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

项目总结/摘要 Mahsa Abassi博士是纽约大学传染病系医学助理教授， 明尼苏达大学。在过去的六年里，她一直从事临床研究，重点是艾滋病毒- 乌干达的神经系统感染。她的长期目标是成为一名独立的临床研究人员 重点是改善神经感染的结果。她的职业发展计划提出， 培训：1）神经学技术（EEG、神经放射学和神经认知评估），2）实验室 与代谢组学应用相关的技术，以及4）生物统计学，重点分析 生物样品中的代谢物。 研究：隐球菌脑膜炎占全球艾滋病毒/艾滋病相关死亡的15%， 非洲成人脑膜炎的常见原因。当时精神状态改变（从谵妄到昏迷） 隐球菌性脑膜炎的诊断始终是死亡率增加的独立预测因素。尽管 反复的研究证实了精神状态改变和死亡之间的强烈联系， 对导致急性精神改变的确切神经异常缺乏了解 的地位，其对死亡率增加的贡献，以及管理的最佳做法。 这项建议的目的是确定神经异常，有助于改变精神 的地位，并了解这是如何有助于增加隐球菌死亡率。总体假设 隐球菌脑膜炎颅内压增高导致脑缺氧， 电活动和中枢神经系统（CNS）的生化变化，这些变化可以通过 脑代谢物CSF分析和用脑血氧测定法和EEG增强的临床监测。这 建议的目的是：1）确定是否有艾滋病毒感染者隐球菌脑膜炎提出改变 诊断时的精神状态（格拉斯哥昏迷量表（GCS）<15）具有可测量的潜在神经功能 脑能量代谢异常和损伤（即氧化代谢不足）， 与精神状态正常的人（GCS=15）相比; 2）确定是否实施标准化的 临床干预可以在30分钟内逆转神经系统异常并改善脑能量代谢。 天的诊断，并减少隐球菌脑膜炎表现的艾滋病毒感染者的30天死亡率 精神状态改变（GCS<15）。上述目标的结果将揭示以前未知的 导致隐球菌性脑膜炎患者精神状态改变的病理生理机制的训练 Abassi博士将获得的神经感染，代谢组学应用和生物统计学将为未来的研究提供信息。 致力于了解各种神经感染的神经病理学并寻找证据的建议- 致力于提高生存率的干预措施。

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.