Associations of TNF-α, MIF, and cortisol with cognitive function in patients with bipolar disorder during acute manic episodes: a short-term follow-up study.

Background: Bipolar disorder (BD) is frequently accompanied by cognitive impairment, and growing evidence suggests that immune-inflammatory activation and hypothalamic-pituitary-adrenal axis dysregulation may contribute to its pathophysiology. This study aimed to examine the associations of tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF), and cortisol (COR) with cognitive function in patients with BD during manic episodes and to characterize their short-term changes. Methods: In this short-term follow-up study, 53 patients with BD during manic episodes and 53 healthy controls (HCs) were enrolled. Plasma TNF-α, MIF, and COR levels were measured using enzyme-linked immunosorbent assay. Cognitive function was assessed using the Chinese Brief Cognitive Test, including information processing speed (IPS), executive function (EF), sustained attention (SAT), and working memory (WM). Patients were evaluated at baseline and after 8 weeks of treatment, whereas HCs were assessed once at baseline. Group comparisons and biomarker-cognition correlation analyses were performed. Multiple testing in the correlation analyses was controlled using the Benjamini-Hochberg false discovery rate (FDR) procedure. Results: At both baseline and follow-up, patients with BD had significantly lower IPS, EF, SAT, and WM scores, but significantly higher plasma TNF-α, MIF, and COR levels, than HCs. After 8 weeks of treatment, cognitive scores in the BD group improved significantly, whereas reductions in TNF-α, MIF, and COR did not reach statistical significance. In exploratory unadjusted Pearson analyses, several biomarker-cognition associations survived FDR correction. However, in the primary adjusted partial correlation analyses, only the negative association between TNF-α and WM remained significant after adjustment for covariates and FDR correction at both baseline and follow-up. Conclusion: Patients with BD during manic episodes exhibited widespread cognitive impairment accompanied by elevated inflammatory and neuroendocrine markers. TNF-α showed the most robust association with working memory after adjustment for covariates and correction for multiple comparisons. Associations involving MIF or cortisol and executive function should be interpreted as exploratory and require validation in larger longitudinal studies.