Targeting Neuropathogenesis of Altered Mental Status to Improve Survival in Cryptococcal Meningitis

点击翻译按钮获取中文摘要

Project Summary / Abstract Dr. Mahsa Abassi is an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of Minnesota. Over the past six years, she has been engaged in clinical research, focusing on HIV- related neuroinfections in Uganda. Her long-term objective is to become an independent clinical researcher with an emphasis on improving outcomes in neuroinfections. Her career development plan proposes mentored training in: 1) neurologic techniques (EEGs, neuroradiology, and neurocognitive assessment), 2) laboratory techniques related to metabolomics applications, and 4) biostatistics with an emphasis of analyzing metabolites in biologic samples. Research: Cryptococcal meningitis accounts for 15% of HIV/AIDS-related deaths globally and is the most common cause of adult meningitis in Africa. Altered mental status (ranging from delirium to coma) at the time of cryptococcal meningitis diagnosis is consistently an independent predictor of increased mortality. Despite repeated studies confirming this strong association between altered mental status and death, there is a fundamental lack of understanding into the exact neurological abnormalities leading to acute altered mental status, its contributions to increased mortality, and the best practices for management. The objective of this proposal is to identify the neurological abnormalities that contribute to altered mental status and to understand how this contributes to increased cryptococcal mortality. The overarching hypothesis is that cryptococcal meningitis with its increased intracranial pressure leads to cerebral hypoxia, abnormal electrical activity, and biochemical changes in the central nervous system (CNS) that can be detected through brain metabolite CSF analysis and enhanced clinical monitoring with cerebral oximetry and EEGs. This proposal aims to: 1) determine if HIV-infected persons with cryptococcal meningitis presenting with altered mental status (Glasgow Coma Scale (GCS) <15) at diagnosis have measurable underlying neurological abnormalities and impairments in cerebral energy metabolism (i.e. insufficient oxidative metabolism) as compared to persons with normal mental status (GCS=15); and 2) determine if implementation of standardized clinical interventions can reverse neurological abnormalities and improve cerebral energy metabolism within 3 days of diagnosis, and reduce 30-day mortality in HIV-infected persons with cryptococcal meningitis presenting with altered mental status (GCS<15). Results of the above aims will shed light into previously unknown pathophysiologic mechanisms that lead to altered mental status in cryptococcal meningitis. The training in neuroinfections, metabolomics applications, and biostatistics that Dr. Abassi will obtain will inform future proposals dedicated to understanding the neuropathology of various neuroinfections and finding evidence- based interventions dedicated to improving survival.