Elucidating the molecular changes that underlie depression and associated symptoms in Bipolar Disorder?I (BD) is critical for diagnostic and therapeutic efficacy. BD is a devastating illness with a lifetime prevalence of 1%. Within BD, depression is the most common and most frequent presenting episode type, and is associated with a high risk of suicide. Unfortunately, currently available pharmacotherapies are not able to provide effective relief to a large portion of individuals with BD, and do not normalize the observed deficits in cognitive functioning in the disorder. Thus, there is a pressing need to identify novel molecular sites, which may prove as treatment targets to reduce the burden of depression and cognitive dysfunction in BD. Significant evidence suggests heightened inflammatory tone in BD, which may contribute to the pathophysiology of the disorder. For example, peripheral markers of inflammation are higher in individuals with BD as compared to controls and individuals with BD have higher prevalence of inflammatory disorders such as heart disease. Furthermore, elevated peripheral inflammatory markers appear to subserve some of the cognitive deficits observed in BD, for which currently there are no targeted treatments. It was previously thought that the brain and peripheral immune system were isolated by the blood-brain-barrier, but we now know that cytokines in the periphery can enter the brain, lead to changes in behavior and initiate a central inflammatory response. In response to signals from the periphery and damaging stimuli, microglial cells become activated and, in their pro-inflammatory state may lead to neuro- and excitotoxicity. Unfortunately, investigation of inflammatory factors in the brains of individuals with BD is limited. However, the existing evidence from postmortem studies and one in vivo imaging study of euthymic individuals with BD supports the hypothesis of elevated neuroinflammatory factors in BD, which can lead to neuronal damage. We propose a novel and critical examination of microglial activation in BD depression using [11C]PBR28 ? a radioligand with high specificity for the Translocator Protein (TSPO), which is upregulated in activated microglia and used as a marker of neuroinflammation. We will scan 15 individuals with BD-Dep and 15 healthy control individuals with to identify whether there is increased neuroinflammation in BD-Dep. We previously showed that [11C]PBR28 is able to detect changes in neuroinflammation following a peripheral immune challenge and is thus an excellent tool to detect neuroinflammation in BD. Importantly, we will address the question of whether the hypothesized increased neuroinflammation in BD is associated with the depressive symptomatology and cognitive deficits in individuals with BD-Dep. We hypothesize that individuals with the greatest degree of neuroinflammation will exhibit more severe depressive symptoms and have the strongest cognitive deficits in executive control, memory, and attention. These results may lead to a breakthrough in the characterization of BD-Dep and the neurobiological basis of its symptoms, which may benefit from treatments with anti-inflammatory agents.

Public Health Relevance

Bipolar disorder is associated with suffering, disability, other medical morbidity and early mortality owing to suicide and evidence suggests untreated episodes can worsen course and prognosis; yet, current treatments are limited in their effectiveness especially for the depressive episodes in BD. Thus, there is a critical need to identify the molecular mechanisms that underlie bipolar disorder and that can serve as new therapeutic targets for more effective treatments for the acute mood and cognitive symptoms of the disorder. We plan an innovative approach using positron emission tomography brain scanning and symptom and cognitive assessments of individuals with bipolar disorder during depression to study the role of neuroinflammation in the pathophysiology of the disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Hillefors, MI
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Yale University
Schools of Medicine
New Haven
United States
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