The Analysis of Blood Based Biomarkers in Bipolar Disorder

Abstract

Introduction: Bipolar disorder (BD) has widely been reported to display deficits in brain morphology, specifically abnormalities in white matter (WM) and myelin content. These deficits have been hypothesized to underlie cognitive dysfunction in domains such as verbal memory and executive function, which stresses the need to better understand the pathophysiology of these deficits and BD. Blood-based biomarkers provide an accessible route to analyze biological differences observed in BD compared to healthy control (HC), such as WM deficits. In this thesis, we first describe the extant literature thus far that has investigated any blood-based biomarkers related to WM and myelin content in BD to demonstrate the associations that have been reported to stress the possibility of using blood-based biomarkers as a proxy for WM deficits. We then expand on the literature by examining the association between peripheral neurofilament light chain (NfL) and intracortical myelin content (ICM). We then conclude by examining a novel biomarker, mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been shown to reduce endoplasmic reticulum (ER) stress in BD. ER stress has previously been observed to reduce cellular resilience and increase cell death in BD. Results: Based on our analysis, a wide range of blood-based biomarkers, including markers within the innate immune response, cytokines, and oxidative stress, were associated with neuroimaging markers of WM and myelin content in BD. Furthermore, NfL was associated with areas of the brain that have previously been observed to display deficits in ICM. In addition, NfL was significantly increased in BD compared to HC, providing further evidence of a neurodegenerative process in BD. Lastly, MANF was reduced in individuals in a depressive phase of BD compared to HC and euthymic individuals, suggesting an inadequate response to ER stress and further supporting the literature that BD is associated with increased ER stress. Conclusion: The results of this thesis underscore the significant role of blood-based biomarkers in better understanding BD pathophysiology. The identification of key differences in blood-based biomarkers in BD compared to HC, and their association with brain morphology, particularly myelin integrity, can help to improve our understanding of BD and encourages further studies. This thesis expands on current literature and provides novel findings regarding peripheral markers in BD pathophysiology, and that blood-based biomarkers may serve as a proxy for central changes.