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

• 批准号: 10467056
• 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
• 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/10467056
• 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

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.

项目摘要 /摘要 Mahsa Abassi博士是医学助理教授在 明尼苏达大学。在过去的六年中，她从事临床研究，重点是HIV- 乌干达相关的神经感染。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了指导 培训：1）神经系统技术（EEG，神经放射学和神经认知评估），2）实验室 与代谢组应用有关的技术，以及4）生物统计学，重点是分析 生物样品中的代谢产物。 研究：隐球菌脑膜炎占全球艾滋病毒/艾滋病相关死亡的15％，是最多的 非洲成人脑膜炎的常见原因。当时的心理状况改变了（从del妄到昏迷） 隐球菌脑膜炎的诊断始终是死亡率增加的独立预测指标。尽管 重复的研究证实了精神状况改变与死亡之间的这种密切的联系，有一个 根本缺乏对确切神经系统异常的理解，导致急性改变了精神 地位，对增加死亡率的贡献以及管理的最佳实践。 该提议的目的是确定导致精神改变的神经系统异常 地位并了解这是如何有助于加密局死亡率增加的。总体假设 是伴有颅内压增加的隐球菌脑膜炎会导致脑缺氧，异常 电活动以及中枢神经系统（CNS）的生化变化，可以通过 脑代谢物CSF分析和用脑血氧饱和度和脑电图增强的临床监测。这 提案的目的是：1）确定患有隐球菌脑膜炎的艾滋病毒感染者是否发生了变化 诊断时的心理状况（Glasgow昏迷量表（GCS）<15）具有可测量的基础神经系统 脑能量代谢的异常和损害（即氧化代谢不足） 与具有正常心理状态的人相比（GCS = 15）； 2）确定是否实施标准化 临床干预措施可以逆转神经系统异常，并改善3 诊断天数，并降低患有隐球菌脑膜炎的艾滋病毒感染者的30天死亡率 心理状况改变（GCS <15）。上述目标的结果将使以前未知 导致隐球菌脑膜炎心理状况改变的病理生理机制。培训 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 致力于理解各种神经感染的神经病理学并找到证据的建议 - 基于致力于改善生存的干预措施。