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

项目摘要/总结 阿尔茨海默病（AD）是痴呆症最常见的原因。大脑中的β-淀粉样斑块 尸检中的 β-淀粉样蛋白是 AD 的关键病理标志之一，但大量针对 β-淀粉样蛋白的临床试验 已经失败了。对 AD 脑标本和动物模型的许多研究表明，铁存在于和 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可以加速认知能力 下降。然而，铁与人类认知能力下降之间的联系机制仍不清楚。阐明 这些机制对于开发潜在的铁靶向疗法至关重要。此举的目的 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，以了解铁与 AD 之间的联系。如果成功的话，这 该提案将澄清铁作为治疗试验中潜在关键上游靶标的作用，以减缓或阻止 AD的发展。本申请针对 80 名老年正常人进行前瞻性研究，其中一半人 将有大脑淀粉样蛋白沉积的 PET 证据。第一个目的是检验以下假设：受试者 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，这是一种脑铁的无创 MRI 测量方法。第二个目的是测试 假设有脑淀粉样蛋白沉积的受试者将具有较高的氧化基线水平 质子 MR 上谷胱甘肽水平较低反映了应激和氧化应激增加率较高 光谱和脑脊液中较高的异前列腺素水平。第三个目的是检验受试者的假设 脑淀粉样蛋白沉积将有更多的 AD 生物标志物基线证据和纵向变化 AD 生物标志物，包括脑脊液中 β-淀粉样蛋白、tau 蛋白和过度磷酸化 tau 蛋白、脑萎缩的标志物 皮质变薄，记忆力下降。该提案的结果将加深我们对 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.