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

基本信息

批准号：
10165441
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
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165441
关键词：
4 hydroxynonenal AD transgenic mice Acute Address Age of Onset Aging Alzheimer&apos s Disease Alzheimer&apos 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&apos s disease spatial memory specific biomarkers tool

项目摘要

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：迫切需要疾病缓解治疗阿尔茨海默病（AD）从一开始就存在这种知识差距，因为。传统方法无法测量最早的体内大脑区域特异性生物标志物通常，会观察到异常行为背后的相关功能障碍。在阿尔茨海默病前驱期，它的发生预示着后来的痴呆症。这种空间混乱是海马体的 CA1 亚区，因为它在编码空间信息的HC氧化应激最常在开始时被识别。 AD，并且在AD的实验模型中，还不可能证明前驱期。相关 CA1 亚区的氧化应激在高危患者中发挥致病作用空间记忆受损，因为传统方法只能测量氧化应激解决这一重大知识差距需要一种新的范式。比较了体内 HC CA1 亚区的抗氧化治疗效果与改进的空间实验模型中的学习和记忆，然后可以转化为患者。在这个提案中，我们提出了一种基于新颖方法的变革性解决方案我们实验室最近发现：淬火辅助 MRI (QUEST MRI) 是一种强大的技术。和敏感工具，已根据“金标准”方法和体内图谱进行了验证例如，小鼠背侧 CA1 中自由基产生过多。 QUEST MRI 指数。特定大脑区域异常大量产生顺磁性自由基是一个更大的问题高于正常的自旋晶格弛豫率 R1 (1/T1)，急性期后可恢复至基线我们的 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导致空间学习能力下降我们还发现，记忆力与离体测量的 HC CA1 氧化应激有关。氧化应激的下游后果，例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 CA1 钙失调和减少背侧 HC CA1 钙依赖性后超极化 (AHP)。统计能力，该提案严格专注于唯一测试特定的工作假设体内背侧 CA1 的氧化应激导致空间记忆恶化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治疗策略，以减轻 AD 患者早期空间记忆衰退，随后人格丧失，具有临床意义。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2-/- Mouse Model of Sporadic Alzheimer's Disease.

散发性阿尔茨海默病 Aldh2-/- 小鼠模型中的神经元钙成像、兴奋性和可塑性变化。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Ghoweri, Adam O;Gagolewicz, Peter;Frazier, Hilaree N;Gant, John C;Andrew, R David;Bennett, Brian M;Thibault, Olivier
通讯作者：
Thibault, Olivier

Multiple Bioenergy-Linked OCT Biomarkers Suggest Greater-Than-Normal Rod Mitochondria Activity Early in Experimental Alzheimer's Disease.

多种与生物能相关的 OCT 生物标志物表明，在实验性阿尔茨海默氏病早期，杆状线粒体活性高于正常水平。