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

脑铁负荷对阿尔茨海默病高危老年人认知功能的贡献

• 批准号: 10255995
• 负责人: Xu Li
• 金额: $ 56.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10255995
• 关键词: 3-Dimensional; Abeta clearance; Abeta synthesis; Adult; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anatomy; Ancillary Study; Atherosclerosis Risk in Communities; Atlases; Brain; Brain Mapping; Brain imaging; Brain region; Calibration; Cerebrum; Clinical; Clinical Data; Communities; Data; Dementia; Development; Disease; Elderly; Elements; Etiology; Event; Failure; Funding; Genetic Determinism; Health; Healthcare Systems; Hippocampus (Brain); Human; Imaging Techniques; Immunotherapy; Impaired cognition; Intracranial Atherosclerotic Disease; Iron; Lead; Magnetic Resonance Imaging; Magnetism; Measurement; Measures; Mendelian randomization; Metabolism; Microvascular Dysfunction; Modification; Neurodegenerative Disorders; Neurofibrillary Tangles; Oxidative Stress; Participant; Pathogenesis; Pathologic; Pathology; Peptides; Performance; Phase; Play; Population; Population Study; Positron-Emission Tomography; Predisposition; Prevalence; Prospective cohort study; Protocols documentation; Resolution; Risk Factors; Role; Sampling; Schedule; Senile Plaques; Signal Transduction; Source; Temporal Lobe; Testing; Therapeutic; Tissues; United States National Institutes of Health; Visit; abeta accumulation; abeta toxicity; aged; aging population; apolipoprotein E-4; base; biobank; biracial; brain tissue; cofactor; cognitive development; cognitive function; cognitive performance; cognitive testing; cohort; demographics; extracellular; frontal lobe; genetic variant; genome wide association study; high risk; hyperphosphorylated tau; imaging genetics; middle age; mild cognitive impairment; pre-clinical; prevent; reconstruction; recruit; tau Proteins; tool; vascular risk factor

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.

项目摘要：由于人口老龄化，痴呆症具有较高的全球患病率 医疗保健系统上的巨大伯恩。阿尔茨海默氏病（AD）是最常见的原因 痴呆症，人们普遍认为淀粉样β（Aβ）胡椒的积累是关键事件 AD的发病机理，代表临床前疾病阶段。脑铁也被强烈牵连为 AD发病机理中的辅助因子，其超载加速了Aβ的产生，并促进 Aβ肽。但是，脑铁负荷的影响及其与区域AβPlaque-Load的综合作用 缺乏在AD及其前体的认知障碍上，轻度认知障碍（MCI）缺乏。我们的整体目标 是研究脑铁负荷的作用及其在AβPlaque-Load中可能的协同作用 认知能力下降，MCI和痴呆症的发展，特别是AD。我们将使用数据进行此类研究 来自两项前瞻性队列研究：社区中的动脉粥样硬化风险（ARIC）研究 在过去30年中，从队列参与者和英国生物银行研究收集了临床数据， 在英国成人人群中收集广泛的临床，成像和遗传数据。在ARIC研究中，混血儿 通过大脑MRI，Florbetapir正电子发射断层扫描（PET）和 研究访问5的认知测试在访问6进行重复测试。我们将利用相位信号 梯度回声MRI数据在访问6（n = 1,000）时以计算定量易感映射（QSM）。脑铁 负载将使用我们最近开发的敏感性多ATLAS工具自动量化。然后我们会 对于目标1，确定脑铁测量是否与认知独立相关 在73-94岁的这些ARIC参与者中，MCI或痴呆症的存在。我们将 还评估已知中年血管危险因素与脑铁之间的可能关联 以晚期测量。对于AIM 2，我们将估计Aβ铂载荷的综合作用，如 ARIC-PET研究中的Florbetapir PET（n = 300），通过QSM测量的大脑铁载荷增加 认知障碍的进展，并调整了人群，当代的贡献 血管危险因素，小血管疾病和APOE-E4状态。进一步建立因果关系 AIM 3中的脑铁和认知功能，我们将与全基因组关联研究（GWAS）与 Mendelian Randomiza- 找到脑铁的遗传决定因素及其与认知的关联 功能。通过QSM测量的脑铁将从英国生物银行脑MRI数据计算 （n〜 = 35,000），而与脑铁负荷相关的遗传变异将对认知进行测试 其余约465,000个独立样本中的功能度量。