Immune gene co-expression signatures implicated in occurence and persistence of cognitive dysfunction in depression.

Cognitive dysfunction contributes significantly to the burden caused by Major Depressive Disorder (MDD). Yet, while compelling evidence suggests that different biological processes play a part in both MDD aetiology and the development of cognitive decline more generally, we only begin to understand the molecular underpinnings of depression-related cognitive impairment. Developments in psychometric assessments, molecular high-throughput methods and systems biology derived analysis strategies advance this endeavour. Here, we aim to identify gene expression signatures associated with cognitive dysfunction and cognitive improvement following therapy using RNA sequencing to analyze the whole blood-derived transcriptome of altogether 101 MDD patients who enrolled in the CERT-D study. The mRNA(Nova)Seq based transcriptome was analyzed from whole blood taken at baseline assessment, and patients' cognitive performance was measured twice at baseline and following eight weeks of therapy by means of the THINC integrated tool. Thirty-six patients showed comparatively low cognitive performance at baseline assessment, and 32 patients showed comparatively strong cognitive improvement following therapy. Differential gene expression analysis was performed using limma to a significance threshold of 0.05 and a logFC cutoff of |1.2|. Although we observed some indications for expression differences related to low cognitive performance and cognitive therapy response, signals did not withstand adjustment for multiple testing. Applying WGCNA, we retrieved altogether 25 modules of co-expressed genes and we used a combination of correlational and linear analyses to identify modules related to baseline cognitive performance and cognitive improvement following therapy. Three immune modules reflected distinct but interrelated immune processes (the yellow module: neutrophil-mediated immunity, the darkorange module: interferon signaling, the tan module: platelet activation), and higher expression of the yellow (r = -0.21, p < .05), the dark orange (r = 0.2, p < .05), and the tan (r = -0.23, p < .05) module correlated significantly negatively with patients' cognitive baseline performance. Patients' cognitive baseline performance was a significant predictor of the darkorange module (b = -0.039, p < .05) and the tan module's expression (b = 0.02, p < .05) and was close to becoming a significant predictor of the yellow module's expression (b = -0.02, p = .05). Furthermore, patients characterized by comparatively low cognitive performance at baseline showed significantly higher expression of the tan module when compared to all other patients F(1,97) = 4.32, p < .05, η= 0.04. Following eight weeks of treatment, we observed altogether significant improvement in patients' cognitive performance (b = 0.30, p < .001), and patients with comparatively high cognitive gain showed noticeably lower, but not significantly lower F(1,98) = 3.76, p = .058, expression of a dark turquoise module, which reflects complement and B-cell-associated immune processes. Noteworthy, the relation between cognitive performance and module expression remained observable after controlling for symptom severity and BMI, which partly accounted for variance in module expression. As such, our findings provide further evidence for the involvement of immune processes in MDD related cognitive dysfunction and they suggest that different immune processes contribute to the development and long-term persistence of cognitive dysfunction in the context of depression.

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