Neuropathology of severe malaria in Thailand: MRI studies

描述（由申请人提供）：该探索性研究项目旨在开发一种新的多学科合作调查和调查培训计划，重点关注泰国严重和脑型疟疾的神经病理学后果。该方案将使泰国医生、科学家和其他卫生专业人员参与疟疾感染引起的大脑疾病的基础和临床研究。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原虫疟疾。我们的项目将利用曼谷玛希隆大学独特的资源和专业知识：㈠曼谷热带病医院，热带医学系，世界著名的疟疾研究机构，㈡ Ramathibodi医院，医学系，放射科，配备了最先进的菲利普斯Achieva 3.0特斯拉磁共振系统，以及（iii）与哥伦比亚大学的研究人员建立了长达十年的合作关系，现在通过与哈奇磁共振研究中心的科学联系得到了加强。本研究的目的是获得初步的前瞻性数据，以检查轴突损伤是负责神经功能障碍的严重和脑型疟疾的假设。我们建议在泰国曼谷进行非侵入性高场（3.0特斯拉）磁共振（MR）研究，以确定脑型疟疾患者、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大于其它形式的严重疟疾患者的假设，如通过MR成像研究所确定的，包括具有相应表观扩散系数（ADC）图的扩散加权成像（DWI）、具有相关分数各向异性图的扩散张量成像（DTI），和液体衰减反转恢复（FLAIR）成像;和（2）检验脑型疟疾的轴突损伤程度大于其他形式的严重疟疾的假设，如通过定量质子（1H）MR波谱测量脑室液中的乳酸盐和脑组织中的N-乙酰天冬氨酸（轴突损伤的指标）所确定的。据我们所知，这些研究将是第一个使用高场（3.0特斯拉）MR检查恶性疟疾患者的研究。这项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，并可能提出新的神经保护策略，用于预防可在全球范围内应用的持续性神经系统疾病。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）磁共振仪器的可用性所创造的研究机会，该仪器紧邻一个致力于疟疾研究的世界级机构。拟议的研究项目将为泰国医生和科学家参与和培训一个调查项目提供近乎理想的机会，该项目旨在导致制定新的神经保护战略，可在全世界应用，以预防严重疟疾造成的终身神经系统疾病。我们尚未确定R 01试验中未来研究的最佳神经保护干预，但正在研究（i）使用哥伦比亚开发的抗体生产新方法的基于抗体的治疗，（ii）基于我们早期的N-乙酰半胱氨酸临床研究，和（iii）穿过血脑屏障的靶向去铁硫菌素铁螯合剂，扩展了我们以前用铁螯合剂、去铁胺和去铁酮的试验。

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.