Imaging Genomics of the Aging Brain

衰老大脑的成像基因组学

• 批准号: 10432059
• 负责人: John Blangero
• 金额: $ 68.74万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432059
• 关键词: Age; Aging; Alzheimer' s Disease; American; Architecture; Biological; Biological Markers; Biology of Aging; Blood; Brain; Brain imaging; Candidate Disease Gene; Child; Chronology; Clinical; Cognitive; Coupled; Data; Data Set; Diabetes Mellitus; Diffusion; Dimensions; Education; Elderly; Environment; Environmental Risk Factor; Evaluation; Gas Chromatography; Generations; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health Sciences; Image; Individual; Lead; Longevity; Longitudinal Studies; MRI Scans; Mass Spectrum Analysis; Measurement; Measures; Medial; Neuroanatomy; Neurocognition; Neurocognitive; Neurocognitive Deficit; Neurologic Examination; Obesity; Parietal Lobe; Parkinson Disease; Participant; Pathway interactions; Persons; Phase; Phenotype; Plasma; Principal Investigator; Quality of life; Recording of previous events; Resources; Rest; Sampling; Scotland; Signal Transduction; Smoking; Socioeconomic Status; Spatial Distribution; Structure; Technology; Temporal Lobe; Testing; Texas; Thick; Time; Universities; Variant; age related; aging brain; base; biobank; brain health; cohort; cost effective; design; detection method; functional MRI scan; genetic approach; genetic architecture; genetic association; genetic pedigree; genome sequencing; genome wide association study; health care service utilization; healthy aging; high dimensionality; human old age (65+); improved; indexing; insight; interest; lipidomics; medical schools; metabolomics; neuroimaging; neurophysiology; non-demented; normal aging; novel; novel strategies; pathological aging; sample archive; socioeconomics; trait; whole genome

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.

项目总结/摘要 我们的目标是描述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数。使用大量随机选取的数据 来自大脑结构和功能遗传学（GOBS）研究的家系，我们以前记录了 基因型×年龄（G×A）的相互作用影响神经认知功能下降和皮质厚度减少， 内侧颞叶和顶叶皮质虽然这些发现暗示了大脑衰老的遗传因素，但它们是 基于横截面数据，缺乏对个体内老化的直接评估。更强大的方法， 健康老龄化的遗传和环境影响的检测需要纵向数据。因此我们 我提出了一个基于谱系的混合纵向研究，以重新表型最古老的700个GOBS个体~10 在最初的评估之后。10年的间隔是测量与年龄相关的认知能力的理想时间， 神经解剖学和神经生理学下降，因为练习效果和其他阶段性改变被最小化。 GOBS组群中的个体具有密集的遗传和表型特征，包括全 基因组测序（WGS），综合神经认知评估，结构和功能脑 成像和血液环境指数。我们的具体目标是（1）记录10年的神经认知 700名非痴呆GOBS参与者（当前年龄69.05 ± 8.4 [57-102]）的神经影像学下降;（2） 采用我们的G×A方法建立纵向脑老化表型;（3）识别序列变异， 以前与正常或病理性衰老相关的影响脑衰老的候选基因/途径 表型，并在档案样本中复制这些发现;（4）应用一种新的统计方法， 最大化系统的环境信号，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 这些变化将提供重要的生物学见解，反过来又可以提供增加 成功衰老的美国人。 博士耶鲁大学的大卫格拉恩和德克萨斯大学格兰德河谷医学院的约翰布朗杰罗博士 学校，是共同的主要研究者对这个应用程序和博士雷内奥尔维拉，得克萨斯州大学健康 科学中心圣安东尼奥，将领导一个。鉴于丰富的表型，环境和 基因型数据已经在这个队列中，拟议的研究代表了一个现成的，成本- 有效的，强大的资源来阐明大脑衰老的机制。