Increased serum levels of eotaxin/CCL11 in late-stage patients with bipolar disorder: An accelerated aging biomarker?

Highlights

• We compared two groups of patients with bipolar disorder in early and late stages of the disease.

• The early and late groups were characterized following the Staging model suggested by Kapczinski et al., 2009a, Kapczinski et al., 2009b based on time of disease, number of episodes and global functioning.

• Oxidative stress biomarkers did not differ between groups. As well neurotrophic factors.

• The inflammatory biomarkers analyzed also did not differ between groups, except by the chemokine eotaxin/CCL11.

• Suggesting a link between atopy and bipolar disorder. The BD as been a process of neuroprogression.

Abstract

Background

Bipolar disorder (BD) is commonly comorbid with many medical disorders including atopy, and appears characterized by progressive social, neurobiological, and functional impairment associated with increasing number of episodes and illness duration. Early and late stages of BD may present different biological features and may therefore require different treatment strategies. Consequently, the aim of this study was to evaluate serum levels of eotaxin/CCL11, eotaxin-2/CCL24, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFNγ, BDNF, TBARS, carbonyl, and GPx in a sample of euthymic patients with BD at early and late stages compared to controls.

Methods

Early-stage BD patients, 12 late-stage patients, and 25 controls matched for sex and age were selected. 10 mL of peripheral blood was drawn from all subjects by venipuncture. Serum levels of BDNF, TBARS, carbonyl content, glutathione-peroxidase activity (GPx), cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFNγ), and chemokines (eotaxin/CCL11 and eotaxin-2/CCL24) were measured.

Results

There were no demographic differences between patients and controls. No significant differences were found for any of the biomarkers, except chemokine eotaxin/CCL11, whose serum levels were higher in late-stage patients with BD when compared to controls (p=0.022; Mann–Whitney U test).

Limitations

Small number of subjects and use of medication may have influenced in our results.

Conclusion

The present study suggests a link between biomarkers of atopy and eosinophil function and bipolar disorder. These findings are also in line with progressive biological changes partially mediated by inflammatory imbalance, a process referred to as neuroprogression.

Introduction

Bipolar disorder (BD) is a chronic psychiatric illness characterized by recurrent episodes of mania and depression (Barnett and Smoller, 2009). It affects about 2.4% of the world population (Merikangas et al., 2011) and often has a negative impact on the lives of patients (Barnett and Smoller, 2009).

Bipolar disorder is also linked with medical comorbidity, particularly auto-immune and atopic disorders including asthma and atopic dermatitis (Perugi et al., 2014). A large population based study showed a significant association between bipolar disorder and asthma (Lin et al., 2014). Similar associations with atopy are found in depression (Sanna et al., 2014). This association implicates the drivers of eosinophil function such as CCL11, a cytokine that recruits eosinophils. It stimulates eosinophil chemotaxis, driving allergic responses. The first papers suggesting enhanced eosinophil responses in bipolar disorder were published over half a century ago (Lehmann et al., 1950).

Evidence suggests that the progressive social, neurobiological, and functional impairment observed in BD is associated with the number of episodes and illness duration (Fries et al., 2012, Gama et al., 2013). Most patients at early disease stages have more favorable clinical outcomes when compared to patients at late stages (Kauer-Sant׳Anna et al., 2009). Illness progression is often associated with shorter inter-episode intervals, poorer adherence to pharmacological treatment, and an increased risk of hospitalization (Kapczinski et al., 2009a, Schuepbach et al., 2008, Swann et al., 1999, Tohen et al., 1990). Furthermore, individuals with a long-term course of illness present significant impairment in cognitive tasks and functioning when compared to both controls and early-stage patients (Berk et al., 2011a, Rosa et al., 2014). Finally, considering that the resilience of patients becomes impaired, their vulnerability to stressor events may contribute to the triggering of new episodes (Kapczinski et al., 2008, Kessing et al., 1998).

Despite a growing body of research, there are no robust biological tests currently available to differentiate between different BD states, or different stages indicating neuroprogression. Some factors have been prioritized in the search for biomarkers, such as neurotrophic factors, especially brain-derived neurotrophic factor (BDNF), cytokines – usually focusing on pro-inflammatory but also anti-inflammatory ones, and oxidative stress markers (Berk et al., 2011b, Gubert et al., 2013, Kunz et al., 2011, Kunz et al., 2008, Munkholm et al., 2013, Pfaffenseller et al., 2013). However, most studies report differences only in acute states (i.e. mania or depression BD), and there seems to be little overall consistency in the data reported.

Evidence points towards an interaction between chemokines and neurotransmitters systems in the brain, playing crucial roles in brain development and function (Capuron and Miller, 2011). Chemokines are a special type of cytokines involved in the attraction of cells to inflammatory sites, being promising in the study of the role of inflammation in BD (Miller et al., 2011, Potvin et al., 2008). High levels of eotaxin/CCL11 and eotaxin-2/CCL24 have been found in patients with schizophrenia and in BD in comparison with healthy subjects (Barbosa et al., 2013, Brietzke et al., 2009, Magalhaes et al., 2014, Teixeira et al., 2008). In addition, high levels of eotaxin/CCL11 have been associated with decreased neurogenesis in the hippocampus, and with impaired learning and memory in mice (Villeda et al., 2011). Interestingly increased levels of eotaxin/CCL11 have been strongly related to the age-related cognitive decline in healthy subjects (Villeda et al., 2011) and in subjects with schizophrenia (SZ) (Asevedo et al., 2013). Eotaxin/CCL11 is implicated in the relationship between severe neuropsychiatric diseases, such as BD and SZ and accelerated aging (Pedrini et al., 2014, Rizzo et al., 2013).

Considering the possible role of atopic pathways, and that early and late stages of BD are clinically different in many aspects and may present different biological features, requiring specific treatment strategies, the aim of this study was to evaluate whether neurotrophic factor, cytokines and oxidative stress parameters are different between them. For this purpose, serum levels of eotaxin/CCL11, eotaxin-2/CCL24, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFNγ, BDNF, TBARS, carbonyl, and GPx were determined in a sample of euthymic patients with BD at early and late stages of the disease compared to healthy controls.