Neural Mechanisms for Associations Between Fitness and Cognition in Aging

衰老过程中体能与认知之间关联的神经机制

• 批准号: 10913650
• 负责人: JEROME CARSON SMITH
• 金额: $ 64.25万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-29 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10913650
• 关键词: Adult; Adverse effects; Age; Age of Onset; Aging; Alleles; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease risk; Apolipoprotein E; Attenuated; Brain; Candidate Disease Gene; Clinical Trials; Cognition; Cognitive; Cross-Sectional Studies; Data; Data Set; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Elderly; Enrollment; Episodic memory; Evidence based practice; Functional Magnetic Resonance Imaging; Genetic Carriers; Genetic Risk; Health; Hippocampus; Histologic; Human; Impaired cognition; Late Onset Alzheimer Disease; Longevity; Magnetic Resonance Imaging; Measures; Mediator; Memory; Memory Loss; Metabolic; Methods; Neurites; Neurophysiology - biologic function; Outcome; Performance; Physical activity; Prevention; Publishing; Reproducibility; Resolution; Rest; Risk; Rodent; Role; Sample Size; Structure; System; Testing; Time; Tissues; Walking; Work; age related; apolipoprotein E-4; attenuation; brain health; candidate identification; cardiorespiratory fitness; cerebral atrophy; cognitive function; cognitive performance; cognitive testing; connectome; cost; density; diffusion weighted; executive function; fitness; gray matter; healthy aging; human data; imaging modality; improved; indexing; innovation; middle age; mild cognitive impairment; modifiable lifestyle factors; neural; neural network; neurogenesis; neuroimaging; neuromechanism; neuroprotection; novel marker; preservation; response; segregation; verbal; white matter; young adult

Declining memory function is not only a common complaint of healthy aging adults. It is also a primary indicator of Alzheimer's disease (AD). The apolipoprotein-E epsilon4 (APOE-ε4) allele is the only clearly identified candidate gene for late-onset AD and is associated with an earlier age of onset of cognitive decline and brain atrophy. Nevertheless, APOE-ε4 allele inheritance is an imperfect predictor of who will develop AD, suggesting that modifiable lifestyle factors such as Physical Activity (PA), and metabolic health indicators such as Cardiorespiratory Fitness (CRF), might influence cognitive trajectory with age. It is not yet known, however, if CRF modifies indices of neural network integrity in healthy asymptomatic older adults at increased genetic risk for AD. In response to NOT-MH-21-175, we will utilize the longitudinal high-quality functional, structural, and diffusion-weighted MR imaging data from the Lifespan Human Connectome Project Aging (HCP-Aging) dataset to determine the moderating role of CRF on cognitive function and human brain network integrity. We will use two innovative approaches to examine how CRF impacts neural connectivity and brain microstructure with age to determine potential neural mechanisms whereby CRF provides neuroprotection in older adults. We will also test the hypothesis that greater CRF protects episodic memory performance, memory network connectivity, and brain microstructural integrity from the harmful impacts of the APOE-4 allele. By leveraging all available functional data in the HCP-Aging dataset (increasing the reproducibility and impact of our work), we will define indices of neural network integrity within the hippocampal cortical memory system that are known to decrease with age and cognitive decline, including network segregation – an index of within-network correlations compared to between-network correlations; and the clustering coefficient - the fraction of a network node's neighbors that are neighbors to each other. We will also utilize the high angular resolution diffusion imaging (HARDI) diffusion- weighted MRI methods provided by the HCP, which are more histologically meaningful and sensitive to underlying tissue microstructure and function than traditional diffusion tensor imaging. We will calculate the Neurite Density Index in gray matter and the Orientation Dispersion Index in white matter to examine associations with CRF. We hypothesize CRF will moderate the relationship of age-related decline in episodic memory, neural network connectivity, and neurite density (and age-related increases in orientation dispersion) such that High CRF will attenuate the reduction with age. Moreover, we hypothesize that High CRF will attenuate the combined impact of the APOE-4 allele and age on the cognitive, network connectivity, and microstructural integrity outcomes in High CRF versus Low CRF ε4-carriers over time. This project is expected to have a high impact through the use of high-quality neuroimaging data from the HCP-Aging, and the determination of mediators of the association between CRF and brain health in older adults. Substantiating these mechanisms will inform evidence-based practice and prevention efforts in healthy aging and those at increased genetic risk for AD.

记忆功能下降不仅是健康老龄化成年人的常见抱怨。它也是主要指标 阿尔茨海默氏病（AD）。载脂蛋白-e epsilon4（apoE-ε4）等位基因是唯一清晰鉴定的 候选候选基因晚期AD，与认知能力下降和大脑发作的早期有关 萎缩。然而，apoe-ε4等位基因继承是谁将开发AD的不完美预测指标，暗示 可修改的生活方式因素，例如体育活动（PA）和代谢健康指标，例如 心肺健康（CRF）可能会随着年龄的增长而影响认知轨迹。但是，尚不知道 CRF修改了健康无症状老年人的神经网络完整性的指标，遗传风险增加 对于广告。为了响应非MH-21-175，我们将利用纵向高质量的功能，结构和 从寿命人类连接项目老化（HCP-Aging）数据集的扩散加权MR成像数据 确定CRF对认知功能和人脑网络完整性的调节作用。我们将使用 两种创新的方法来研究CRF如何随着年龄的增长而影响神经元连通性和脑微观结构 为了确定潜在的神经力学，CRF在老年人中提供神经保护作用。我们也会 检验以下假设，即更大的CRF保护情节内存性能，内存网络连接和 大脑微结构完整性来自APOE-4等位基因的有害影响。通过利用所有可用的 HCP-AGGEG数据集中的功能数据（增加了工作的可重复性和影响），我们将定义 海马皮质记忆系统中神经网络完整性的指标，已知会下降 随着年龄和认知能力的下降，包括网络隔离 - 网络内相关性的指数比较 到网络之间的相关性；和聚类系数 - 网络节点的邻居的分数 我们还将利用高角度分辨率扩散成像（HARDI）扩散 - HCP提供的加权MRI方法在组织学上更有意义且敏感 与传统的扩散张量成像相比，基础组织微结构和功能。我们将计算 灰质中的神经突密度指数和白质中的方向分散指数检查关联 与CRF。我们假设CRF将调节情节记忆中与年龄相关的年龄下降，中性 网络连通性和神经蛋白密度（以及与年龄相关的方向分散体增加），使得高 CRF会随着年龄的增长而减少减少。此外，我们假设高CRF会衰减合并 APOE-4等位基因和年龄对认知，网络连通性和微结构完整性的影响 随着时间的推移，高CRF与低CRFε4接机的结果。预计该项目将产生很大的影响 通过使用HCP衰老的高质量神经影像学数据，并确定 老年人CRF与大脑健康之间的关联。证实这些机制将告知 循证实践和预防健康衰老的努力以及AD遗传风险增加的工作。