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

用于治疗前驱阿尔茨海默病模型中空间记忆丧失的新型成像生物标志物

• 批准号: 9925773
• 负责人: BRUCE A. BERKOWITZ
• 金额: $ 55.87万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925773
• 关键词: 4 hydroxynonenal; AD transgenic mice; Acute; Address; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animal Model; Antioxidants; Autopsy; Behavior; Biological Markers; Brain region; Calcium; Clinic; Clinical; Cognitive deficits; Confusion; Cross-Sectional Studies; Data; Dementia; Deterioration; Disease; Disease Progression; Disorientation; Dorsal; Electrophysiology (science); Etiology; Evaluation; Experimental Models; Free Radicals; Functional disorder; Goals; Gold; Hippocampus (Brain); Human; Image; Impairment; Knowledge; Learning; Lipid Peroxidation; Location; Magnetic Resonance Imaging; Maps; Measurement; Measures; Mediating; Memory; Memory Loss; Memory impairment; Methods; Modeling; Molecular; Mus; Neurons; Oxidative Stress; Pathogenicity; Patients; Personhood; Pharmacology; Play; Problem Solving; Production; Public Health; Relaxation; Research; Risk; Rodent; Role; Technology; Testing; Therapeutic; Tissues; Translating; Treatment Efficacy; base; cognitive neuroscience; cost effective; evidence base; experience; experimental study; familial Alzheimer disease; imaging biomarker; imaging modality; improved; in vivo; in vivo evaluation; indexing; innovation; morris water maze; mouse model; novel; personalized management; photobiomodulation; prodromal Alzheimer' s disease; spatial memory; specific biomarkers; tool

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.

项目摘要 /摘要：迫切需要修改疾病的治疗 阿尔茨海默氏病（AD）从一开始就开始。这个知识差距仍然是因为 常规方法无法测量最早的体内大脑区域特异性生物标志物 相关功能障碍的基本异常行为。通常，观察到空间迷失方向 在前驱AD及其发生预测的过程中，以后的痴呆症。大脑区域有助于 这种空间混乱是海马的CA1子场，因为它在 编码空间信息。 HC氧化应激最常见于一开始 AD，以及AD的实验模型。然而，不可能证明那个前辈 相关的CA1子场中的氧化应激在处于危险中的患者中起致病作用 空间记忆受损，因为传统方法仅测量来自 验尸组织。解决这一主要知识差距需要一个新的范式 比较体内HC CA1子区域的抗氧化剂治疗效率和改进的空间 在实验模型中学习和记忆，然后可以将其转化为患者。 这项建议，我们基于一种新方法提出了解决此问题的变革解决方案 我们的实验室最近发现：Quench辅助MRI（Quest MRI）。 Quest MRI是一个强大的 和敏感的工具，该工具已通过“黄金标准”方法和图中的地图进行了验证 过度自由基产生，例如鼠背CA1。任务MRI指数 特定大脑区域中顺磁性自由基的高产量也很高是一个更大的 急性后可以返回基线的比正常自旋晶格松弛率R1（1/T1） 抗氧化剂给药。我们的任务MRI研究已证实背侧HC CA1特异性 在空间学习中的赞助和家庭AD鼠标模型中的氧化应激模型下降 与HC CA1氧化应激结合得出的记忆和记忆。我们也发现 氧化应激的下游后果，例如脂质的含量大于正常 过氧化产物4-羟基烯烯（HNE），背HC CA1钙失调和 背侧HC CA1钙依赖性后极化后（AHP）的减少。改进 统计能力，该提案紧密专注于唯一测试特定工作 假说体内背侧CA1中的氧化应激会导致空间记忆恶化 实验模型。我们经验丰富的专家团队的高度创新研究将 验证一种用于测试体内抗氧化剂治疗策略的新桥接工具以减轻 临床上重要的早期下降的空间记忆是在后来的AD人为丧失之前。