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

University Of Minnesota, Minneapolis MN

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Abstract

Dr. Mahsa Abassi is an Assistant Professor of Medicine in the Division of Infectious Diseases at the University of Minnesota. She has been engaged in clinical research, focusing on AIDS related neuroinfections in Uganda. Her long-term objective is to become an independent clinical researcher with an emphasis on improving outcomes in neuroinfections. Dr. Abassi’s Career Development Plan will provide her with the mentorship support, didactic course work, and hands-on training she will need to become an expert in clinical and translational research with a focus on HIV-associated neuroinfections. Her career development plan proposes mentored training in: 1) neurologic techniques (EEGs and neuroradiology), 2) laboratory techniques related to metabolomics applications, 3) advanced training in clinical research and translational medicine, and 4) biostatistics with an emphasis of analyzing metabolites in biologic samples. Research: Cryptococcal meningitis accounts for 15% of HIV/AIDS-related deaths, globally. Altered mental status 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 altered mental status, its contributions to increased mortality, and 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 it 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, EEGs, and ECGs. 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 and 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 metabolomics applications and clinical research that Dr. Abassi will obtain will inform future proposals on evidence-based interventions dedicated to improving survival in HIV-associated neuroinfections.