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

运动减慢预示着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。 我们的目的是确定线粒体功能障碍和脑铁沉积是否预测来自英国生物银行（UKB）前瞻性队列的50万名参与者中伴有和不伴有运动功能障碍的痴呆事件。 线粒体功能障碍是衰老的标志，并参与AD的发病机制。已经提出，根据全基因组测序数据估计为血液中线粒体DNA拷贝数的线粒体质量是脑中线粒体质量的替代量度。丰富的UKB数据将使我们能够评估超过125，000名参与者的线粒体功能障碍，并将这些数据与长达14年的随访中的痴呆事件相关联。 脑铁沉积发生在AD中，但其因果关系尚不清楚。我们在前20，000例MRI中的初步工作表明，男性铁过载血色素沉着症HFE p.C282Y纯合子突变与脑铁沉积增加、痴呆发病率加倍、虚弱和肌肉力量低下有关。基于MRI的脑铁沉积数据将在100，000名UKB参与者中提供。我们将使用极大扩展的MRI和诊断数据来扩展这项工作。有一个强有力的理由相信，线粒体功能障碍和铁沉积可能是协同导致脑损伤。线粒体功能障碍会增加活性氧自由基（ROS）的产生，包括可能与铁沉积物反应并产生高毒性羟基自由基（芬顿反应）的过氧化氢。 预防铁积累的治疗方法已经存在，一些可以改善线粒体功能的药物目前正在临床试验中进行测试。因此，更好地了解线粒体功能障碍对阿尔茨海默病和相关痴呆症的贡献可以支持进一步的研究，特别是在脑能量学方面，这是NIA校内研究计划中不断发展的计划之一。

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.