Clinical and Pathological Studies in the Oldest Old

项目简介（由申请人提供）：项目概述启动于2003年，90+研究的目标是对90岁及以上人群进行前瞻性临床、病理和遗传调查。通过《90+研究》中大量的认知测试、实验室研究、身体表现测量、遗传和其他数据，以及自1981年以来作为《休闲世界队列研究》的一部分收集的这些个体的调查信息，我们将估计发病率并评估痴呆（目标1）、功能残疾和虚弱（目标2）以及老年人认知和功能衰退（目标3）的风险和保护因素。我们的研究强调潜在的可改变因素（血氧饱和度、贫血和身体表现）是该年龄组痴呆和残疾的危险因素，并可能为未来对老年人的干预研究提供基础。根据我们的初步研究，我们假设动脉氧饱和度低是认知能力下降和痴呆的危险因素，而贫血和身体表现指标（如步行速度和握力）是痴呆和非痴呆个体残疾、虚弱和功能下降的危险因素。在这个年龄范围内，一半的痴呆受试者没有明显的典型AD或其他病理来解释认知丧失。在这个应用中，新的合作加强了我们的临床病理研究，研究了最老老年人认知的生物学相关性（Aim 4）。加州大学欧文分校、宾夕法尼亚大学和约翰霍普金斯医学院的研究人员将对我们的研究对象的脑组织进行研究，以验证我们的假设，即90岁以上老年人的认知丧失可能与A2、tau和1突触核蛋白的可溶性（而不是不可溶性）寡聚物有关（Aim 4b），与神经元完整性和回路相关的非AD病理，可能通过其他与年龄相关的机制导致认知丧失（Aim 4c）。最后，我们将开发我们的临床数据和生物样本（脑组织和DNA）作为一个资源，积极与世界各地的科学家共享。了解影响我们社会中最年长成员的认知和功能状态的因素是本提案的主要目标。在我们对老年痴呆、残疾和虚弱的前瞻性研究中，我们将调查动脉氧饱和度、贫血、身体表现指标和其他可能适合干预的因素与痴呆、残疾和虚弱的关系。我们的最终目标是找到延长九十岁和百岁老人无残疾寿命的方法。如果低氧饱和度、贫血或身体表现不佳与超长寿命中痴呆或残疾风险增加有关，这将为实验研究提供基础，以确定氧气治疗、贫血治疗或运动是否可以预防或延缓老年人认知和日常生活活动的丧失。对我们人口中增长最快的部分来说，潜在的公共卫生影响是巨大的。公共卫生相关性：了解影响我们社会中最年长成员的认知和功能状态的因素是本提案的主要目标。在我们对老年人痴呆、残疾和虚弱的前瞻性研究中，我们将调查动脉氧饱和度、贫血、身体表现指标和其他可能适合干预的因素与痴呆、残疾和虚弱的关系。我们的最终目标是找到延长九十岁和百岁老人无残疾寿命的方法。如果低氧饱和度、贫血或身体表现不佳与超长寿命中痴呆或残疾风险增加有关，这将为实验研究提供基础，以确定氧气治疗、贫血治疗或运动是否可以预防或延缓老年人认知和日常生活活动的丧失。对我们人口中增长最快的部分来说，潜在的公共卫生影响是巨大的。

DESCRIPTION (provided by applicant): Project Summary Initiated in 2003, the goal of The 90+Study is to perform prospective clinical, pathological, and genetic investigations in a population based sample of people aged 90 years and older. With a wealth of cognitive tests, laboratory studies, physical performance measures, genetic and other data in The 90+ Study, plus survey information collected on these individuals since 1981 as part of the Leisure World Cohort Study, we will estimate incidence rates and evaluate risk and protective factors for dementia (Aim 1), functional disability and frailty (Aim 2), as well as cognitive and functional decline in the oldest old (Aim 3). Our studies emphasize potentially modifiable factors (oxygen saturation, anemia, and physical performance) as risk factors for dementia and disability in this age group, and could potentially provide the basis for future intervention studies in the oldest old. Based on our preliminary studies, we hypothesize that poor arterial oxygen saturation is a risk factor for cognitive decline and dementia, while anemia and physical performance measures (such as walk speed and handgrip) are risk factors for the development of disability, frailty, and functional decline in demented and non demented individuals. Half of all demented subjects in this age range do not have significant classical AD or other pathologies to explain cognitive loss. In this application, new collaborations enhance our clinical pathological studies investigating the biological correlates of cognition in the oldest old (Aim 4). Brain tissues from our well characterized subjects will be studied by investigators at the University of California, Irvine, University of Pennsylvania, and Johns Hopkins School of Medicine as we test our hypotheses that soluble, rather than insoluble, oligomeric species of A2, tau and 1 synuclein may be responsible for cognitive loss in 90+ year olds (Aim 4b) and that non AD pathologies, relevant to neuronal integrity and circuits, may contribute to cognitive loss through other age related mechanisms (Aim 4c). Finally, we will develop our clinical data and biological samples (brain tissues and DNA) as a resource to be actively shared with scientists worldwide. Project Narrative Understanding factors that influence the cognitive and functional status of the most senior members of our society is a major goal of this proposal. In our prospective studies of dementia, disability, and frailty in the oldest old, we will investigate the relationship to dementia, disability, and frailty of arterial O2 saturation, anemia, physical performance measures, and other factors that might be amenable to intervention. Ultimately our goal is to find ways to extend life without disability in nonagenarians and centenarians. If low O2 saturation, anemia or poor physical performance is associated with increased risk of dementia or disability in exceptionally long life, it would provide the basis for experimental studies to determine if oxygen therapy, treatment of anemia, or exercise could prevent or delay the loss of cognition and activities of daily living in the oldest old. The potential public health implications are enormous for the fastest growing segment of our population. PUBLIC HEALTH RELEVANCE: Understanding factors that influence the cognitive and functional status of the most senior members of our society is a major goal of this proposal. In our prospective studies of dementia, disability, and frailty in the oldest-old, we will investigate the relationship to dementia, disability, and frailty of arterial O2 saturation, anemia, physical performance measures, and other factors that might be amenable to intervention. Ultimately our goal is to find ways to extend life without disability in nonagenarians and centenarians. If low O2 saturation, anemia or poor physical performance is associated with increased risk of dementia or disability in exceptionally long life, it would provide the basis for experimental studies to determine if oxygen therapy, treatment of anemia, or exercise could prevent or delay the loss of cognition and activities of daily living in the oldest-old. The potential public health implications are enormous for the fastest growing segment of our population.