The VETSA Longitudinal MRI Twin Study of Aging

 描述（由申请人提供）：尽管近年来一直迫切呼吁尽早识别认知能力下降和痴呆症风险人群，但中年和从中年到老年早期的过渡仍然相对研究不足，并且没有得到很好的理解。然而，这一关键的过渡期需要成为研究的重点，以便深入了解什么预示着好的或坏的结果。我们的主要目标是更好地了解这一时期认知和大脑老化的遗传和环境基础，并着眼于继续随访到晚年。为了实现这一目标，从一个狭窄的中年年龄段开始前瞻性地跟踪一个大的、遗传信息丰富的样本是有利的。我们开始了越南时代双胞胎衰老研究（VETSA），当时参与者平均年龄为55岁（51-60岁），我们在平均年龄61岁时进行了随访。这项研究是第三波多模态神经成像，平均年龄为66岁。我们将讨论影响变化的遗传和环境因素。目标1是扩展VETSA MRI数据库--中年开始的最大MRI研究之一--以包括第三个时间点沿着所有VETSA认知、生物医学和心理社会数据，并在研究完成后公开提供。我们预计约80%的回报率。目的2是前瞻性地描述中年到老年早期认知和大脑老化轨迹的异质性。 广泛的年龄范围研究将50-60岁描述为脑组织收缩或心室扩大的斜率增加的拐点，但它们只能捕捉平均趋势。我们假设拐点的时间和大脑各区域的变化率存在相当大的差异。我们将研究的一些关键因素是认知储备，MCI的早期识别和APOE基因型的交互作用。利用新的纵向轨迹数据，我们还将比较受试者仅在50多岁时MCI的不同操作定义，以确定最能预测MCI稳定或下降的定义。目的3是研究生物医学，心理社会和人格因素对大脑和认知老化的影响。一些关键焦点是心脏代谢因素和对压力的反应。我们现在将拥有全基因组基因分型数据（本项目不需要任何费用）。因此，我们所有的双胞胎模型现在都将纳入在大型外部全基因组关联研究中验证的多基因风险/倾向评分（PRS），以便我们可以根据测量的遗传方差加上剩余的潜在遗传方差来确定总遗传方差。我们还将使用我们团队成员开发的新基因富集和遗传多效性方法，以提高这些PRS的能力。这项纵向的、基于社区的MRI双胞胎研究（3个时间点）将在这一重要的老龄化时期产生前所未有的丰富信息，这将成为未来研究的资源。研究结果可能会对公共卫生产生深远的影响，因为早期识别可以改善干预的前景，从而大大减少痴呆症病例的数量，改善后期功能和生活质量。

 DESCRIPTION (provided by applicant): Although in recent years there has been an urgent appeal for earlier identification of people at risk for cognitive decline and dementia, middle age and the transition from middle- to early-old-age are still relatively under- studied and not well understood. Yet this critical transition period needs to be the focus of study in order to gain insights into what foreshadows good or poor outcomes. Our primary goal is a better understanding of the genetic and environmental underpinnings of cognitive and brain aging during this period with an eye toward continued follow-up into later old age. To accomplish that goal it is advantageous to prospectively follow a large, genetically-informative sample beginning in a narrow midlife age band. We began the Vietnam Era Twin Study of Aging (VETSA) when participants were average age 55 (51-60) and we conducted a follow-up at average age 61. The proposed study is a third wave of multi-modal neuroimaging at average age 66. We will address genetic, and environmental factors that influence change. Aim 1 is to extend the VETSA MRI database-one the largest MRI studies beginning in middle age-to include the third timepoint along with all VETSA cognitive, biomedical, and psychosocial data, and make it publicly available after study completion. We anticipate an ~80% return rate. Aim 2 is to prospectively characterize the heterogeneity of midlife to early- old-age cognitive and brain aging trajectories. Wide age range studies characterize ages 50-60 as a point of inflection when the slope of brain tissue shrinkage or ventricular enlargement increases, but they can only capture average trends. We hypothesize considerable variation in timing of inflection points and in rates of change across brain regions. Some key factors that we will examine are cognitive reserve, early identification of MCI, and interactive effects of APOE genotype. With new longitudinal trajectory data, we will also compare our different operational definitions of MCI when subjects were only in their 50s, to determine those most predictive of stability of MCI or decline. Aim 3 is to examine influences of biomedical, psychosocial, and personality factors on brain and cognitive aging. Some key foci are cardiometabolic factors and responses to stress. We will now have genome-wide genotyping data (at no cost to this project). As such, all of our twin models will now incorporate polygenic risk/propensity scores (PRSs) validated in large external genome-wide association studies, so that we can determine total genetic variance based on measured genetic variance plus remaining latent genetic variance. We will also use novel gene enrichment and genetic-pleiotropy- informed methods developed by members of our team in order to boost the power of those PRSs. This longitudinal, community-based MRI twin study with 3 time points will generate an unprecedented wealth of information during this important aging period that will be a resource for future investigations. The study results can have profound public health impact as early identification improves prospects for intervention that could substantially reduce the number of dementia cases and improve later functioning and quality of life.