Contribution of Cerebral Iron Load to Cognitive Function in Older Adults with High Risk to Develop Alzheimer's Disease

项目摘要：由于人口老龄化，痴呆症在全球范围内有很高的患病率 给医疗系统带来了巨大的负担。阿尔茨海默病(AD)是导致 人们普遍认为淀粉样β蛋白(Aβ)多肽的积聚是痴呆的一个关键事件。 阿尔茨海默病的发病机制，代表临床前疾病阶段。大脑铁也被强烈地牵连为一种 辅助因子在AD发病机制中的作用及其过载加速A-β的产生并促进其毒性 Aβ多肽。然而，脑铁负荷的影响及其与局部A-β斑块负荷的联合作用 关于AD及其前驱--轻度认知损害(MCI)的研究尚缺乏。我们的总目标是 目的是研究脑内铁负荷的作用及其与β斑块负荷的可能协同作用 认知功能减退、MCI和痴呆症，尤其是阿尔茨海默病。我们将使用数据进行这样的研究 来自两项前瞻性队列研究：社区动脉粥样硬化风险(ARIC)研究，该研究具有 收集了过去30年队列参与者的临床数据和英国生物库研究，该研究 收集英国成年人的临床、影像和遗传数据。在ARIC的研究中，一个混血儿 对老年人的样本进行了脑MRI、氟倍他皮正电子发射断层扫描(PET)和 研究访问5的认知测试和访问6的重复测试正在进行。我们将利用来自 6次访问时(n=1,000)的梯度回波MRI数据，以计算定量磁化率图(QSM)。脑铁 负荷将使用我们最新开发的磁化率多图谱工具自动量化。到时候我们会的 目标1确定大脑铁含量增加是否与认知能力独立相关 这些73-94岁的ARIC参与者的表现与MCI或痴呆的存在有关。我们会 也要评估已知的中年血管危险因素与脑铁的可能联系。 是在晚年测量的。对于目标2，我们将评估β斑块负荷的综合影响，通过 在ARIC-PET研究中的florbetapir PET(n=300)和QSM测量的脑铁负荷增加 认知障碍的进展与人口统计学的贡献调整，当代 血管危险因素、小血管疾病和载脂蛋白E-E4状态。进一步确立两国之间的因果关系 在Aim 3中，我们将进行一项全基因组关联研究，研究对象为 孟德尔随机化研究大脑铁的遗传决定因素及其与认知能力的关系 功能。QSM测量的大脑铁将根据英国生物库脑MRI数据计算 (n~=35,000)，而与大脑铁负荷相关的遗传变异将针对认知能力进行测试 在剩余的465,000个独立样本中进行了功能测量。

Project Summary: Dementia has a high global prevalence due to the aging population and places an enormous burden on health care systems. Alzheimer’s disease (AD) is the most common cause of dementia, and it is widely believed that the accumulation of Amyloid beta (Aβ) peptide is a key event in the pathogenesis of AD, representing preclinical disease stages. Cerebral iron is also strongly implicated as a cofactor in the pathogenesis of AD, and its overload accelerates Aβ production and promotes the toxicity of the Aβ peptide. However, the impact of brain iron load, and its combined effect with regional Aβ-plaque-load on cognitive impairment in AD and its precursor, mild cognitive impairment (MCI), is lacking. Our overall aim is to study the role of brain iron load and its possible synergistic effect with Aβ-plaque-load in the development of cognitive decline, MCI and dementia, in particular AD. We will perform such study using data from two prospective cohort studies: the Atherosclerosis Risk in Communities (ARIC) study, which has collected clinical data from cohort participants over the past 30 years and the UK biobank study, which collects extensive clinical, imaging and genetic data in the UK adult population. In the ARIC study, a biracial sample of elderly adults was evaluated by brain MRI, florbetapir positron emission tomography (PET), and cognitive tests at study visit 5 with repeat testing underway at visit 6. We will utilize the phase signal from gradient echo MRI data at visit 6 (n=1,000) to compute quantitative susceptibility mapping (QSM). Brain iron load will be automatically quantified using our recent developed susceptibility multi-atlas tool. We will then for Aim 1 determine if increased cerebral iron measures are independently associated with cognitive performance with the presence of MCI or dementia in these ARIC participants aged 73-94 years. We will also assess possible associations between known midlife vascular risk factors with cerebral iron as measured in late-life. For Aim 2, we will estimate the combined effects of Aβ-plaque-load as measured by florbetapir PET in the ARIC-PET study (n=300) and increased cerebral iron-load as measured by QSM on the progression of cognitive impairment with adjustment for contributions from demographic, contemporary vascular risk factors, small vessel diseases and APOE-e4 status. To further establish the causality between brain iron and cognitive function in Aim 3, we will perform a genome-wide association study (GWAS) with Mendelian randomization to find genetic determinants of cerebral iron and their association with cognitive function. Cerebral iron as measured by QSM will be calculated from UK biobank brain MRI data (n~=35,000), while genetic variants associated with cerebral iron load will tested against the cognitive function measures in the remaining ~465,000 independent samples.