Neurocognitive Impairment in Acute Respiratory Failure and Shock: Understanding the Role of Neuronal Excitotoxicity

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Project Summary Cardiopulmonary failure due to acute respiratory failure or shock is the most common syndrome necessitating intensive care unit services. Patients with cardiopulmonary failure often develop burdensome neurocognitive sequelae that threaten both short and long-term outcomes. In the short-term, these patients frequently develop delirium, a severe alteration in attention and cognition that is associated with increased mortality as well as longer durations of mechanical ventilation and ICU stay. After recovering, 1 in 4 survivors suffer long-term cognitive impairment (LTCI) similar to dementia. Despite the impact delirium and LTCI have on these patients, there are currently no proven pharmacologic therapies aimed at preventing these neurocognitive sequelae. Sepsis accounts for over 1 million hospitalizations per year and is the most common cause of cardiopulmonary failure, making it an ideal population to investigate the underlying mechanisms of delirium and LTCI. Our group and others have shown that delirium and LTCI are characterized by injury to the hippocampus and frontal cortex. Animal models show a similar pattern of neuronal injury, and implicate alterations in glutamate homeostasis and kynurenine metabolism as key downstream pathways of neuronal injury that can be therapeutically targeted. However, a lack of data on these pathways in humans and an inability to identify which patients would most likely benefit from early therapy are key knowledge gaps limiting the translation of these findings to clinical trials. To address these knowledge gaps, this proposal will investigate the role of glutamate and kynurenine dysregulation in an ongoing cohort of septic patients with cardiopulmonary failure who are followed prospectively for delirium and subsequent cognitive impairment. In addition to the proposed research, the candidate will engage in a rigorous training program designed to support his transition into an independent scientist. The specific objectives of this proposal are to: 1) determine the association of glutamate and kynurenine dysregulation with delirium and cognitive impairment in septic patients with cardiopulmonary failure, 2) identify risk factors for cognitive impairment and develop a predictive tool that could be used to guide enrollment in future clinical trials, 3) train the candidate in cognitive neuroscience, mechanisms of neuronal injury and repair, cohort study design and conduct, molecular laboratory techniques and advanced statistics, and 4) provide the candidate with individualized mentoring to support his transition to independence. The candidate's attainment of specific research and training benchmarks will be regularly reviewed by his mentors and advisory committee. Through completion of this proposal, the candidate will enhance our understanding of the underlying mechanisms of delirium and LTCI in these patients, and position himself to successfully compete for R01 funding of future projects aimed at testing neuroprotective therapies.