Imaging Genomics of the Aging Brain

项目摘要/摘要 我们的目标是表征遗传和环境对正常衰老相关变化的影响 神经解剖学、神经生理学和神经认知指标。使用大量随机选择的数据 来自大脑结构和功能遗传学(GOBS)研究的家系，我们之前记录了 基因×年龄(G×A)交互作用影响神经认知功能减退和大脑皮质厚度降低 内侧颞叶和顶叶皮质。虽然这些发现表明遗传因素与大脑老化有关，但它们是 基于横断面数据，缺乏对个体内部老龄化的直接评估。更强大的方法 检测健康老龄化对遗传和环境的影响需要纵向数据。因此，我们 提出一项基于系谱的混合纵向研究，对700只最老的山羊个体~10进行重新表型研究 在他们最初评估的几年后。每隔10年测量与年龄相关的认知能力是理想的， 神经解剖学和神经生理学的下降，因为练习的影响和其他阶段的变化是最小的。 山羊群中的个体具有密集的遗传和表型特征，包括 基因组测序(WGS)、综合神经认知评估、结构和功能脑 成像和基于血液的环境指数。我们的具体目标是(1)记录10年的神经认知 700名非精神错乱的gobs参与者(当前年龄69.05 8.4[57-102])的神经成像下降； 采用我们的G×A方法建立纵向脑老化表型；(3)确定序列变异 先前与影响脑老化的正常或病理性衰老相关的候选基因/途径 并在档案样本中复制这些发现；以及(4)应用一种新的统计方法 最大化系统环境信号，以确定环境对大脑老化表型的影响。 描述与年龄相关的神经认知和神经成像的遗传和环境结构 变化将提供重要的生物学见解，进而可能提供战略，以增加 成功变老的美国人的数量。 耶鲁大学的David Glahn博士和德克萨斯大学里奥格兰德山谷医学院的John Blangero博士 是这项申请的联合首席调查员，德克萨斯大学卫生分校的Rene Olvera博士 圣安东尼奥科学中心将牵头一项分包合同。鉴于表型、环境和 根据这一队列中已有的基因类型数据，拟议的研究代表了一种现成的、成本- 为阐明脑老化机制提供了有效而有力的资源。

PROJECT SUMMARY/ABSTRACT Our goal is to characterize the genetic and environmental influences on normal aging-related changes in neuroanatomic, neurophysiologic and neurocognitive indices. Using data collected in large, randomly selected pedigrees from the Genetics of Brain Structure and Function (GOBS) study, we previously documented genotype × age (G×A) interactions influencing neurocognitive decline and reduced cortical thickness within medial temporal and parietal cortices. While these findings implicate genetic factors in brain aging, they are based on cross-sectional data and lack direct evaluation of intra-individual aging. More powerful methods for the detection of genetic and environmental influences of healthy aging require longitudinal data. Thus, we propose a pedigree-based, mixed longitudinal study to re-phenotype the oldest 700 GOBS individuals ~10 years after their initial assessment. A 10-year interval is ideal for measuring age-related cognitive, neuroanatomic and neurophysiological declines as practice effects and other phasic alterations are minimized. Individuals in the GOBS cohort have intensive genetic and phenotypic characterization, including whole genome sequencing (WGS), comprehensive neurocognitive assessment, structural and functional brain imaging and blood-based environmental indices. Our specific aims are to (1) document 10-year neurocognitive and neuroimaging declines in 700 non-demented GOBS participants (current age 69.05+8.4 [57-102]); (2) employ our G×A approach to establish longitudinal brain aging phenotypes; (3) identify sequence variation in candidate genes/pathways previously associated with normal or pathological aging that influencing brain aging phenotypes and replicate these findings in archival samples; and (4) apply a novel statistical approach to maximize systematic environmental signals to identify environmental influences on brain aging phenotypes. Delineating the genetic and environmental architecture of age-related neurocognitive and neuroimaging changes will offer important biological insights which in turn could provide strategies for increasing the numbers of Americans who successfully age. Dr. David Glahn, Yale University, and Dr. John Blangero, University of Texas Rio Grande Valley Medical School, are co-principal investigators on this application and Dr. Rene Olvera, University of Texas Health Science Center San Antonio, will lead a subcontract. Given the wealth of phenotypic, environmental and genotypic data already available in this cohort, the proposed study represents a readily available, cost- effective, and powerful resource for elucidating mechanisms of brain aging.