The effects of iron on oxidative stress and Alzheimer's biomarkers in amyloid-positive and negative elderly normal

铁对淀粉样蛋白阳性和阴性正常老年人氧化应激和阿尔茨海默病生物标志物的影响

• 批准号: 10390491
• 负责人: GLORIA Chia-Yi CHIANG
• 金额: $ 58.57万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10390491
• 关键词: Affect; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Animal Model; Apolipoprotein E; Atrophic; Autopsy; Brain; Brain region; Cerebrospinal Fluid; Cerebrum; Clinical Trials; Cognition; Cognitive; Dementia; Development; Diffuse; Disease; Elderly; Enrollment; Glutathione; Health; Human; Hydroxyl Radical; Imaging Techniques; Impaired cognition; In Vitro; Individual; Iron; Iron Chelation; Isoprostanes; Knowledge; Lateral; Link; Lipid Peroxidation; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Memory; Memory Loss; Microglia; Mission; Modeling; Monitor; Nerve Degeneration; Neuronal Injury; Nitrogen; Oxidative Stress; Oxygen; Parietal Lobe; Pathogenesis; Pathologic; Personal Satisfaction; Persons; Pittsburgh Compound-B; Positron-Emission Tomography; Predisposition; Process; Prospective Studies; Prostaglandins; Protons; Public Health; Reaction; Research; Research Support; Role; Sampling; Senile Plaques; Specimen; Suggestion; Temporal Lobe; Testing; Therapeutic Trials; Thinness; Tissues; Tracer; abeta deposition; base; cerebral atrophy; cognitive testing; cohort; frontal lobe; hyperphosphorylated tau; imaging biomarker; improved; in vivo; in vivo imaging; mild cognitive impairment; neurofibrillary tangle formation; neuron loss; neuropsychiatric disorder; new therapeutic target; oxidative damage; preclinical study; prospective; targeted treatment; tau Proteins; tau-1; therapeutic target

PROJECT ABSTRACT/SUMMARY Alzheimer's disease (AD) is the most common cause of dementia. Beta-amyloid plaques in the brain on autopsy are one of the key pathological hallmarks of AD, but numerous clinical trials targeting beta-amyloid have failed. Many studies in brain specimens and animal models of AD have shown that iron is found in and adjacent to beta-amyloid plaques and may contribute to neuronal injury. People with evidence of beta-amyloid plaques on positron emission tomography (PET) and high levels of brain iron have accelerated cognitive decline. However, the mechanisms linking iron to cognitive decline in humans remain unclear. Elucidating these mechanisms is critical for the development of potential iron-targeted therapies. The objective of this proposal is to use state-of-the-art magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) markers of iron, oxidative stress, and neuronal injury to understand the link between iron and AD. If successful, this proposal will clarify iron's role as a potential key upstream target in therapeutic trials to slow or stop the development of AD. This application is for a prospective study of 80 elderly normal individuals, half of whom will have PET evidence of cerebral amyloid deposition. The first aim is to test the hypothesis that subjects with cerebral amyloid deposition will have higher baseline levels of brain iron and higher rates of iron accumulation, using quantitative susceptibility mapping, a noninvasive MRI measure of brain iron. The second aim is to test the hypothesis that subjects with cerebral amyloid deposition will have higher baseline levels of oxidative stress and higher rates of increase in oxidative stress, as reflected by lower glutathione levels on proton MR spectroscopy and higher isoprostane levels in the CSF. The third aim is to test the hypothesis that subjects with cerebral amyloid deposition will have greater baseline evidence of AD biomarkers and longitudinal change in AD biomarkers, including CSF markers of beta-amyloid, tau, and hyperphosphorylated tau, brain atrophy and cortical thinning, and memory decline. The results of this proposal will advance our understanding of the role of iron in AD pathogenesis and as a potential therapeutic target for clinical trials.

项目摘要/摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因。大脑中的β-淀粉样斑块 尸检是AD的关键病理标志之一，但针对β-淀粉样蛋白的许多临床试验 失败了。大脑标本和AD动物模型的许多研究表明，在中发现了铁和 毗邻β-淀粉样蛋白斑块，可能导致神经元损伤。有β-淀粉样蛋白的证据的人 正电子发射断层扫描（PET）和高水平脑铁的斑块已加速认知 衰退。但是，将铁与人类认知能力下降联系起来的机制尚不清楚。阐明 这些机制对于潜在靶向铁的疗法的发展至关重要。这个目的 建议是使用最先进的磁共振成像（MRI）和脑脊液（CSF）标记 铁，氧化应激和神经元损伤，以了解铁与AD之间的联系。如果成功，这 提案将阐明铁作为治疗试验的潜在关键目标的作用，以减慢或停止 广告的开发。该申请是针对80名老年人的前瞻性研究，其中一半 将有宠物证据表明脑淀粉样蛋白沉积。第一个目的是检验与受试者的假设 脑淀粉样蛋白沉积将具有较高的基线脑铁和较高的铁积聚速率， 使用定量敏感性映射，这是一种无创的脑铁MRI测量。第二个目的是测试 脑淀粉样蛋白沉积受试者的假设将具有较高的氧化基线水平 质子MR上较低的谷胱甘肽水平反映了应力和较高的氧化应激率增加率 CSF中的光谱和较高的异丙烷水平。第三个目的是检验主体的假设 随着脑淀粉样蛋白沉积，将有更多的基线证据证明AD生物标志物和纵向变化 在AD生物标志物中，包括β-淀粉样蛋白，TAU和高磷酸化的TAU的CSF标记，脑萎缩 和皮质稀疏，记忆力下降。该提案的结果将提高我们对 铁在AD发病机理中的作用以及作为临床试验的潜在治疗靶标。