Elevated levels of cerebrospinal fluid soluble triggering receptor expressed on myeloid cells 2 in multiple system atrophy: a marker of disease-associated microglial activation

Multiple system atrophy (MSA) is increasingly being recognized to be characterized by neuroinflammation, especially involving the activation of microglia. Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been proposed as a biomarker of microglial activation; however, its role in MSA remains unclear. Levels of glycoprotein nonmetastatic melanoma protein B (GPNMB) and neurofilament light chain (NfL) may also indicate MSA-related neuroinflammatory and neurodegenerative processes. In this cross-sectional study, we analyzed CSF samples from 44 MSA patients, 46 Parkinson's disease patients, 34 patients with progressive supranuclear palsy or corticobasal syndrome, and 40 age- and sex-matched controls enrolled from a hospital-based registry. CSF sTREM2, GPNMB, and NfL levels were quantified using enzyme-linked immunosorbent assays. STREM2 levels were compared among groups. In the MSA group, we examined correlations between sTREM2 levels and clinical variables, including GPNMB and NfL. CSF sTREM2 levels were significantly higher in all disease groups compared with controls, with the highest levels observed in the MSA group. In the MSA group, sTREM2 level was not correlated with most clinical scores; however, individuals with elevated sTREM2 levels tended to have higher depression scores. Additionally, sTREM2 level correlated strongly with CSF GPNMB (r = 0.467, p = 0.001) and NfL (r = 0.408, p = 0.006). Multiple regression further identified GPNMB and age at examination as significant predictors of sTREM2 abundance. Our findings suggest that sTREM2 reflects microglial activation and its association with the neuroinflammatory and neurodegenerative processes of MSA.