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

针对精神状态改变的神经发病机制以提高隐球菌性脑膜炎的生存率

基本信息

批准号：
10325249
负责人：
Mahsa Abassi
金额：
$ 20.14万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-16 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10325249
关键词：
AIDS/HIV problem Accounting Acquired Immunodeficiency Syndrome Acute Address Adult Africa Africa South of the Sahara Biochemical Biological Biometry Brain Cell Respiration Central Nervous System Infections Cerebral Hypoxia Cerebrospinal Fluid Cerebrum Cessation of life Clinical Clinical Research Coma Communicable Diseases Congenital neurologic anomalies Cryptococcal Meningitis Cryptococcus Data Delirium Detection Development Development Plans Diagnosis Early identification Electroencephalogram Energy Metabolism Evidence based intervention Excess Mortality Functional disorder Future Glasgow Coma Scale Glucose Goals Grant Guidelines HIV Impairment Infection International Intervention Intracranial Hypertension Laboratories Lead Leukocytes Light Measurable Medicine Meningitis Mentors Mentorship Microbiology Minnesota Monitor Neuraxis Neurocognitive Neurologic Neuropathogenesis Oxygen saturation measurement Pathogenesis Pathology Patients Persons Pharmaceutical Preparations Practice Management Pyruvate Reporting Research Research Personnel Sampling Seizures Standardization Supportive care Techniques Testing Time Training Uganda Universities antiretroviral therapy career development experience improved improved outcome innovation insight laboratory experience low income country mental state metabolomics mortality neuropathology professor therapy design

项目摘要

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.

项目概要/摘要 Mahsa Abassi 博士是该大学传染病科的医学助理教授明尼苏达大学。六年来，她一直从事临床研究，专注于HIV- 乌干达的相关神经感染。她的长期目标是成为一名独立的临床研究员重点是改善神经感染的结果。她的职业发展计划提出辅导培训内容：1) 神经学技术（脑电图、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，重点是分析生物样品中的代谢物。研究：隐球菌性脑膜炎占全球艾滋病毒/艾滋病相关死亡的 15%，是最常见的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）隐球菌性脑膜炎诊断的准确性始终是死亡率增加的独立预测因素。尽管反复研究证实精神状态改变与死亡之间存在密切关联，对导致精神急性改变的确切神经异常缺乏根本性的了解状况、其对死亡率增加的贡献以及最佳管理实践。该提案的目的是确定导致精神改变的神经系统异常状况并了解这如何导致隐球菌死亡率增加。总体假设隐球菌性脑膜炎伴其颅内压增高，导致脑缺氧，异常中枢神经系统 (CNS) 的电活动和生化变化可通过以下方式检测脑代谢脑脊液分析以及通过脑血氧饱和度和脑电图增强临床监测。这该提案旨在：1) 确定患有隐球菌性脑膜炎的艾滋病毒感染者是否表现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系统症状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相比（GCS=15）； 2) 确定是否实施标准化临床干预可在3年内逆转神经异常并改善脑能量代谢诊断天数，并降低患有隐球菌性脑膜炎的 HIV 感染者 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情况导致隐球菌性脑膜炎精神状态改变的病理生理机制。此次培训在 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提案- 致力于改善生存的干预措施。