Cerebral Autoregulation, Metabolic derangement, and Edema in Encephalopathy Outcome (CAMEEO)

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Project Summary/Abstract This K23 award application is for Eric Liotta, MD, a neurointensivist and Associate Professor of Neurology at Northwestern University. Dr. Liotta’s long-term goal is to become an independent physician scientist with expertise in the interactions between the brain and the body, in order to improve neurologic outcomes and reduce the risk of subsequent dementia following acute medical illness. To accomplish this goal, he will pursue a patient-oriented research agenda focused on delirium and encephalopathy with hepatic encephalopathy (HE) and COVID-19 associated encephalopathy (CAE) models. His mentored research program leverages career development activities through applications to the proposed research, culminating in his transition to research independence. He will develop broadly applicable expertise in systemic metabolic analysis, neurophysiologic evaluation, cognitive impairment and quality of life outcomes assessment, and patient-oriented research methods. He has assembled a team of mentors who will guide him in the transition to independent researcher. Farzaneh Sorond, MD PhD (mentor) is a neurointensivist who studies cerebral autoregulation, aging, and vascular cognitive impairment; Shyam Prabhakaran, MD MS (co-mentor) is a vascular neurologist who studies acute cerebrovascular disease with a focus on imaging-based markers of risk; and W. Taylor Kimberly, MD PhD (co-mentor) is a neurointensivist who studies cerebral and systemic metabolism in acute stroke. Acute encephalopathy (frequently called delirium) is pervasive in hospitalized patients. Encephalopathy survivors are at increased risk for cognitive impairment, vascular dementia, and Alzheimer’s dementia, though the mechanisms are unknown. Treating encephalopathy is hampered by incomplete knowledge of the relevant systemic derangements and the brain’s physiologic response to those derangements and their clinicopathologic syndromes. Dr. Liotta will investigate the hypothesis that osmolality and amino acid metabolic derangements result in cellular brain injury, cerebral edema, and impaired cerebral autoregulation that manifest acutely as encephalopathy, and chronically as cognitive impairments and elevated risk of early dementia development. Aim 1 will investigate the mechanism between metabolic derangements and cellular injury, cerebral edema, and cerebral autoregulation. Aim 2 will investigate the mechanism between cellular injury, cerebral edema, and cerebral autoregulation and clinical encephalopathy (delirium) severity. Aim 3 will investigate the mechanism between encephalopathy (delirium) burden and subsequent cognitive impairment. The study will use (1) repeated assessments of metabolic and physiologic derangements to elucidate the relationship with encephalopathy severity and (2) longitudinal follow up to investigate the relationship to cognitive impairment. By completing these aims, Dr. Liotta will gain a substantive foundation in brain-body interactions during acute illness that can be utilized to elucidate mechanistic targets to reduce cognitive impairment and risk of vascular dementia and Alzheimer’s dementia following encephalopathy and acute medical illness.