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：迫切需要疾病修正治疗 阿尔茨海默病(AD)从一开始就是这样。这种知识差距仍然存在，因为 常规方法不能在活体内测量最早的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，人们会观察到空间定向障碍。 在先兆AD期间，它的出现预示着以后的痴呆症。大脑的一个区域对 这种空间混乱是海马区的CA1亚区，因为它在 对空间信息进行编码。HC氧化应激在最开始的时候是最常见的 AD，以及在AD的实验模型中。然而，还不可能证明这一先兆 相关CA1亚区的氧化应激在高危患者中起致病作用 空间记忆受损，因为传统方法只测量氧化应激 尸检组织。解决这一重大知识差距需要一种新的范式， 比较体内HC CA1亚区和改善空间的抗氧化剂治疗效果 在实验模型中的学习和记忆，然后可以转化为患者。在……里面 在这个方案的基础上，我们提出了一个基于一种新方法的变革性的解决方案 我们实验室最近发现的：猝灭辅助核磁共振(Quest MRI)。Quest MRI是一款强大的 和灵敏的工具，已经在活体中对照“黄金标准”方法和地图进行了验证 例如，在小鼠背侧CA1中产生过多的自由基。Quest MRI指数 顺磁自由基在特定脑区的异常高产生是一种更大的- 比正常自旋晶格弛豫速率r1(1/t1)，在急性发作后可恢复到基线 抗氧化剂管理。我们的Quest核磁共振研究证实了背侧HC CA1的特异性 自发性和家族性阿尔茨海默病模型小鼠空间学习能力下降的氧化应激 并结合HC CA1氧化应激在体外测量记忆。我们还发现 氧化应激的下游后果，如脂类含量超过正常水平 过氧化产物4-羟基壬烯醛(HNE)，背侧HC CA1钙调节失调和 背侧HC CA1钙依赖性后超极化(AHP)减少。为了提高 统计能力，这项建议紧紧地集中在唯一测试一个特定的工作 体内背侧CA1区氧化应激导致大鼠空间记忆恶化的假说 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 验证一种新的桥梁工具，用于测试体内抗氧化治疗策略，以缓解 临床上重要的AD患者早期空间记忆下降先于后期人格丧失。