Neuropathology of severe malaria in Thailand: MRI studies

描述(申请人提供)：这一探索性研究项目旨在开发一种新的多学科合作的调查和调查培训计划，重点是泰国严重和脑疟疾的神经病理后果。该计划将邀请泰国医生、科学家和其他卫生专业人员对疟疾感染引起的脑部疾病进行基础和临床研究。在世界范围内，感染人类中枢神经系统的最重要的寄生虫病是恶性疟疾。我们的项目将利用曼谷Mahidol大学独特的资源和专业知识集合：(I)曼谷热带疾病医院热带医学院，这是世界著名的疟疾研究机构；(Ii)Ramathibodi医院，医学院，放射科，配备先进的Phillips Achieva 3.0特斯拉磁共振系统，以及(Iii)与哥伦比亚大学研究人员建立的长达十年的已建立的合作关系，现在通过与哈奇磁共振研究中心的科学联系而得到加强。这项研究旨在获得初步的前瞻性数据，以检验轴突损伤是重症和脑型疟疾患者神经功能障碍的原因这一假说。我们建议进行无创性高场(3.0特斯拉)磁共振(MR)研究，以确定泰国曼谷脑型疟疾患者、其他形式的严重和无并发症疟疾患者以及未感染对照组的轴突损伤程度。拟议的研究有两个具体目标：(1)检验脑型疟疾患者的轴突损伤程度将比其他形式的重症疟疾患者更大的假设，如磁共振成像研究，包括扩散加权成像(DWI)和相应的表观扩散系数(ADC)图，扩散张量成像(DTI)和相关分数各向异性图，以及液体衰减反转恢复(FLAIR)成像；以及(2)通过定量质子(1H)磁共振波谱测量脑室液中的乳酸和脑组织中的N-乙酰天冬氨酸，来检验脑型疟疾的轴突损伤程度比其他形式的严重疟疾更严重的假设。据我们所知，这些研究将是第一次使用高场(3.0特斯拉)MR检查恶性疟疾患者。这一探索性研究项目的结果将为恶性疟疾神经病理学的长期研究和培训提供基础，并可能为预防持续性神经疾病提出新的神经保护策略，可在全球范围内应用。公共卫生相关性：本申请中提出的研究提供了一种系统和逻辑的方法来确定轴突损伤在脑型疟疾神经功能障碍发病机制中的作用。我们的项目利用了最先进的高场(3.0特斯拉)磁共振仪器创造的研究机会，该仪器紧挨着一家致力于疟疾研究的世界级机构。拟议的研究项目将提供一个近乎理想的机会，让泰国医生和科学家参与和培训一个调查项目，该项目旨在开发新的神经保护战略，可在世界各地应用，以预防严重疟疾引起的终生神经疾病。我们还没有为未来的R01试验研究确定最佳的神经保护干预措施，但正在检查(I)一种使用哥伦比亚大学开发的产生抗体的新方法的基于抗体的疗法，(Ii)一种跨越血脑屏障的硫醇抗氧化剂N-乙酰半胱氨酸酰胺，它建立在我们早先对N-乙酰半胱氨酸的临床研究的基础上，以及(Iii)靶向去铁硫蛋白铁络合剂，它跨越血脑屏障，延长了我们之前使用铁螯合剂、去铁胺和去铁酮进行的试验。

DESCRIPTION (provided by applicant): This exploratory research project is designed to develop a novel multidisciplinary collaborative program of investigation and investigative training focused on the neuropathological consequences of severe and cerebral malaria in Thailand. This program will engage Thai physicians, scientists and other health professionals in basic and clinical studies of brain disorders resulting from malarial infection. Worldwide, the most important parasitic disease infecting the central nervous system of humans is Plasmodium falciparum malaria. Our project will take advantage of a unique convergence of resources and expertise at Mahidol University in Bangkok: (i) the Bangkok Hospital for Tropical Disease, Faculty of Tropical Medicine, a world-renowned malarial research facility, (ii) the Ramathibodi Hospital, Faculty of Medicine, Department of Radiology, fully equipped with a state-of-the-art Phillips Achieva 3.0 Tesla Magnetic Resonance system, and (iii) an established, decade-long collaborative relationship with investigators at Columbia University, now enhanced by a scientific linkage with the Hatch Magnetic Resonance Research Center. This investigation is designed to obtain preliminary prospective data to examine the hypothesis that axonal injury is responsible for neurological dysfunction in severe and cerebral malaria. We propose non-invasive high-field (3.0 Tesla) magnetic resonance (MR) studies to determine the extent of axonal injury in patients with cerebral malaria, in patients with other forms of severe and uncomplicated malaria, and in uninfected controls in Bangkok, Thailand. The proposed research has two specific aims: (1) to test the hypothesis that the degree of axonal injury will be greater in patients with cerebral malaria than in patients with other forms of severe malaria, as determined by MR imaging studies, including diffusion- weighted imaging (DWI) with the corresponding apparent diffusion coefficient (ADC) maps, diffusion tensor imaging (DTI) with correlating fractional anisotropy maps, and fluid attenuated inversion recovery (FLAIR) imaging; and (2) to test the hypothesis that the degree of axonal injury is greater in cerebral malaria than in other forms of severe malaria, as determined by quantitative proton (1H) MR spectroscopic measurements of lactate in brain ventricular fluid and of N-acetylaspartate, an indicator of axonal damage, in brain tissue. To our knowledge, these studies will be the first to examine patients with falciparum malaria using high-field (3.0 Tesla) MR. The results of this exploratory research project will provide the foundation for long-term research and training in the neuropathology of falciparum malaria and could suggest new neuroprotective strategies for the prevention of persistent neurological disorders that could be applied worldwide. PUBLIC HEALTH RELEVANCE: The research proposed in this application provides a systematic and logical approach to determining the role of axonal injury in the pathogenesis of neurological dysfunction in cerebral malaria. Our project takes advantage of the research opportunity created by the availability of a state-of-the-art high-field (3.0 Tesla) magnetic resonance instrument immediately adjacent to a world-class institution dedicated to the study of malaria. The proposed research project will provide a near ideal opportunity for the involvement and training of Thai physicians and scientists in an investigative project that is designed to lead to the development of new neuroprotective strategies that could be applied worldwide for the prevention of lifelong neurological disorders resulting from severe malaria. We have not yet determined the optimal neuroprotective intervention for future study in an R01 trial but are examining (i) an antibody-based therapy using a novel approach for antibody production developed at Columbia, (ii) a thiol antioxidant that crosses the blood brain barrier, N-acetyl cysteine amide, building on our earlier clinical studies with N-acetyl cysteine, and (iii) targeted desferrithiocin iron chelators that cross the blood brain barrier, extending our previous trials with the iron chelators, desferrioxamine, and deferiprone.