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: 10618867
• 负责人: Xu Li
• 金额: $ 51.37万
• 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/10618867
• 关键词: 3-Dimensional; Abeta clearance; Abeta synthesis; Acceleration; 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; Genetic Determinism; Healthcare; Healthcare Systems; Hippocampus; Human; Image; Imaging Techniques; Immunotherapy; Impaired cognition; Intracranial Atherosclerotic Disease; Iron; Magnetic Resonance Imaging; Magnetism; Maps; 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; Production; 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; Variant; Visit; abeta accumulation; abeta toxicity; aged; aging population; apolipoprotein E-4; biobank; biracial; brain magnetic resonance imaging; brain tissue; cofactor; cognitive function; cognitive performance; cognitive testing; cohort; demographics; extracellular; frontal lobe; genetic variant; genome wide association study; gray matter; high risk; hyperphosphorylated tau; 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，痴呆症在全球范围内发病率很高，并且 给医疗保健系统带来巨大负担。阿尔茨海默病 (AD) 是最常见的病因 痴呆症，人们普遍认为β淀粉样蛋白（Aβ）肽的积累是痴呆症的关键事件。 AD 的发病机制，代表临床前疾病阶段。脑铁也与 AD 发病机制中的辅助因子，其过载会加速 Aβ 的产生并增强 Aβ 的毒性 Aβ肽。然而，脑铁负荷的影响及其与区域 Aβ 斑块负荷的综合影响 缺乏对AD认知障碍及其前兆轻度认知障碍（MCI）的研究。我们的总体目标 目的是研究脑铁负荷的作用及其与 Aβ 斑块负荷可能的协同作用 认知能力下降、MCI 和痴呆，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：社区动脉粥样硬化风险 (ARIC) 研究，该研究 收集了过去 30 年队列参与者的临床数据和英国生物银行研究，其中 收集英国成年人群的广泛临床、影像和遗传数据。在 ARIC 研究中，混血儿 通过脑部 MRI、氟倍他酯正电子发射断层扫描 (PET) 和 第 5 次研究访问时进行认知测试，第 6 次访问时正在进行重复测试。我们将利用来自 第 6 次访视时的梯度回波 MRI 数据 (n=1,000)，用于计算定量磁化率图 (QSM)。脑铁 负载将使用我们最近开发的磁敏度多图集工具自动量化。我们随后将 对于目标 1，确定增加的脑铁含量是否与认知能力独立相关 这些年龄为 73-94 岁的 ARIC 参与者在患有 MCI 或痴呆症的情况下的表现。我们将 还评估已知的中年血管危险因素与脑铁之间的可能关联 在晚年测量。对于目标 2，我们将估计 Aβ 斑块负载的综合影响，测量方法为 ARIC-PET 研究 (n=300) 中的氟倍他吡 PET 以及通过 QSM 测量的脑铁负荷增加 认知障碍的进展，根据人口、当代因素的影响进行调整 血管危险因素、小血管疾病和 APOE-e4 状态。为了进一步确定两者之间的因果关系 在目标 3 中，我们将进行全基因组关联研究 (GWAS) 孟德尔随机化寻找脑铁的遗传决定因素及其与认知的关系 功能。 QSM 测量的脑铁含量将根据英国生物银行脑部 MRI 数据计算得出 (n~=35,000)，而与脑铁负荷相关的遗传变异将针对认知能力进行测试 函数测量剩余的约 465,000 个独立样本。