Neural Correlates and Modifiers of Cognitive Aging

认知衰老的神经相关因素和调节因素

• 批准号: 9335773
• 负责人: NAFTALI RAZ
• 金额: $ 73.74万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335773
• 关键词: Address; Adenosine Triphosphate; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Anisotropy; Area; Attention; Autopsy; Award; Benchmarking; Biochemistry; Biological Markers; Biological Preservation; Blood Pressure; Blood Vessels; Brain; Brain region; Cerebellum; Cognition; Cognitive; Cognitive aging; Complement; Corpus striatum structure; Data; Dementia; Deposition; Deterioration; Elderly; Endowment; Energy Metabolism; Episodic memory; Evaluation; Failure; Fiber; Foundations; Free Radicals; Functional disorder; Future; Genetic; Glycosylated Hemoglobin; Goals; Hippocampus (Brain); Homocysteine; Human; Impaired cognition; Individual Differences; Inflammation; Inflammatory; Insulin; Interleukin-6; Intervention; Investigation; Iron; Knowledge; Laboratories; Lead; Link; Lipids; Liquid substance; Longevity; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Measurable; Measurement; Measures; Medial; Mediating; Mediator of activation protein; Membrane; Metabolic; Methods; Myelin; Neurocognitive; Neuropil; Oxidative Stress; Performance; Phosphocreatine; Phospholipid Metabolism; Phospholipids; Phosphorus; Physiological; Play; Population; Prefrontal Cortex; Prevalence; Process; Proxy; Reactive Oxygen Species; Recruitment Activity; Research; Risk; Risk Factors; Role; Sampling; Shapes; Short-Term Memory; Sorting - Cell Movement; Structure; Study models; Symptoms; TNF gene; Testing; Time; Vocabulary; Water; Work; age difference; age related; aging brain; arm; brain health; brain morphology; brain volume; circulating biomarkers; cognitive ability; cognitive function; cognitive performance; cognitive process; cognitive skill; cohort; design; executive function; fasting glucose; frontal lobe; genetic variant; imaging modality; in vivo; indexing; inorganic phosphate; insight; neural correlate; neuroimaging; neuromechanism; normal aging; oxidative damage; processing speed; programs; relating to nervous system; theories; water diffusion; white matter

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.

项目摘要 衰老与大脑的多种差异变化有关，并了解神经机制 那种与年龄相关的认知下降非常重要的问题。绘制自然衰老的过程 健康的成年人并阐明了变化的神经机制及其修饰符是总体的 过去二十年来我们的研究工作的目标。过去二十年来我们的研究结果证实 早期发现大脑区域特定脆弱性的发现（海马，轨道 - 额叶皮层， 连接这些 区域。研究这些变化的可能机制，我们发现铁的增加 纹状体的含量（氧化应激的代理）会影响该区域的收缩并介导变化 在认知技能（例如工作记忆）中。我们还发现，尽管年龄敏感的大脑收缩 区域预测重要认知能力的变化，基线时具有更好认知捐赠的潜力 预测最重要的大脑区域之一的收缩较少 - 前额叶皮层，因此表明 在衰老中，大脑与认知之间的关系是相互的，更好的认知能力可能 充当衰老的神经保护剂。此外，我们发现 血管和代谢风险以及对系统性炎症的倾向在促进与年龄有关的 大脑下降。在拟议的延续研究中，我们将继续收集在 该项目的成立将为我们提供检查与年龄相关变化的形状的机会 轨迹并测试非线性课程的可能性。同时，我们将扩大搜索的重点 对于认知衰老的机制，通过将注意力转移到两个在认知衰老中重要性的领域 在过去的十年中一直被血管生成：维持皮质下和皮质髓磷脂和保存 大脑能量代谢。我们将（这是第一次）在这两个领域中进行纵向评估 与继续引入的脑体积，白质微观结构的继续测量的结合 和铁的积累。我们将检验与大脑和认知暂时动态有关的假设 衰老并将检查脑能量代谢之间的滞后关系（假设为 神经认知衰老的主要煽动者），结构收缩和髓磷脂损失和铁的积累（ 结构变化的主要介体）。我们将研究大脑变化和年龄变化的相互作用 - 敏感的认知功能以及血管，代谢和炎症风险因素的调节作用 这些关系。我们希望理解基于正常认知的大脑机制 衰老会以必要的知识为武装，并将有助于制定旨在减轻年龄的干预措施 - 相关认知能力下降。最终，我们认为这项研究将有助于建立规范 理解阿尔茨海默氏病和其他痴呆症所需的基准。