Differential levels of inflammatory and neuroendocrine markers in the hippocampus and anterior cingulate cortex of bipolar disorder subjects: A post-mortem study

Bipolar disorder (BD) is a severe and recurrent neuropsychiatric illness that causes high rates of disability, with onset frequently during adolescence and early adulthood 1. Devastating health and social consequences of BD are associated with the fact that the illness is often misdiagnosed, which leads to inappropriate or delayed treatments 2,3. Misdiagnosis is also a consequence of the fact that the etiology of BD still poorly understood. Disturbances in multiple systems have been proposed to play a role in BD pathophysiology, including metabolic, neuroendocrine and immune-inflammatory 4–6. Metabolic comorbidities are associated with BD burden, such as diabetes, obesity and cardiovascular diseases, supporting the role of systemic inflammation in BD 7–9. In two different meta-analysis, elevated peripheral levels (serum or plasma) of pro-inflammatory cytokines IL-4, IL-6, IL-10, and TNF-α were found in BD patients, when compared to controls 10,11. In a meta-analytic study comparing mood episodes, increased levels of peripheral IL-6 were found in mania. In addition, increased levels of TNF-α were found in mania and depression, and increased levels of IL-6 and C-reactive protein (CRP) were found in euthymia 12. CRP is an inflammatory factor related to acute immune response 13 that has been investigated previously in the blood of BD patients 14. Higher levels of CRP were also associated with cognitive dysfunction in BD 15. Cortisol is a glucocorticoid closely involved in inflammation and cytokine regulation 16. Increased cortisol levels in serum/plasma or urine have been found in BD, especially during mania and euthymia 17, supporting a contribution of the hypothalamic–pituitary–adrenal (HPA) axis in this disorder. Although several shreds of evidence from peripheral measures strongly support the role of inflammation and neuroendocrine changes in BD, the consequences of these systemic alterations to the brain and the potential presence of neuroinflammation still poorly understood. A recent meta-analysis conducted in BD post-mortem brains revealed important evidence of neuroinflammation regarding cell types and molecules involved 18. Among the addressed molecular parameters, the cytokines TNF-α, IL-1β, and IL-6 were found to be increased in the pre-frontal cortex of BD patients 19. For the purpose of this study, that meta-analysis revealed that the majority of the post-mortem studies in BD brains addressed frontal cortex. There has not been any study focusing on the same inflammatory and neuroendocrine factors in different brain regions. Furthermore, IL-17, CRP and cortisol have not been evaluated in post-mortem brain samples of BD patients. Here, we investigated different neuroinflammatory markers, including a panel of cytokines (IL-1β, IL-6, IL-10, IL-17A and TNF-α) and CRP, as well as cortisol levels in the hippocampus and anterior cingulate cortex (ACC) in post-mortem brains of BD subjects. These two brain regions have been consistently investigated and implicated in the pathophysiology via neuroimaging studies 20,21 and are morphologically and biochemically altered in BD showing volume reduction and glutamatergic abnormalities 22,23