Dopaminergic and Neuroplastic Influences on Longitudinal Change in Cognitive and Brain Aging

多巴胺能和神经可塑性对认知和大脑衰老纵向变化的影响

• 批准号: 9925201
• 负责人: Kristen M. Kennedy
• 金额: $ 51.15万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925201
• 关键词: Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Autopsy; Award; Axon; Biological; Brain; Brain region; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cognition; Cognitive; Cognitive aging; Collection; Corpus striatum structure; Cross-Sectional Studies; DRD2 gene; Data; Data Set; Dendrites; Dendritic Spines; Dopamine; Environmental Risk Factor; Ethics; Functional Magnetic Resonance Imaging; Future; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genotype; Goals; Health; Image; Imaging Techniques; Impaired cognition; Individual; Individual Differences; Intervention; Investigation; Longevity; Longitudinal Studies; MRI Scans; Magnetic Resonance Imaging; Maintenance; Measurement; Measures; Mediating; Nerve Degeneration; Nerve Growth Factors; Neurites; Neurocognitive; Neuronal Plasticity; Neurophysiology - biologic function; Neuropsychology; Outcome; Parietal; Participant; Persons; Positron-Emission Tomography; Predisposition; Prefrontal Cortex; Process; Public Health; Randomized; Regulation; Research; Resolution; Resources; Risk; Role; Sampling; Shapes; Single Nucleotide Polymorphism; Specificity; Structure; Synapses; System; Techniques; Thick; Thinness; Time; abeta deposition; age effect; age related; aged; aging brain; base; brain repair; brain-derived growth factor; cognitive ability; cognitive performance; cohort; density; design; dopaminergic neuron; experience; follow-up; gray matter; health goals; healthy aging; in vivo imaging; indexing; innovation; longitudinal design; molecular imaging; multimodality; neuroimaging; neurotrophic factor; normal aging; novel; pathological aging; preservation; protective factors; relating to nervous system; resilience; response; risk variant; white matter; β-amyloid burden

PROPOSAL SUMMARY (ABSTRACT) Distinguishing normal from pathological aging (such as Alzheimer’s Disease) is a major scientific goal. The projects in this application seek to utilize longitudinal design, neuroimaging techniques, and carefully selected candidate genes (single nucleotide polymorphisms; SNPs) to help uncover biological mechanisms in individual differences in brain and cognitive aging. This within-­person approach is necessary to track how an individual (of any age) ages across time, and to selectively investigate the role of specific risk/protective factors while holding other variables constant (within-­person design). Here we leverage data collected from R00 NIA award on 190 individuals aged 20-­94 years to begin Wave 2 follow-­up in Year 1 and Wave 3 in Year 4 of the proposed project. This will allow for three waves of data spanning 6.5 years in a five-­year study, providing crucial information about individual differences in brain and cognitive aging. Specifically, this project aims to capitalize on the known biological effects of SNPs in the dopaminergic system (COMTval158 and DRD2 C/T) and in the regulation of neuroplasticity (BDNFval66met). Aging is accompanied by stark diminution to the dopamine neurons and those major brain regions they originate from and innervate. However, the brain is surprisingly plastic to these changes, and a major factor in regulating neuroplasticity is brain-­derived growth factor. The first specific aim of the project is to investigate within-­person change in persons with or without predisposition to reduced availability of dopamine in the synapses in frontal-­parietal and fronto-­striatal brain regions. We will examine change in ability to modulate this circuitry in functional MRI studies of cognitive challenge over the course of three follow-­up points. We will further examine the brain structural changes (degradation of white matter connectivity, cortical thinning) that may mediate this change in neural function, as well as cognitive decline or preservation that results from these changes. The second specific aim will similarly examine within-­person changes in modulation of brain activation to difficulty in persons with or without predisposition to reduced availability of neuroplasticity factors, particularly in limbic circuitry and the changes to brain structure that may mediate these functional changes and predict cognitive outcome. Our third aim utilizes an innovative neuroimaging technique, NODDI (neurite orientation dispersion and density imaging), to image with more specificity than previously possible the neurites which form synaptic units. We will introduce this in Wave 2, with follow-­up in Wave 3 to measure change in dendrite/synaptic density, another marker of neuroplasticity. We will then further associate level and change in dendritic density in individuals based on genetic risk for reduced BDNF levels and at risk for Alzheimer’s Disease by examining neurite density in amyloid positive vs amyloid negative individuals, as well as those with APOEe4 positivity. Understanding biological mechanisms that guide individuals toward normal or pathological aging, like Alzheimer’s Disease, will help identify whom may respond best to future interventions to increase resilience to aging’s effects.

提案摘要（摘要） 将正常与病理衰老（例如阿尔茨海默氏病）区分开是一个主要的科学目标。这 该应用程序中的项目旨在利用纵向设计，神经影像技术和精心选择 候选基因（单核苷酸多态性； SNP），以帮助发现个体的生物学机制 大脑和认知衰老的差异。这种实体方法对于跟踪个人的方式是必要的 （任何年龄的）年龄跨时间，并有选择地研究特定风险/保护因素的作用 保持其他变量恒定（人体内设计）。在这里，我们利用从R00 NIA奖收集的数据 在190名20-94岁的人中，开始了第1年的第2次随访，并在第4年的第4次浪潮 拟议项目。这将允许在一项五年的研究中进行三波数据跨度6。5年 有关大脑和认知衰老的个体差异的关键信息。具体而言，该项目的目的是 利用SNP在多巴胺能系统中的已知生物学效应（COMTVAL158和DRD2 C/T） 在调节神经可塑性（BDNFVAL66MET）中。衰老是通过减少到衰老而实现的 多巴胺神经元及其源自支配的主要大脑区域。但是，大脑是 令人惊讶的是，这些变化的塑料以及调节神经可塑性的主要因素是脑衍生的生长 因素。该项目的第一个具体目的是调查有或没有的人内部变更 易于降低前纹状体和前纹状体大脑突触中多巴胺的可用性 地区。我们将检查在认知功能MRI研究中调节该电路的能力的变化 挑战在三个后续点的过程中。我们将进一步研究大脑结构的变化 （白质连通性的降解，皮质稀疏）可能会介导这种神经功能的变化，例如 以及这些变化导致的认知下降或保存。第二个特定目标也将同样 检查或没有或没有的人的大脑激活调节的人体内部变化 降低神经塑性因素的可用性的倾向，特别是在边缘电路中 可能介导这些功能变化并预测认知结果的大脑结构。我们的第三个目标利用 一种创新的神经影像学技术，NODDI（神经突导向分散和密度成像），以形象 比以前更具体的神经运动形成突触单位。我们将在此中介绍 波2，在波3中随访以测量树突/突触密度的变化，另一个标记 神经可塑性。然后，我们将进一步关联个体的树突密度和基于树突密度的变化 遗传风险降低了BDNF水平，并通过检查神经蛋白酶密度而受到阿尔茨海默氏病的风险 淀粉样蛋白阳性与淀粉样蛋白负个个体以及APOEE4阳性的个体。理解 引导个体正常或病理衰老的生物学机制，例如阿尔茨海默氏病， 将有助于确定谁可能对未来的干预措施做出最佳反应，以提高对衰老影响的弹性。