Novel Imaging Biomarker for Treating Spatial Memory Loss in Prodromal Alzheimer's Disease Models

项目摘要/摘要：目前迫切需要改善疾病的治疗， 阿尔茨海默病（AD）从其发病开始。这种知识差距仍然存在，因为 常规方法不能测量最早脑缺血的体内脑区域特异性生物标志物， 异常行为背后的相关功能障碍。通常，观察到空间定向障碍 在前驱AD期间，并且其发生预测后期痴呆。一个大脑区域 这种空间混乱是海马体的CA1亚区，因为它在海马体的发育中起着重要作用。 编码空间信息。HC氧化应激最常见于 AD，以及AD的实验模型。然而，还不能证明前驱症状 相关CA1子区的氧化应激在高危患者中起致病作用， 受损的空间记忆，因为传统的方法只能测量氧化应激， 尸体组织解决这一重大知识差距需要一种新的范式， 比较体内HC CA 1亚区中的抗氧化剂治疗功效与改善的空间分布 在实验模型中的学习和记忆，然后可以转化为患者。在 这个建议，我们提出了一个变革性的解决方案，这个问题的基础上，一种新的方法 我们实验室最近发现的：QUEnch-assisted MRI（QUEST MRI）。QUEST MRI是一种强大的 已根据"金标准"方法和体内图谱进行验证的灵敏工具 在例如鼠背侧CA 1中过量的自由基产生。QUEST MRI指数 在特定的大脑区域异常高的顺磁性自由基的产生是一个更大的， 比正常的自旋晶格弛豫速率R1（1/T1），可以返回到基线后急性 抗氧化剂给药。我们的QUEST MRI研究证实了背侧HC CA1特异性 自发性和家族性AD小鼠模型中的氧化应激伴空间学习能力下降 和记忆与离体测量的HC CA 1氧化应激结合。我们还发现 氧化应激的下游后果，如脂质含量高于正常水平， 过氧化产物4-羟基壬烯醛（HNE），背侧HC CA 1钙调节异常， 背侧HC CA1钙依赖性后超极化（AHP）减少。提高 统计能力，该提案紧紧集中在独特的测试一个特定的工作 假设在体内背侧CA1中氧化应激导致空间记忆的恶化， 实验模型我们由经验丰富的专家团队进行的高度创新的研究将 验证一种新的桥接工具，用于测试体内抗氧化剂治疗策略，以减轻 在AD中，在后期人格丧失之前的具有临床意义的空间记忆早期衰退。

Project Summary / Abstract: There is an urgent need for disease-modifying treatment of Alzheimer's disease (AD) starting at its very onset. This knowledge gap remains because conventional approaches cannot measure in vivo brain region-specific biomarkers of the earliest relevant dysfunction underlying abnormal behavior. Often, spatial disorientation is observed during prodromal AD, and its occurrence predicts later dementia. A brain region contributing to this spatial confusion is the CA1 subfield of hippocampus because of its essential role in encoding spatial information. HC oxidative stress is most commonly identified at the very start of AD, and in experimental models of AD. Yet, it has not been possible to prove that prodromal oxidative stress in the relevant CA1 subfield plays a pathogenic role in at-risk patients showing impaired spatial memory because conventional methods only measure oxidative stress from post-mortem tissue. Addressing this major knowledge gap requires a new paradigm that compares antioxidant treatment efficacy in HC CA1 subregions in vivo with improved spatial learning and memory in experimental models, and that can then be translated into patients. In this proposal, we present a transformative solution to this problem based on a novel method recently discovered by our lab: QUEnch-assiSTed MRI (QUEST MRI). QUEST MRI is a robust and sensitive tool that has been validated against “gold standard” methods and maps in vivo excessive free radical production in, for example, murine dorsal CA1. The QUEST MRI index of abnormally high production of paramagnetic free radicals in specific brain regions is a greater- than-normal spin-lattice relaxation rate R1 (1/T1) that can be returned to baseline after acute antioxidant administration. Our QUEST MRI studies have confirmed dorsal HC CA1-specific oxidative stress in spontaneous and familial AD mouse models with declines in spatial learning and memory in conjunction with HC CA1 oxidative stress measured ex vivo. We also find downstream consequences of oxidative stress such as greater-than-normal amounts of the lipid peroxidation product 4-hydroxynonenal (HNE), dorsal HC CA1 calcium dysregulation and reductions in dorsal HC CA1 calcium-dependent afterhyperpolarization (AHP). To improve statistical power, this proposal is tightly focused on uniquely testing a specific working hypothesis that oxidative stress in dorsal CA1 in vivo causes deterioration of spatial memory in experimental models. Our highly innovative studies by an experienced team of experts will validate a new bridging tool for testing in vivo antioxidant therapeutic strategies to mitigate a clinically important early decline in spatial memory preceding later loss of personhood in AD.