Clinical, Imaging, and Pathological Studies in the Oldest Old: The 90+ Study

描述（由申请人提供）：90岁及以上的人（最老的老人）是人口增长最快的部分，痴呆症的发病率最高。尽管如此，人们对这个年龄组痴呆症的原因知之甚少。大约一半的痴呆症老人似乎没有明显的病理学来解释认知丧失，而类似比例的非痴呆症老人在保持良好认知的同时患有高水平的阿尔茨海默病（AD）和其他病理学。此外，在这个年龄组中，风险因素在很大程度上是未知的，似乎是自相矛盾的，传统的风险因素，如高血压，似乎对痴呆症有保护作用。我们的建议的主要目标是更好地了解表达的风险因素和生物基质， 老年痴呆症的发病率将我们的研究集中在痴呆的临床病理学不一致性以及该年龄组对风险因素的知识缺乏上，我们假设AD、血管和其他病理学代表非痴呆高龄老人的临床前疾病（无痴呆的显著病理学），因此在前瞻性研究中与认知能力下降和痴呆的发生率更高相关（Aim 1）。相比之下，患有痴呆症而没有显著病理的个体实际上具有低水平的多种病理，这些病理有助于认知障碍（目的2）。 由于多种痴呆病理，而不仅仅是AD，似乎有助于老年人的认知丧失，我们将调查与尸检或成像确定的特定病理相关的风险因素（Aim 3）。在休闲世界队列研究（20世纪80年代）和90+研究（2003年至今）中收集的风险因素数据将为我们的调查提供跨越几十年的丰富数据集，并有助于我们了解风险因素与年龄的变化关系。除了传统的风险因素，如载脂蛋白E，运动和体能，我们将研究新的因素（血压和血氧饱和度的波动）。对于这些研究，我们的流行病学研究中增加了新的程序，包括神经影像学（结构MRI和florbetapir淀粉样蛋白PET）和动态24小时血压（BP）和O2饱和度监测。我们假设血压正常是痴呆的危险因素，因为白天和夜间血压波动导致低血压，增加微梗死和血管性认知障碍的风险。高龄老人的缺氧将与淀粉样蛋白沉积增加和AD相关病理以及微梗死相关，从而增加痴呆的风险。 我们预计超过2/3的受试者将参与90+尸检研究，为我们在这些充分表征的人群受试者中的临床、遗传和成像研究增加更多价值。在完成90+研究后，我们预计将所有数据公开用于研究（目标4）。90岁以上的研究将提供有关最年长者的丰富信息，这是我们人口中一个重要且不断增长的部分。从这些调查中获得的知识可能会对公共卫生产生深远的影响。

DESCRIPTION (provided by applicant): People aged 90 and older (the oldest-old) comprise the fastest growing segment of the population and have the highest rates of dementia. Nonetheless, little is known about the causes of dementia in this age group. Approximately half of demented of oldest-old individuals do not appear to have significant pathology to explain cognitive loss, while a similar proportion of non-demented oldest-old have high levels of Alzheimer's disease (AD) and other pathologies while maintaining good cognition. Moreover, risk factors are largely unknown in this age group and appear paradoxical, with traditional risk factors such as hypertension appearing to be protective for dementia. The primary goal of our proposal is a better understanding of the risk factors and biological substrates for the expression of dementia in the oldest-old. Focusing our studies on the clinical pathological discordance for dementia and the paucity of knowledge of risk factors in this age group, we hypothesize that AD, vascular, and other pathologies represent preclinical disease in non-demented oldest-old (significant pathology without dementia) and thus will be associated with greater rates of cognitive decline and dementia in prospective studies (Aim1). In contrast, individuals who have dementia without significant pathology will, in fact, have low levels of multiple pathologies that contribute additively to cognitive impairment (Aim 2). Because multiple dementing pathologies, not just AD, appear to contribute to cognitive loss in people with advanced age, we will investigate risk factors in relation to specific pathologies, identified on autopsy or imaging (Aim 3). Risk factor data collected in the Leisure World Cohort Study (1980s) and The 90+ Study (2003-present) will provide our investigations with a rich dataset spanning several decades, and can contribute to our understanding of the changing relationship of risk factors with age. In addition to traditional risk factors, such as APOE, exercise, and physical performance, we will study novel factors (fluctuations in blood pressure and O2 saturation). For these investigations, new procedures have been added to our epidemiological study, including neuroimaging (structural MRI and florbetapir amyloid PET) and ambulatory 24-hour monitoring of blood pressure (BP) and O2 saturation. We hypothesize that normal BP is a risk factor for dementia because daytime and nocturnal BP fluctuations lead to hypotension increasing the risk of microinfarcts and vascular cognitive impairment. Hypoxia in the oldest-old will be associated with increased amyloid deposition and AD related pathologies, as well as with microinfarcts, thereby increasing the risk of dementia. We anticipate more than 2/3 of our subjects will participate in The 90+ Autopsy Study, adding further value to our clinical, genetic, and imaging studies in these well characterized population-based subjects. On completion of The 90+ Study, we anticipate making all of our data publicly available for research (Aim 4). The 90+ Study will provide a wealth of information about the oldest-old, an important and growing segment of our population. The knowledge obtained from these investigations can have profound public health impact.