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，痴呆症在全球的患病率很高， 给医疗保健系统带来巨大负担。阿尔茨海默病（AD）是阿尔茨海默病最常见的原因。 广泛认为淀粉样蛋白β（Aβ）肽的积累是痴呆的关键事件， AD的发病机制，代表临床前疾病阶段。脑铁也强烈暗示， A β是AD发病机制中的辅助因子，其超负荷加速Aβ的产生并促进A β的毒性。 Aβ肽。但是，脑铁负荷的影响，以及其与局部Aβ斑块负荷的联合作用， 对AD及其前体轻度认知障碍（MCI）的认知功能障碍的研究缺乏。我们的整体目标 目的：探讨脑铁负荷及其与Aβ斑块负荷的协同作用在脑缺血再灌注损伤中的作用。 认知能力下降、MCI和痴呆，特别是AD的发展。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， 收集了过去30年来队列参与者的临床数据和英国生物银行研究， 在英国成年人群中收集广泛的临床，成像和遗传数据。在ARIC的研究中， 通过脑MRI、florbetapir正电子发射断层扫描（PET）和 研究访视5时进行认知测试，访视6时进行重复测试。我们将利用相位信号从 第6次访视时的梯度回波MRI数据（n= 1，000），以计算定量磁化率图（QSM）。脑铁 负载将使用我们最近开发的磁化率多图谱工具自动量化。然后我们将 对于目标1，确定增加的脑铁测量是否与认知功能独立相关， 这些年龄在73-94岁的ARIC参与者中存在MCI或痴呆的表现。我们将 还评估了已知的中年血管危险因素与脑铁之间的可能联系， 在晚年衡量。对于目标2，我们将估计Aβ-斑块负荷的联合效应，通过 ARIC-PET研究中的氟倍他平PET（n=300）和通过QSM测量的脑铁负荷增加， 根据人口统计学、当代 血管危险因素、小血管疾病和APOE-e4状态。为了进一步确定 在目标3中，我们将进行全基因组关联研究（GWAS）， 用孟德尔随机化法寻找脑铁的遗传决定因素及其与认知功能的关系 功能通过QSM测量的脑铁将根据UK生物样本库脑MRI数据计算 （n~= 35，000），而与脑铁负荷相关的遗传变异将针对认知功能进行测试。 在剩余的约465，000个独立样本中进行功能测量。