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Background: Inflammatory cytokines like interleukin-6 (IL-6) are implicated in depression, but most studies have hitherto focused on circulating levels of IL-6 rather than its activity. IL-6 trans-signalling is thought to be responsible for most of the pathogenic effects of IL-6 and is implicated in autoimmune diseases like rheumatoid arthritis. We tested the association between a multi-protein-derived measure of IL-6 trans-signalling and clinical and cognitive outcomes in patients with depression. We hypothesised that this novel measure of IL-6 activity/bioavailability would be associated with clinical and cognitive measures previously reported to be associated with inflammation in depression., Methods: Using data from 86 patients with International Classification of Diseases-10 diagnosis of depression, we calculated a ratio score representing IL-6 activity/bioavailability using serum IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein 130 levels. We tested the relationship of this novel biomarker with 12 cytokines using correlation analyses and with cognitive and clinical measures using multivariable linear regression, following z-transformation of all immune exposures., Results: The novel measure of IL-6 activity/bioavailability was correlated with IL-6 (r=0.42, P=0.03), C-reactive protein (CRP) (r=0.42, P=0.03), sIL-6R (r=0.91, P<0.01), and tumour necrosis factor alpha (r=0.43, P=0.03). The IL-6 activity/bioavailability measure was associated with higher somatic symptoms of depression (β=1.09; 95% CI 0.30, 1.88; P FDR =0.01), fatigue (β=4.34; 95% CI 1.26, 7.42; P FDR =0.03), depression severity (β=3.06; 95% CI 0.71, 5.40; P=0.02), poorer quality of life (β=-0.07; 95% CI -0.13, -0.01; P FDR =0.045), and decreased psychomotor speed (β=-5.46; 95% CI -9.09, -1.84; P FDR =0.01),. There was little evidence of associations with reaction time, anhedonia, anxiety, emotional perception and recall, executive function, and sustained attention (Ps>0.05). The effect estimates for the associations of the novel measure with depression outcomes were comparable to those for individual immune proteins (i.e., IL-6, CRP, sIL-6R)., Conclusion: A novel multi-protein-derived measure of IL-6 activity/bioavailability shows robust associations with various inflammation-related clinical and cognitive outcomes in depression and performs well in comparison to single inflammatory proteins. We need replication of these findings in other samples, experiments for mechanistic validity of this novel biomarker, and clinical studies to assess its usefulness as a marker of illness risk and prognosis., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Factors of increased prevalence among individuals with Black racial identity (e.g., cardiovascular disease, CVD) may influence the association between exposure to repetitive head impacts (RHI) from American football and later-life neurological outcomes. Here, we tested the interaction between racial identity and RHI on neurobehavioral outcomes, brain volumetric measures, and cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated tau (p-tau181), and Aβ1–42 in symptomatic former National Football League (NFL) players. Methods: 68 symptomatic male former NFL players (ages 40–69; n = 27 Black, n = 41 White) underwent neuropsychological testing, structural MRI, and lumbar puncture. FreeSurfer derived estimated intracranial volume (eICV), gray matter volume (GMV), white matter volume (WMV), subcortical GMV, hippocampal volume, and white matter (WM) hypointensities. Multivariate generalized linear models examined the main effects of racial identity and its interaction with a cumulative head impact index (CHII) on all outcomes. Age, years of education, Wide Range Achievement Test, Fourth Edition (WRAT-4) scores, CVD risk factors, and APOE ε4 were included as covariates; eICV was included for MRI models. P -values were false discovery rate adjusted. Results: Compared to White former NFL players, Black participants were 4 years younger (p = 0.04), had lower WRAT-4 scores (mean difference = 8.03, p = 0.002), and a higher BMI (mean difference = 3.09, p = 0.01) and systolic blood pressure (mean difference = 8.15, p = 0.03). With regards to group differences on the basis of racial identity, compared to White former NFL players, Black participants had lower GMV (mean adjusted difference = 45649.00, p = 0.001), lower right hippocampal volume (mean adjusted difference = 271.96, p = 0.02), and higher p-tau181/t-tau ratio (mean adjusted difference = −0.25, p = 0.01). There was not a statistically significant association between the CHII with GMV, right hippocampal volume, or p-tau181/t-tau ratio. However, there was a statistically significant Race x CHII interaction for GMV (b = 2206.29, p = 0.001), right hippocampal volume (b = 12.07, p = 0.04), and p-tau181/t-tau ratio concentrations (b = −0.01, p = 0.004). Conclusion: Continued research on racial neurological disparities could provide insight into risk factors for long-term neurological disorders associated with American football play. [ABSTRACT FROM AUTHOR]