Epidemiology of Dementia in the Framingham Study

描述（由申请人提供）：自1989年以来，由NIA资助，痴呆症流行病学研究的重点是识别痴呆症的事件病例，并确定与临床痴呆症相关的风险因素，特别是在大型前瞻性社区Fracket研究中的阿尔茨海默病（AD）。从1976年至1978年建立无痴呆症队列开始，这项研究记录了超过600名患有痴呆症的受试者，主要来自1948年招募的原始队列。近年来，随着原始队列的儿童（及其配偶）的老龄化，这些第二代受试者中的一些人已被记录为具有认知能力下降，脑损伤的MRI标志物以及轻度认知障碍（MCI）和痴呆。我们提供了基于社区的AD发病率和终生风险、卒中后痴呆风险的估计，并确定了许多生活方式、血管、新型生物标志物和最近的AD遗传风险因素。通过1995年建立的一个正在进行的大脑捐赠计划，我们对大约140个大脑进行了详细的神经病理学检查。 在本申请中，我们将通过加强监测来识别亚临床疾病患者，以识别可能患有MCI的受试者，并将对他们进行年度评估。我们将把以前收集的大量危险因素与AD和所有痴呆的发病风险、AD内表型以及从MCI转化为临床AD的风险联系起来。这些风险因素包括遗传（全基因组、候选基因和基因表达）和环境（自中年以来反复收集的生活方式、血管、代谢指标）数据、循环生物标志物水平和基线成像数据。 对于这一系列假定的风险标志物，我们建议增加：（1）一个关键的生物标志物，循环β-淀粉样蛋白（2）第三轮定量脑MRI和NP测试，以更精确地记录变化，并区分具有脑萎缩和认知下降的一致迹象的那些人，其处于转变为MCI和/或痴呆的最高风险;以及（3）对来自先前和新获取的MRI图像的额外感兴趣区域进行详细的后处理MR分析，以增强对大脑形态随时间的细微变化的检测。我们的目标是将这些新的和现有的数据纳入AD和痴呆的风险预测评分，并在独立的流行病学队列中进行验证。该风险特征的目的是确定AD发生风险最高的人群，从而允许有针对性的预防和治疗干预，包括招募易感受试者进行有希望的治疗的临床试验。 公共卫生相关性：自1989年以来由NIA资助，痴呆症流行病学研究的重点是确定痴呆症的发病率和风险因素，特别是阿尔茨海默病（AD），在一项大型，多代，以社区为基础的前瞻性流行病学研究中。由于早期发现疾病对于有效预防非常重要，我们最近专注于识别轻度认知障碍（MCI）患者。我们对参与者进行了研究，两组大脑MRI和认知测试相隔5年。在这次更新中，我们增加了一个关键的生物标志物（β-淀粉样蛋白），更好的成像和认知数据。我们建议根据这些新数据以及现有的遗传、生活方式、血管、代谢、生物标志物和成像数据（收集了4- 60年）制定痴呆（和AD）风险评分。该风险评分的目的是准确识别预防和治疗试验中招募的高风险人员。

DESCRIPTION (provided by applicant): Funded by NIA since 1989, the Epidemiology of Dementia Study has focused on identifying incident cases of dementia and determining the risk factors associated with clinical dementia, particularly Alzheimer's disease (AD) in the large prospective community-based Framingham Study. Beginning with the establishment of a dementia-free cohort in 1976-78, this study has documented >600 subjects with incident dementia, largely from the Original cohort recruited in 1948. In recent years, with the aging of the children of the Original cohort (and their spouses), a number of these Generation 2 subjects have been documented to have cognitive decline, and MRI markers of brain injury as well as Mild Cognitive Impairment (MCI) and dementia. We have provided community-based estimates of incidence and lifetime risk of AD, the risk of dementia following stroke, and have identified a number of lifestyle, vascular, novel biomarker and more recently genetic risk factors for AD. Through an ongoing brain donation program established in 1995, we have performed detailed neuropathologic examination of approximately 140 brains. In this application we will focus on identifying persons with subclinical disease by intensifying surveillance to identify subjects with probable MCI and will follow them with annual assessments. We will relate a wealth of previously collected risk factors to the risk of incident AD and all-dementia, to AD endophenotypes, and to the risk of conversion from MCI to clinical AD. These risk factors include genetic (genome-wide, candidate gene and gene expression) and environmental (lifestyle, vascular, metabolic measures gathered repeatedly since midlife) data, circulating biomarker levels and baseline imaging data. To this array of putative risk markers we propose to add: (1) a key biomarker, circulating beta-amyloid (A240 and A242) levels; (2) a third round of quantitative brain MRI and NP testing to more precisely document change, and distinguish those with consistent signs of brain atrophy and cognitive decline at highest risk of transitioning to MCI and/or dementia; and, (3) detailed post-processing MR analyses of additional regions of interest from prior and newly acquired MRI images to enhance detection of subtle changes in brain morphology over time. The goal is to incorporate these new and existing data into a risk prediction score for AD and dementia and validate it in an independent epidemiological cohort. The aim of this risk profile is to identify persons at highest risk for developing AD, thus permitting targeted preventive and therapeutic interventions, including enrollment of susceptible subjects for clinical trials of promising therapies. PUBLIC HEALTH RELEVANCE: Funded by NIA since 1989, the Epidemiology of Dementia Study has focused on determining the incidence and risk factors predisposing to dementia generally, and Alzheimer's disease (AD) specifically, in a large, multi-generational, community-based prospective epidemiologic study. Since detecting early disease is important for effective prevention, we have recently focused on identifying persons with Mild Cognitive Impairment (MCI). We have studied participants, with two sets of brain MRI and cognitive tests done 5 years apart. In this renewal we have added a key biomarker (beta-amyloid), better imaging and cognitive data. We propose to develop a dementia (and AD) risk score based on these new data, and on the genetic, lifestyle, vascular, metabolic, biomarker and imaging data already available (collected over 4-6 decades). The purpose of this risk score is to accurately identify high-risk persons for enrollment in preventive and treatment trials.