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

项目摘要/摘要 阿尔茨海默病(AD)是导致痴呆症的最常见原因。大脑中的β-淀粉样斑块 尸检是阿尔茨海默病的主要病理特征之一，但许多针对β-淀粉样蛋白的临床试验 都失败了。许多对阿尔茨海默病的脑标本和动物模型的研究表明，铁存在于 邻近β-淀粉样斑块，可能导致神经元损伤。有β-淀粉样蛋白证据的人 正电子发射断层扫描(PET)上的斑块和高水平的脑铁促进了认知 拒绝。然而，将铁与人类认知能力下降联系起来的机制仍不清楚。澄清 这些机制对于开发潜在的铁靶向疗法至关重要。这样做的目的是 建议使用最先进的磁共振成像(MRI)和脑脊液(CSF)标记物 铁、氧化应激和神经元损伤，以了解铁和阿尔茨海默病之间的联系。如果成功，这将是 一项提案将澄清铁在治疗试验中作为潜在关键上游靶点的作用，以减缓或阻止 AD的发展。这项申请是为了对80名老年正常人进行前瞻性研究，其中一半 会有脑部淀粉样蛋白沉积的PET证据。第一个目标是检验这样一个假设，即受试者 大脑淀粉样蛋白沉积将具有更高的脑铁基线水平和更高的铁积累率， 使用定量磁化率图，一种无创性的脑铁核磁共振测量方法。第二个目标是测试 大脑淀粉样蛋白沉积的受试者将有更高的氧化基线水平的假设 应激和更高的氧化应激增加速率，反映在质子磁共振上较低的谷胱甘肽水平 脑脊液中的光谱和较高的异前列腺素水平。第三个目标是检验受试者 大脑淀粉样蛋白沉积将有更多的AD生物标志物和纵向变化的基线证据 在AD生物标志物中，包括脑脊液中的β-淀粉样蛋白、tau和过度磷酸化tau的标志物，脑萎缩 皮质变薄，记忆力下降。这项建议的结果将促进我们对 铁在AD发病机制中的作用以及作为临床试验的潜在治疗靶点。

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.