Novel CSF inflammatory markers MIF and TREM‐1 are increased in Alzheimer’s disease

Abstract

AbstractBackgroundThere is a lack of biomarkers reflecting Alzheimer‐relevant pathological processes such as inflammation, to improve Alzheimer’s differential diagnosis. Our recent discovery cerebrospinal fluid (CSF) proteomics study, revealed potential AD‐specific biomarkers related to inflammatory pathology, such as migration inhibitory factor (MIF) and triggering receptor expressed on myeloid cells 1 (TREM‐1). Here, we aimed to validate these findings including also samples from patients with dementia with Lewy Body (DLB) using a novel sensitive technology purposed for clinical implementation.MethodMIF and TREM‐1 levels were measured in CSF from patients with AD (n=38, 66 ± 6 years, 97% males), DLB (MIF: n=50, TREM‐1: n=40, 67 ± 7 years, 95% males) and controls (cognitively unimpaired, n=37, 66 ± 6 years, 95% males) using assays on the antibody‐based SimplePlex technology, in‐house validated for CSF analysis. Differences in protein levels between diagnostic groups and correlations to AD CSF biomarkers and mini‐mental state examination (MMSE) scores were tested by analysis of covariance (corrected for age and sex) and Spearman correlations. An optimal prediction panel was identified using backward elimination logistic regression analysis with likelihood ratio and ROC analyses.ResultCSF MIF levels were increased in AD (1.2‐fold, p=0.002) and DLB (1.14‐fold, p=0.036) compared to controls (figure 1A). MIF levels correlated with total‐ and phosphorylated‐Tau (t‐Tau, ρ=0.670, p<0.001; p‐Tau, ρ=0.686 p<0.001) and Amyloid‐beta 42 (Aβ42, ρ=‐0.189, p<0.05) but not with MMSE (p>0.05). CSF TREM‐1 levels were increased in AD compared to DLB (1.4‐fold, p=0.016) and controls (1.5‐fold, p=0.003, figure 1B) and correlated with all three AD CSF biomarkers (t‐Tau: ρ =0.472, p=0.001; p‐Tau: ρ=0.414, p=0.001; Aβ42: ρ=‐0.267, p=0.018) but not with MMSE (p>0.05). A panel combining MIF, t‐Tau and p‐Tau differentiated AD from DLB with high accuracy (AUC=0.941 (95%CI: 0.892‐0.989, 88% sensitivity, 89% specificity, figure 2).ConclusionInflammatory‐related proteins MIF and TREM‐1 are increased in AD. We here validated previous proteomics findings in an independent cohort using a technology that is used as a first preparatory step towards clinical implementation. This data highlights the importance of biomarkers reflecting different pathological processes as these proteins could be used to provide insight into an ongoing neuroinflammatory response.