Neural Correlates and Modifiers of Cognitive Aging

项目摘要 衰老与大脑中的多种差异变化有关，并与了解神经机制有关 这种与年龄相关的认知能力下降是一个非常重要的问题。绘制人类衰老的自然过程图 健康成人和阐明改变的神经机制及其修饰物一直是一个重要的课题 这是我们过去二十年研究工作的目标。我们过去二十年的研究结果证实了 早期发现大脑区域(海马体、眶-额叶皮质、 内嗅觉/海马旁皮质和小脑)和连接它们的相关白色哑光纤维 区域。在研究这些变化背后的可能机制时，我们发现铁的增加 纹状体的含量(氧化应激的代用品)影响该区域的收缩并调节变化。 在工作记忆等认知技能方面。我们还发现，尽管对年龄敏感的大脑萎缩 地区预测重要认知能力的变化，在基线拥有更好的认知天赋 预测最重要的大脑区域之一--前额叶皮质的萎缩程度较小，因此表明 在衰老过程中，大脑和认知之间的关系是相互作用的，更好的认知能力可能 作为衰老的神经保护修饰物。此外，我们还发现，生理和遗传指标 血管和代谢风险以及对全身炎症的倾向在促进年龄相关方面发挥了作用 大脑衰退。在拟议的延续研究中，我们将继续收集在 这一项目的开始，因为它将为我们提供一个机会来审查与年龄有关的变化的形态 并测试弹道和非线性航向的可能性。同时，我们将扩大搜索的重点 通过关注认知老化中的两个领域来研究认知老化的机制 在过去十年中得到了支持：维持皮质下和皮质髓鞘，并保存 大脑能量代谢。我们将(首次)在这两个领域进行纵向评估 结合先前介绍的脑体积、脑白质微观结构的连续测量 和铁的积累。我们将测试与大脑和认知的时间动力学有关的假设 并将研究大脑能量代谢之间的滞后-领先关系(假设为 神经认知老化的主要诱因)、结构萎缩、髓鞘丢失和铁积累( 结构变化的主要调解人)。我们将研究大脑和年龄变化的相互作用- 血管、代谢和炎症危险因素的敏感认知功能及调节作用 这些关系。我们希望，对支撑正常认知的大脑机制的理解 老龄化将为我们提供必要的知识，并将有助于开发旨在缓解衰老的干预措施-- 相关的认知能力下降。最终，我们相信，这项研究将有助于建立规范的 了解阿尔茨海默病和其他痴呆症所需的基准。

Project Summary Aging is associated with multiple differential changes in the brain, and understanding the neural mechanisms that drive age-related cognitive declines is a matter of great importance. Charting the natural course of aging in healthy adults and elucidating the neural mechanism of change and their modifiers has been an overarching goal of our research work in the past two decades. The results of our studies in the past two decades confirm earlier findings of particular vulnerability in the brain regions (hippocampus, orbital–frontal cortex, entorhinal/parahippocampal cortex and cerebellum) and association white matte fibers that connect these areas. In investigating the possible mechanism underlying these changes, we found that increase in iron content (a proxy for oxidative stress) of the striatum influences shrinkage of that region and mediate changes in cognitive skill such as working memory. We also found that whereas shrinkage of age-sensitive brain regions predicts changes in important cognitive abilities, possession of better cognitive endowment at baseline predicted lesser shrinkage of one of the most important brain regions – the prefrontal cortex, thus suggesting that in aging, the relationship between brain and cognition is reciprocal and that better cognitive abilities may act as a neuroprotective modifier of aging. In addition, we found that physiological and genetic indicators of vascular and metabolic risk as well as proneness to systemic inflammation play a role in promoting age-related brain declines. In the proposed continuation study, we will carry on collecting longitudinal data initiated at the inception of this project as it will provide us with an opportunity to examine the shape of age-related change trajectory and test the possibility of non-linear course. At the same time, we will expand the focus of our search for mechanisms of cognitive aging by turning attention to two domains whose importance in cognitive aging has been bolstered in the past decade: maintenance of subcortical and cortical myelin and preservation of the brain energy metabolism. We will conduct (for the first time) longitudinal assessment in these two domains in conjunction with continuing previously introduced measurement of brain volume, white matter microstructure and iron accumulation. We will test hypotheses pertaining to the temporal dynamics of brain and cognitive aging and will examine the lag-lead relationships between brain energy metabolisms (hypothesized as the primary instigator of neurocognitive aging), structural shrinkage, and myelin loss and iron accumulation (the main mediators of structural change). We will examine the reciprocal role of changes in the brain and age- sensitive cognitive functions as well as moderating role of vascular, metabolic and inflammatory risk factors in these relationships. It is our hope that understanding of the brain mechanisms that underpin normal cognitive aging will arm us with necessary knowledge and will aid in developing interventions aimed at mitigating age- related cognitive declines. Ultimately, we believe that this research will help to establish the normative benchmarks necessary for understanding Alzheimer’s disease and other dementias.