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(年龄最大的)是人口中增长最快的部分，也是痴呆症发病率最高的人群。尽管如此，人们对这个年龄段痴呆症的原因知之甚少。年龄最大的痴呆者中，大约有一半似乎没有明显的病理学来解释认知障碍，而同样比例的非痴呆症高龄老人在保持良好认知的同时，有高水平的阿尔茨海默病(AD)和其他病理。此外，风险因素在这个年龄段很大程度上是未知的，似乎是矛盾的，传统的风险因素，如高血压，似乎对痴呆症具有保护作用。我们建议的主要目标是更好地了解表达的风险因素和生物学基础。 最年长的老人患有痴呆症。我们的研究集中在痴呆症的临床病理不一致性和对该年龄段危险因素知识的缺乏上，我们假设AD、血管和其他病理学代表非痴呆性高龄老人的临床前疾病(没有痴呆的显著病理学)，因此在前瞻性研究中将与认知能力下降和痴呆症的更高比率相关(Aim1)。相比之下，没有重大病理的痴呆症患者实际上会有较低水平的多种病理，这些疾病会增加认知障碍(目标2)。由于多种痴呆病理，而不仅仅是阿尔茨海默病，似乎会导致高龄人群的认知障碍，我们将调查与尸检或成像(AIM)确定的特定病理相关的风险因素 3)。在休闲世界队列研究(1980年代)和90+研究(2003-至今)中收集的风险因素数据将为我们的调查提供跨越数十年的丰富数据集，并有助于我们理解风险因素随年龄变化的关系。除了传统的危险因素，如载脂蛋白E、运动和体能表现，我们还将研究新的因素(血压和氧气饱和度的波动)。对于这些调查，我们的流行病学研究增加了新的程序，包括神经成像(结构MRI和FLOBETAPIR淀粉样蛋白PET)和24小时动态血压(BP)和氧气饱和度监测。我们假设血压正常是痴呆的危险因素，因为白天和夜间的血压波动会导致低血压，增加微梗塞和血管认知障碍的风险。最年长的老年人缺氧将与淀粉样蛋白沉积增加和AD相关病理以及微梗塞相关，从而增加痴呆症的风险。我们预计超过2/3的受试者将参与90+尸检研究，进一步增加我们对这些以人群为基础的受试者的临床、遗传和影像研究的价值。在90多项研究完成后，我们预计将我们所有的数据公开用于研究(目标4)。这项90岁以上的研究将提供大量关于高龄老人的信息，高龄老人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.