Cerebral Hemodynamics and Stroke in HIV-associated TB Meningitis.

摘要 脑膜炎（TBM）严重影响低收入和中等收入国家的人们， 与高发病率和死亡率相关。脑卒中是TBM的常见并发症，可导致严重的 不可逆转的神经系统残疾然而，对TBM相关卒中病理学的研究集中在 主要针对未感染艾滋病毒的人。本提案的总体目标是使用经颅多普勒， 脑成像，了解脑血管和脑血流的变化，以确定 脑血管反应性的变化，表征中风的模式，并描述长期 HIV相关TBM的神经认知结果。核心假设是，在艾滋病毒感染者中， TBM引起广泛的脑血管狭窄和脑血管反应性受损， 脑血流，最终导致中风将通过追求三个具体目标来检验中心假设： 1)描述HIV相关TBM中脑血管反应性的变化; 2）描述 HIV相关TBM中的中风，并确定其是否与血管病变和/或 脑血管反应性;和3）确定受损的脑血管反应性是否预测长期- HIV相关TBM的远期神经学结局根据目标1，经颅多普勒将用于 重复测量大脑中动脉血流速度和搏动指数。研究的子集 受试者还将响应于刺激（吸入的CO2、血液中的变化）进行动态测量 压力和运动任务）。我们将确定HIV患者的脑血管反应性是否受损- 相关的TBM通过比较测量与那些没有神经系统感染的对照患者。下 目标2，所有研究受试者将在TBM治疗的前2周内进行脑部MRI，以确定 脑动脉中风的存在和相关的脑动脉区域。我们将比较TCD 有或没有中风的参与者之间的读数。在目标3下，我们将研究TCD测量如何在 研究入组与第2个月的神经认知测试结果和第2个月的功能评估结果相关。 6.最终，该提案的长期目标是描述脑血管反应性受损是如何在 HIV相关的TBM有助于中风的发展和导致的神经认知障碍， 残疾。本申请中提出的研究是创新的，因为它结合了使用 经颅多普勒在床边，用于真实的时间，在与TBM受试者的护理。拟议 研究是重要的，因为它预计将提供强有力的科学理由的发展， 未来的临床试验测试有针对性的干预措施，以改善脑血管反应性， HIV相关TBM中中风的发展。最终，这种知识有可能防止 发展不可逆的神经损伤和改善短期和长期结果。

Abstract Tuberculous meningitis (TBM) disproportionally affects people in low- and middle-income countries and is associated with high morbidity and mortality. Stroke is a common complication in TBM and can lead to severe irreversible neurological disability. Studies on TBM-associated stroke pathology, however, have focused primarily on HIV-uninfected individuals. The overall objective of this proposal is to use transcranial doppler and brain imaging to understand changes in cerebral blood vessels and cerebral blood flow in order to determine changes in cerebrovascular responsiveness, characterize patterns of stroke, and describe long-term neurocognitive outcomes in HIV-associated TBM. The central hypothesis is that in HIV-infected individuals, TBM causes extensive cerebral vascular narrowing and impaired cerebrovascular responsiveness, decreased cerebral blood flow, and ultimately stroke. The central hypothesis will be tested by pursuing three specific aims: 1) describe changes in cerebrovascular responsiveness in HIV-associated TBM; 2) characterize the patterns of stroke in HIV-associated TBM and determine whether it is associated with vasculopathy and/or impairments in cerebrovascular responsiveness; and 3) determine if impaired cerebrovascular responsiveness predicts long- term neurological outcome in HIV-associated TBM. Under Aim 1, transcranial doppler will be used to take repeated measurements of the middle cerebral artery flow velocity and pulsatility index. A subset of study subjects will also have dynamic measurements made in response to stimuli (inhaled CO2, changes in blood pressure, and motor tasks). We will determine whether cerebrovascular responsiveness is impaired in HIV- associated TBM by comparing measurements to those of control patients with no neurological infection. Under Aim 2, all study subjects will have a brain MRI performed within the first 2-weeks of TBM treatment to identify the presence of a cerebral artery stroke and the associated cerebral artery territory. We will compare TCD readings between participants with or without stroke. Under Aim 3, we will examine how TCD measurements at study enrolment relate to the results of neurocognitive testing at month 2 and functional assessment at month 6. Ultimately, the long-term goal of the proposal is to describe how impaired cerebrovascular responsiveness in HIV-associated TBM contributes to the development of strokes and resulting neurocognitive impairment and disability. The research proposed in this application is innovative because it incorporates the use of transcranial doppler at the bedside, to be used in real time, in the care of subjects with TBM. The proposed research is significant because it is expected to provide strong scientific justification for the development of future clinical trials testing targeted interventions to improve cerebrovascular responsiveness and prevent the development of strokes in HIV-associated TBM. Ultimately, such knowledge has the potential of preventing the development of irreversible neurological injury and improving both short and long-term outcomes.