Dynamic Inflammatory and Mood Predictors of Cognitive Aging in Bipolar Disorder

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As the population ages, the burden on individuals and society due to the cognitive and health effects of serious mental illnesses, such as bipolar disorder (BD), will increase. Premature and accelerated aging trajectories in BD are beginning to be recognized in many health and cognitive domains, but specific mechanisms have not yet been identified, particularly for the course of cognitive aging. Markers of inflammatory function, such as cytokine levels, are known to affect cognition, change with age, and predict declines in mentally healthy individuals. Cytokine levels also appear to be abnormal in those with BD, but mood instability in BD makes measurement of short- and long-term changes in both inflammatory and cognitive measures challenging. Nonetheless, studies within this population afford a unique opportunity to better understand how variations in the degree of emotional and behavioral dysregulation may moderate or mediate immune-cognitive associations. We propose to use an innovative multi-cohort burst longitudinal design (MBLD) to characterize trajectories of cognitive and inflammatory response and identify: 1) relationships between cognition and inflammation in the short term while accounting for effects of mood variability, 2) baseline measures and levels of short-term variability in inflammatory markers that might predict long-term trajectories of cognitive change, and 3) relationships between inflammatory, cognitive, and mood variables in the long-term (i.e., mechanisms of change). We will assess 144 adults (35-60 years old) with clinically-relevant symptoms of mood dysregulation, as indicated by Bipolar I diagnosis, and 115 similarly aged non-BD comparison (NC) participants without mental illnesses. Cognition, cytokine levels, and mood (along with other potential contributing variables) will be measured weekly or daily over a two week period using intensive remote monitoring and home visits (burst assessment). Burst assessments will be repeated annually (longitudinal assessment) for three years in the BD group, and at one year in the NC group. This project addresses NIMH Strategic Objective # 2: charting mental illness trajectories to determine when, where, and how to intervene. Specifically, using an innovative design that allows us to account for, and measure the impact of, variability in mood symptoms, we can discover inflammatory markers (both static and dynamic) that predict the course of cognitive change among individuals with mood instability. By understanding the complex and dynamic interplay between inflammation, cognition, and mood, pharmacologic and behavioral interventions can be designed to slow or reverse the trajectory of declining function in bipolar disorder.