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. 2018 Jun 15:319:19-27.
doi: 10.1016/j.jneuroim.2018.03.003. Epub 2018 Mar 20.

Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease

L M Bekris  1 , M Khrestian  2 , E Dyne  3 , Y Shao  2 , J A Pillai  4 , S M Rao  4 , S M Bemiller  5 , B Lamb  5 , H H Fernandez  6 , J B Leverenz  4
Affiliations

Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease

L M Bekris et al. J Neuroimmunol. .

Abstract

Alzheimer's disease (AD) has been genetically and pathologically associated with neuroinflammation. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor involved in innate immunity. TREM2 rare protein coding genetic variants have been linked to AD. A soluble TREM2 (sTREM2) cleavage product is elevated in AD. It is unclear whether there is a relationship between elevated sTREM2 and markers of inflammation. The hypothesis of this investigation was that central and peripheral inflammation play a role in sTREM2 levels in AD. A consistent association of peripheral or central markers of inflammation and CSF sTREM2 levels was not found, suggesting a limited impact of general inflammation on sTREM2 levels. An association between peripheral sTREM2 levels and CSF sTREM2, as well as an association between CSF sTREM2 and a marker of blood brain barrier integrity, was observed in AD, suggesting a potential role of peripheral TREM2 in central TREM2 biology.

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Figures

Figure 1
Figure 1. CSF AD Biomarkers
CSF Aβ42 levels are significantly lower in MCI (p<0.0001; p=0.0067) and AD (p<0.0001; p=0.002) compared to HC and PD respectively. PD is lower than HC (p=0.0134) (A). CSF T-Tau levels are significantly higher in MCI (p=0.048) and AD (p<0.0001; p<0.0001) compared to HC and PD respectively, as well as in AD (p=0.0245) compared to MCI (B). CSF P-Tau levels are significantly higher in MCI (p=0.0027; p=0.0003) and AD (p<0.0001; p<0.0001) compared to HC and PD respectively, as well as in AD (p=0.0003) compared to MCI (C). Graphs and p-values are one-way ANOVA uncorrected Fisher’s LSD derived after removal of outliers.
Figure 2
Figure 2. CSF and Plasma Soluble TREM2 levels
Soluble TREM2 (sTREM2) levels in healthy controls (HC), mild cognitive impairment (MCI), Alzheimer’s disease (AD) and Parkinson disease (PD) in the CSF cohort are significantly different between HC and MCI (p=0.0056) and between HC and AD (p=0.0249) (A). Plasma sTREM2 Levels were not significantly different between disease groups in the plasma cohort. ANOVA Fisher’s LSD test p-values are shown (B). CSF sTREM2 is associated with age (p=0.012) in the group as a whole but not upon stratification by disease group (C). Plasma and CSF sTREM2 levels were significantly correlated in AD (p=0.042) and for the groups as a whole (when not stratified by disease group: p=0.017) (D).
Figure 3
Figure 3. CSF sTREM2 Correlation with CSF AD Biomarkers
CSF sTREM2 levels significantly positively correlate with CSF Aβ42 in HC (p=0.011) and AD (p=0.001) (A). CSF sTREM2 levels significantly positively correlate with CSF Total-tau levels in AD (p=0.045) as well as the group as a whole (p=0.016) (B). CSF sTREM2 levels do not significantly correlate with CSF phosphorylated-tau levels (C).
Figure 4
Figure 4. CSF sTREM2 Correlation with Central Nervous System (CNS) Biomarkers of Inflammation
CSF sTREM2 levels significantly correlate with the CSF Albumin / Serum Albumin ratio in HC (p=0.023) and in AD (p=0.020) as well as the groups as a whole (p=0.003) (A). CSF sTREM2 levels did not significantly correlate with CNS IgG Synthesis (B). CSF sTREM2 levels do not significantly correlate with IgG Index (C). Only subjects that had a blood draw on the same day as the CSF were included.
Figure 5
Figure 5. CSF sTREM2 Correlation with Peripheral Biomarkers of Inflammation
CSF sTREM2 levels do not significantly correlate with high-sensitivity C-reactive protein (CRP) (A), CSF sTREM2 levels significantly correlate with sedimentation rate in MCI (p=0.005) (B). CSF sTREM2 levels significantly correlate with white blood cell count (WBC) in HC (p=0.020) (C). Only subjects that had a blood draw on the same day as the CSF were included (CSF and Plasma from the same visit).
Figure 6
Figure 6. Plasma sTREM2 Correlation with Peripheral Biomarkers of Inflammation
Plasma sTREM2 levels are significantly correlated with C-reactive protein (CRP-ultra) in MCI (p=0.005) and PD (p=0.007) (A), not sedimentation rate (B), and not with white blood cell count (WBC) (C).
Figure 7
Figure 7. Protein levels associated with rs7748513 genotype
CSF sTREM2 levels are marginally higher in carriers of the AD GWAS risk allele for rs7748513 (G+; GG or AG) in the group as a whole (p=0.053) and after taking into account disease status, age, sex and APOE ε4 status (p=0.026) (A). The IgG Index is higher in carriers of the AD GWAS risk allele for rs7748513 (G+; GG or AG) in the group as a whole (p=0.002) and after taking into account disease status, age, sex and APOE ε4 status (p=0.004) (B). Linear regression models were used to analyze the difference between protein markers both with and without covariates. Graphs are without taking into account covariates.
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