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

建议书摘要(摘要) 区分正常衰老和病理性衰老(如阿尔茨海默病)是一个主要的科学目标。这个 此应用程序中的项目寻求利用纵向设计、神经成像技术和精心挑选的 有助于揭示个体生物学机制的候选基因(单核苷酸多态；SNPs) 大脑和认知老化的差异。这种面对面的方法对于跟踪个人如何 (任何年龄)不同时间的年龄，并选择性地调查特定风险/保护因素的作用，同时 保持其他变量不变(人内设计)。在这里，我们利用从R00 NIA奖中收集的数据 关于190名年龄在20岁至94岁之间的人，他们在第一年和第四年开始第二波跟进和第三波跟进 建议的项目。这将在一项为期五年的研究中考虑到跨越6.5年的三波数据，提供 关于大脑和认知老化的个体差异的关键信息。具体地说，该项目旨在 利用单核苷酸多态性在多巴胺能系统中的已知生物学效应(COMTval158和DRD2 C/T) 和神经可塑性的调节(BDNFval66met)。年龄的增长伴随着年龄的急剧减少。 多巴胺神经元以及它们起源和支配的大脑主要区域。然而，大脑是 令人惊讶的是，这些变化是可塑性的，调节神经可塑性的一个主要因素是脑源性生长 因素。该项目的第一个具体目标是调查有或没有人的人的内部变化 额顶和额纹状体脑内突触中多巴胺可获得性降低的易感性 地区。我们将在认知功能核磁共振研究中检查调节这一回路的能力的变化。 在三个后续要点的过程中进行挑战。我们将进一步检查大脑结构的变化 (白质连接性退化，皮质变薄)，可能介导这种神经功能的变化，如 以及这些变化导致的认知能力下降或保存。第二个具体目标将类似地 检查患有或不患有困难的人的大脑激活对困难的调节的人内变化 神经可塑性因子的可获得性降低的易感性，特别是在边缘回路和 可能调节这些功能变化并预测认知结果的大脑结构。我们的第三个目标是利用 一种创新的神经成像技术，NODI(轴突定向分散和密度成像)，用于成像 形成突触单位的神经突起比以前可能的更具特异性。我们将在 波2，并在波3随访以测量树突/突触密度的变化，这是 神经可塑性。然后，我们将进一步关联个体树突密度的水平和变化 脑源性神经营养因子水平降低的遗传风险和阿尔茨海默病的风险 淀粉样蛋白阳性与淀粉样蛋白阴性的个体，以及APOE4阳性的个体。理解 引导个体走向正常或病理性衰老的生物机制，如阿尔茨海默病， 将有助于确定谁对未来的干预措施反应最好，以提高对老龄化影响的适应能力。

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.