The objective of this K23 application is to provide additional training and mentored research experience for Dr. Vacas to establish herself as an independent investigator focused on understanding the mechanisms mediating Postoperative Neurocognitive Disorders (PNCD) in at-risk populations, such as patients with obstructive sleep apnea (OSA). The career development plan consists of obtaining further training in brain magnetic resonance imaging (MRI), data acquisition and analysis techniques, clinical science research, and administration of cognitive tests. To achieve training goals, Dr. Vacas has developed a focused research study and assembled an outstanding mentoring team. The primary mentor, Rajesh Kumar, PhD, is an expert in radiologic MRI techniques and interpretation, as well as neuroscience. Dr. Vacas? co-mentors, Jeffrey Saver, MD, Daniel Cole, MD, and Nancy Pike, PhD will assist in the development of the clinical study, anesthetic management, and assessment of cognition, respectively. Dr. Vacas also assembled a Research Advisory Committee, consisting of outstanding faculty members of the UCLA research community, including Maxime Cannesson, MD, PhD (who will provide support regarding hemodynamic management), Barbara Van de Wiele, MD (who will serve as mentor in the departmental Faculty Career Development and Growth program), and David Elashoff, PhD (who will provide statistical support). The plan is designed to provide the additional training and mentored research experience needed to extend Dr. Vacas?s research program, deepen its impact by integrating the biological interface between PNCD and brain sites and compete successfully for future R01 funding. PNCD, which include postoperative delirium and both acute and long-lasting neurocognitive deficits, are a significant public health problem, leading to a cascade of deleterious complications. Although the exact pathophysiology remains poorly understood, surgery and/or anesthesia-induced neuro-inflammation can exacerbate the underlying state of chronic neuro-inflammation present within at-risk populations. The confluence of these events provide us with a window to examine and understand PNCD processes and mechanisms. Reports of links between PNCD and brain changes in humans are scarce and small in number. This project will use a consistent intraoperative anesthetic plan which will reduce variability introduced from these potentially confounding factors. The study proposes that neuro-inflammation is associated with measurable brain morphologic findings that can be discovered with non-invasive diffusion tensor imaging and blood biomarkers. In summary, the overall purpose of this study is to examine the mechanisms of brain injury contributing to PNCD in an at-risk population (OSA) undergoing surgery. The proposed study has the potential to dramatically impact clinical practice, benefiting not only OSA, but also the general surgical population. In addition, this study will also provide critical pilot data to support an R01 application for future intervention-based studies to develop preventive measures that improve patient outcomes.
/PUBLIC HEALTH RELEVANCE Postoperative neurocognitive disorders are a common occurrence in at-risk populations such as patients with obstructive sleep apnea, leading to an estimated $150 billion annual expense in the US alone. Although some risk factors have been identified (like obstructive sleep apnea), the exact pathophysiology of postoperative neurocognitive disorders remains poorly understood. We will examine the potential mechanisms of brain injury and neuro-inflammation contributing to postoperative delirium, delayed cognitive recovery and neurocognitive disorders (postoperative) opening up groundbreaking avenues for future interventions that identify, prevent and treat these diseases, and thus reduce morbidity and mortality in surgical patients.