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  • Here we examine the associations

    2020-11-16

    Here, we examine the associations between serum pro and anti-inflammatory cytokines and cognitive functioning in early-stage bipolar I disorder (BDI) patients. As per previous studies, ‘early-stage’ was defined as being within three years of the first manic episode (Kauer-Sant'Anna et al., 2009). We examine 3 pro- inflammatory (TNFα, IL-6 and IL-1 family) and 2 anti-inflammatory (IL-4 and IL-10) cytokines that have been consistently associated with cognitive functioning and found to be abnormally expressed in BDI. We hypothesize that pro-inflammatory cytokines are associated with cognitive dysfunction and anti-inflammatory with improved cognition; however, as BDI patients appear to have abnormalities in pro-inflammatory cytokines from illness onset, these cytokines may have a stronger association with cognition compared to anti-inflammatory cytokines in early stage patients. By identifying specific markers that impact cognition early in the disease course, our aim is to identify potential targets for early therapeutic intervention and further understanding of pathogenesis in early stage BDI.
    Materials and methods
    Results
    Discussion TNFα levels in this sample of early stage patients were higher than healthy controls at trend level significance. In addition, TNFα emerged as an independent negative predictor of global cognition, processing speed and working memory, after accounting for medication use, mood symptoms, and other clinical/demographic variables. Previous studies using subjects with longer illness duration have associated TNFα with verbal memory and inhibitory control in BDI patients (Rosenblat et al., 2015). Higher levels of soluble TNFα receptor 1 levels, the receptor through which TNFα exerts many of its neurotoxic effects, has also been linked to poorer memory in BDI patients with psychosis (Rosenblat et al., 2015). Our results extend these findings by suggesting that, rather than being a sequelae of long-term exposure to persistently elevated TNFα (Kapczinski et al., 2009), cognitive functioning is deleteriously impacted by TNFα even in early stages of disease. This association is consistent with the known neurotoxic effects of TNFα. At elevated levels, TNFα can directly injure Adenosine sale by initiating apoptotic cascades and increasing glutamate mediated excitotoxicity (Bortolato et al., 2015; Muneer, 2016). In addition, TNFα can inhibit hippocampal long-term potentiation, and increased TNFα receptor signaling is associated with cerebral atrophy, hippocampal neuronal loss and increased risk of cognitive decline (Bortolato et al., 2015; Sudheimer et al., 2014). Furthermore, animal studies have found that TNFα inhibition prevents stress and neuroinflammation induced cognitive impairments, as well as preventing cognitive decline in transgenic mouse models of Alzheimer's dementia (Belarbi et al., 2012; Gabbita et al., 2012; Sahin et al., 2015). There is additionally preliminary evidence in humans that TNFα inhibition may improve cognition in Alzheimer's dementia (Tobinick et al., 2006). While there is some evidence that TNFα inhibitors may be beneficial in the treatment of mood disorders (Bortolato et al., 2015), and that current treatments for BDI may reduce expression of TNFα (Boufidou et al., 2004), the direct effects of TNFα inhibition on cognition in mood disorder patients has not yet been investigated. As well, it is not clear whether it is the direct neuronal injury caused by TNFα, as opposed to the downstream effects of TNFα activation, that impacts cognition. For example, pro-inflammatory cytokines activate the HPA axis and reduce glucocorticoid receptor sensitivity to negative feedback (Rosenblat et al., 2015). The resultant chronic hypercortisolemia may then have negative cognitive effects independent of TNFα (Young et al., 2004). IL-6 and IL-1α were not significantly associated with cognition in this analysis, contrasting with previous studies that have correlated these cytokines with cognitive dysfunction in chronic BDI (Rosenblat et al., 2015). This suggests that these cytokines may not mediate neurotoxic activities to the same degree as TNFα early in the disease course. It should be noted that while we did not find an association with IL-1α and cognition, previous studies have associated cognition with related components of the IL-1 family and signaling pathways, such as IL-1 receptor antagonist or IL-1β (Huang and Sheng, 2010; Rosenblat et al., 2015). The possibility that these specific factors are associated with cognition in early stage patients cannot be ruled out. Additionally, anti-inflammatory cytokines IL-4 and IL-10 did not significantly contribute to the variance in cognitive performance above TNFα, despite their physiologic actions of suppressing TNFα expression and attenuating inflammation induced cognitive impairment (Derecki et al., 2010; Gadani et al., 2012; Lobo-Silva et al., 2016; Richwine et al., 2009). While previous research has suggested that these anti-inflammatory cytokines are elevated in BDI as part of a compensatory mechanism to counteract chronic inflammation (Muneer, 2016), in this study they were not increased relative to the control group. However, our sample, particularly with respect to the healthy control group (n = 20), may have been underpowered to detect a difference, as a previous study comparing 30 early stage patients drawn from this same sample population to 60 healthy controls found significantly higher IL-10 levels in patients (Kauer-Sant'Anna et al., 2009). Our findings in the regression analysis, however, do not indicate that these cytokines have a significant neuroprotective effect in early stage disease. Deficient signalling between the pro- and anti-inflammatory pathways, resulting in insufficient production of IL-10, has been found in depression (Dhabhar et al., 2009), and there may be similar failures in the production of sufficient anti-inflammatory cytokines to counteract inflammation in BDI. It is also possible that anti-inflammatory cytokines in BDI patients have decreased biologic activity compared to healthy populations, resulting in reduced ability to regulate inflammation and the resultant neurotoxicity.