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，了解神经机制 是一个非常重要的问题。绘制人类衰老的自然过程 健康成年人和阐明变化的神经机制及其修饰剂一直是一个总体的 这是我们过去二十年来研究工作的目标。我们过去二十年的研究结果证实 早期发现大脑区域（海马体、眶额皮质， 内嗅/海马旁皮质和小脑）和连接这些的相关白色哑光纤维 地区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（氧化应激的代表）影响该区域的收缩并介导变化 工作记忆等认知技能。我们还发现，尽管对年龄敏感的大脑萎缩， 区域预测重要认知能力的变化，在基线时拥有更好的认知天赋 预测最重要的大脑区域之一--前额叶皮层的萎缩较小，因此表明 随着年龄的增长，大脑和认知之间的关系是相互的，更好的认知能力可能会 作为老化的神经保护调节剂。此外，我们发现，生理和遗传指标的 血管和代谢风险以及全身性炎症的倾向在促进年龄相关的 大脑衰退在建议的延续研究中，我们将继续收集在 这个项目的开始，因为它将为我们提供一个机会，研究与年龄有关的变化的形状 轨迹和测试的可能性，非线性课程。与此同时，我们将扩大我们搜索的重点 通过将注意力转向两个在认知老化中重要的领域， 在过去的十年里，这种观点得到了支持：维持皮质下和皮质髓鞘， 大脑能量代谢我们将于二○ ○二年（首次）就这两个范畴进行纵向评估。 结合继续先前引入的脑体积、白色物质微观结构的测量 铁的积累。我们将测试有关大脑和认知的时间动力学的假设 老化，并将检查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（ 结构变化的主要媒介）。我们将研究大脑和年龄变化的相互作用- 敏感的认知功能以及血管、代谢和炎症危险因素在 这些关系。我们希望，对支撑正常认知的大脑机制的理解， 老龄化将使我们掌握必要的知识，并有助于制定旨在减轻年龄的干预措施， 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的必要基准。

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.