should also be considered when comparisons are made between cohorts in longitudinal outcomes (Dubois et al, 2007;Pillai et al, 2016). It is likely these are some possible reasons behind significant differences in sTREM2 levels reported by prior studies across the AD spectrum (Kleinberger et al, 2014;Gispert et al, 2016b;Henjum et al, 2016;Bekris et al, 2018;Suárez-Calvet et al, 2019;Knapskog et al, 2020).…”

“…Clinical reports regarding cerebrospinal fluid (CSF) levels of sTREM2, a soluble TREM2 protein fragment produced by the cleavage of TREM2, have demonstrated varying levels of this protein in the different stages of AD (Wunderlich et al, 2013 ). Although most studies have shown that CSF sTREM2 is increased in the presence of AD biomarkers, the results are somewhat inconsistent regarding sTREM2 levels in amyloid-positive (A+) and tau-positive (T+) cognitively normal (CN) individuals (Ewers et al, 2019 ; Suárez-Calvet et al, 2019 ), patients with mild cognitive impairment (MCI) (Gispert et al, 2016b ; Henjum et al, 2016 ; Suárez-Calvet et al, 2016b , 2019 ; Ewers et al, 2019 ; Knapskog et al, 2020 ), and those with AD dementia (Gispert et al, 2016b ; Piccio et al, 2016 ; Suárez-Calvet et al, 2016b , 2019 ). Some studies have demonstrated no differences in sTREM2 levels across the AD spectrum (Gispert et al, 2016a ; Henjum et al, 2016 ; Knapskog et al, 2020 ), whereas other research has demonstrated decreased levels of sTREM2 in patients with AD dementia, perhaps partially reflecting the variability in clinical symptoms even within the same stage of AD (Kleinberger et al, 2014 ; Bekris et al, 2018 ).…”

“…Although most studies have shown that CSF sTREM2 is increased in the presence of AD biomarkers, the results are somewhat inconsistent regarding sTREM2 levels in amyloid-positive (A+) and tau-positive (T+) cognitively normal (CN) individuals (Ewers et al, 2019 ; Suárez-Calvet et al, 2019 ), patients with mild cognitive impairment (MCI) (Gispert et al, 2016b ; Henjum et al, 2016 ; Suárez-Calvet et al, 2016b , 2019 ; Ewers et al, 2019 ; Knapskog et al, 2020 ), and those with AD dementia (Gispert et al, 2016b ; Piccio et al, 2016 ; Suárez-Calvet et al, 2016b , 2019 ). Some studies have demonstrated no differences in sTREM2 levels across the AD spectrum (Gispert et al, 2016a ; Henjum et al, 2016 ; Knapskog et al, 2020 ), whereas other research has demonstrated decreased levels of sTREM2 in patients with AD dementia, perhaps partially reflecting the variability in clinical symptoms even within the same stage of AD (Kleinberger et al, 2014 ; Bekris et al, 2018 ). However, other studies have found that CSF sTREM2 has a dynamic response in the tracking of AD progression (Suárez-Calvet et al, 2016c , 2019 ; Ma et al, 2020 ), and a study in patients with MCI or AD dementia who had A+ and T+ biomarkers found that higher concentrations of sTREM2 in CSF were associated with reduced memory decline, lower CSF p-tau levels, and hippocampal shrinkage (Ewers et al, 2019 ).…”

Biomarcadores gliais da doença de Alzheimer

“…sTREM2 tem seu nível elevado já na fase présintomática, e foi visto aumento de 18%-23% em indivíduos em estado demencial 41 , porém aparenta ter seu pico na fase prodrômica, o que seria uma limitação para seu uso, complicando o desenvolvimento de um ponto de corte clínico 31,58 . Uma forte associação foi observada entre sTREM2 e a idade, patologia tau, YKL-40 e injuria neuronal, mas pouca ou nenhuma com níveis de Aβ 21,26,28,35,41,58 . No estudo de Henjum et al 27 , entretanto, só foi vista a correlação entre sTREM2, t-tau e p-tau em LCR no grupo de controles saudáveis, e não nos grupos com CCL ou DA, usando um novo ELISA foi desenvolvido para esse estudo.…”