Understanding two novel factors related to motor impairment in the development of dementia - UK Biobank project (Alzheimer's disease concept)

了解与痴呆症发展过程中运动障碍相关的两个新因素 - 英国生物银行项目（阿尔茨海默病概念）

• 批准号: 10691059
• 负责人: Qu Tian
• 金额: $ 3.35万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10691059
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Brain; Brain Injuries; Clinical Trials; DNA copy number; Data; Data Set; Dementia; Deposition; Development; Diagnostic; Free Radicals; Goals; Hemochromatosis; Homozygote; Human; Hydrogen Peroxide; Hydroxyl Radical; Intramural Research Program; Iron; Iron Overload; Lead; Magnetic Resonance Imaging; Measures; Mitochondria; Mitochondrial DNA; Motor; Mutation; Oxidative Stress; Participant; Pathogenesis; Pathology; Pharmaceutical Preparations; Production; Prognostic Marker; Prospective cohort; Proxy; Reaction; Reactive Oxygen Species; Research; Role; Testing; Whole Blood; Work; biobank; brain based; brain health; data submission; follow-up; frailty; genome sequencing; improved; men; mild cognitive impairment; mitochondrial dysfunction; motor disorder; motor impairment; novel; prevent; reduced muscle strength

Motor slowing predicts mild cognitive impairment and Alzheimers disease (AD) up to 12 years later. Potential mechanisms for this relationship include brain oxidative stress related to mitochondrial dysfunction and iron deposition, but data that connect these factors with brain health in humans is scarce. We aim to determine whether mitochondrial dysfunction and brain iron deposition predict incident dementia with and without motor dysfunction in the 500,000 participants from the UK Biobank (UKB) prospective cohort. Mitochondrial dysfunction is a hallmark of aging and has been involved in AD pathogenesis. It has been suggested that mitochondrial mass estimated as mitochondrial DNA copy number in blood from whole-genome sequencing data is a proxy measure of mitochondrial mass in the brain. The wealth of UKB data will allow us to assess mitochondrial dysfunction in over 125,000 participants and to correlate these data to incident dementia over up to 14 years of follow-up. Brain iron deposition occurs in AD, but its causal significance is unclear. Our preliminary work in the first 20,000 MRIs has shown that the iron overload hemochromatosis HFE p.C282Y homozygote mutations in men are associated with increased brain iron deposition, a doubling of incident dementia, frailty, and low muscle strength. MRI-based brain iron deposition data will be available in 100,000 UKB participants. We will extend this work using the greatly expanding MRI and diagnostic data. There is a strong rationale to believe that mitochondrial dysfunction and iron deposition may be synergic in causing brain damage. Mitochondrial dysfunction increases the production of Reactive Oxygen Radicals (ROS), including hydrogen peroxide that may react with iron deposits and produce highly toxic hydroxyl free radicals (Fenton reaction). Treatments to prevent iron accumulation are already available and a number of drugs that can improve mitochondrial function are currently tested in clinical trials. Thus, a better understanding of the contribution of mitochondria dysfunction to Alzheimers disease and related dementias could support further research particularly in brain energetics, one of the evolving plans in NIAs Intramural Research Program.

运动迟缓预示着12年后的轻度认知障碍和阿尔茨海默病（AD）。这种关系的潜在机制包括与线粒体功能障碍和铁沉积相关的脑氧化应激，但将这些因素与人类大脑健康联系起来的数据很少。