The VETSA Longitudinal MRI Twin Study of Aging (VETSA MRI 4)

项目摘要/摘要 阿尔茨海默病(AD)费用昂贵，负担沉重。随着美国人口老龄化，AD对公共健康的影响 继续增长。美国国立卫生研究院和阿尔茨海默氏症协会的共识声明表明，早期理解 从中年开始的疾病发展阶段--如轻度认知障碍(MCI)--是 延缓痴呆症的发病。据估计，及早识别高危人群也能节省大量资金。 尽管阿尔茨海默病的脑病理进展漫长，但人们对其从中期到中期的时间进程知之甚少 至老年，尤其是神经影像指标。越南时代双胞胎老龄化研究(VETSA)专注于 早期识别MCI/AD的风险和AD相关的脑变化从受试者50多岁开始。 拟议的Vetsa MRI第4波项目，平均年龄为74岁(67-78岁)，发生在 事件MCI/AD。这与我们的纵向数据相结合，可以提高确定 神经成像与运动轨迹和它们的预测因素相关。继续收集数据将使我们能够检查 从发病前到发病后的过渡期以及从中年到中年的预测 个体数量。该项目与资助的一般Vetsa 4赠款(AG050595)相关联，该基金收集 每个受试者10-12小时的认知、健康/医学、心理社会和生物标记物数据。此外，我们还可以 通过结合双胞胎和全基因组阐明遗传和环境对这些过程的影响 基因分型/多基因得分数据。我们还利用早期(20岁)的认知数据，这是一个独特的特征 使我们能够将认知衰退与长期存在的差异区分开来。我们申请资金来支付核磁共振成像费用 采集、处理和分析(n=500)，利用Vetsa 4的相关正在进行的工作 格兰特。目标是：1)开发、验证和表征MCI/AD的新的早期大脑风险指标。我们会 开发并验证了一种新的基于扩散磁共振的AD脑信号，并表明该脑信号 只有50多岁的成年人改善了发展为MCI的预测。我们还假设，正直 蓝斑是tau沉积的最早的大脑部位，这将是另一个早期的、敏感的风险指标。 2)研究脑血管危险因素及其与认知和AD生物标志物的关系。 脑血管疾病(CVD)是阿尔茨海默病(AD)最常见的病理表现，可能导致 疾病进展或成为大脑和认知能力下降的独立来源。我们特别关注心血管疾病 脑白质高信号的标记物和动脉自旋标记(ASL)灌注。3)量化大小 从中年到老年早期的神经退化及其潜在的遗传和环境影响。 我们将考察基因对宏观和微观大脑结构测量纵向变化的影响。我们的 方法包括确定风险因素在整个生命周期内的中介/调节效应，并利用 我们的双胞胎和全基因组的基因数据。这个项目持续了大约18年，将成为推动 早期识别MCI/AD风险的知识，有可能对公共卫生产生深远影响。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is costly and burdensome. As the US population ages, AD’s public health impact continues to grow. NIH and Alzheimer’s Association consensus statements indicate that understanding early phases of disease progression—such as mild cognitive impairment (MCI)—beginning in middle age is key to slowing dementia onset. Identifying at-risk individuals early is also estimated to result in massive savings. Despite the protracted progression of AD brain pathology, little is known about its temporal course from middle to older age, particularly for neuroimaging indices. The Vietnam Era Twin Study of Aging (VETSA) focuses on early identification of risk for MCI/AD and AD-related brain changes beginning when subjects were in their 50s. The proposed VETSA MRI wave 4 project, with a mean age of 74 (67-78), occurs during a time of increased incident MCI/AD. That, in combination with our longitudinal data, allows for improved ability to determine neuroimaging correlates, trajectories, and their predictors. Continued data collection will allow us to examine the transition period from pre- to post-disease onset and expand on prediction from midlife for an increasing number of individuals. This project is linked to the funded general VETSA 4 grant (AG050595) which collects 10-12 hours per subject of cognitive, health/medical, psychosocial and biomarker data. In addition, we can elucidate genetic and environmental influences on these processes via combined twin and genome-wide genotyping/polygenic score data. We also capitalize on early (age 20) cognitive data, a unique feature enabling us to differentiate cognitive decline from longstanding differences. We request funds to cover MRI acquisition, processing, and analysis (n=500), leveraging associated ongoing work in the general VETSA 4 grant. Aims are: 1) Develop, validate, and characterize novel early brain indicators of risk for MCI/AD. We will develop and validate a novel AD brain signature based on diffusion MRI and show that this brain signature of adults who are only in their 50s improves prediction of progression to MCI. We also hypothesize that integrity of the locus coeruleus—the earliest brain site of tau deposition—will be another early, sensitive risk indicator. 2) Examine cerebrovascular risk factors and their relationship with cognition and AD biomarkers. Cerebrovascular disease (CVD) is the most common pathology concomitant with AD and may contribute to disease progression or be an independent source of brain and cognitive decline. We particularly focus on CVD markers of white matter hyperintensities and arterial spin labeling (ASL) perfusion. 3) Quantify the magnitude of neurodegeneration from midlife to early old age and its underlying genetic and environmental influences. We will examine genetic influences on longitudinal change in macro- and micro-structural brain measures. Our approach includes identifying mediating/moderating effects of risk factors across the lifespan and leveraging our twin and genome-wide genotype data. Covering ~18 years, this project will be a resource for advancing knowledge about early identification of risk for MCI/AD, with potential for a profound public health impact.