Proteomic analysis of plasma from rheumatoid arthritis patients with mild cognitive impairment

Rheumatoid arthritis (RA) patients may suffer from comorbid neuropsychiatric symptoms including mild cognitive impairment (MCI). Although comorbidity of MCI is common, there are currently no validated plasma biomarkers to aid MCI diagnosis. This study screened plasma from patients with RA with and without comorbid MCI to identify potential biomarkers useful in the differential diagnosis of comorbid MCI. Plasma samples were collected from patients with RA without comorbid MCI, with comorbid MCI, and from healthy controls. Plasma samples were examined by tandem mass tags (TMT) combined with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MSMS) to analyze protein expression. Differentially expressed proteins were identified by bioinformatics and validated by enzyme-linked immunosorbent assay (ELISA). A total of 746 reliable proteins and 158 differentially expressed proteins were identified. Fourteen patients with RA-MCI showed differential protein expression (six proteins upregulated and eight proteins downregulated) compared with those patients without MCI and with healthy controls. Bioinformatics analysis showed that the differentially expressed proteins were primarily involved in biological processes, such as cell adhesion, coagulation, apoptosis, and body fluid regulation. The results of the ELISA experiments, similar to those of the proteomic analysis, demonstrated that sonic hedgehog (SHH) was upregulated and serum paraoxonase (TTR) was downregulated in patients with RA-MCI. These results indicate that SHH and TTR may be candidate plasma biomarkers that could be used to distinguish patients with RA and comorbid MCI from those without comorbid MCI.