Neural Mechanisms for Associations Between Fitness and Cognition in Aging

记忆功能下降不仅是健康老年人的常见症状。这也是一个主要的指标 阿尔茨海默病(AD)。载脂蛋白-E-epsilon4(apoE-ε4)等位基因是唯一被明确识别的 晚发性阿尔茨海默病的候选基因与认知功能减退和脑功能减退的早期发病年龄相关 萎缩。然而，ApoE-ε4等位基因遗传并不能完美地预测谁会患上AD，这表明 可改变的生活方式因素，如体力活动(PA)，以及代谢健康指标，如 心肺功能(CRF)可能会随着年龄的增长而影响认知轨迹。然而，目前还不清楚，如果 CRF在遗传风险增加的健康无症状老年人中修改神经网络完整性指数 对于AD。针对NOT-MH-21-175，我们将利用纵向高质量的功能、结构和 来自寿命人类连接组项目老化(HCP-Aging)数据集的扩散加权磁共振成像数据 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 两种研究慢性肾功能衰竭如何随年龄变化影响神经连通性和脑微结构的创新方法 确定CRF在老年人中提供神经保护的潜在神经机制。我们还将 测试以下假设：更大的CRF保护情节记忆性能、记忆网络连通性和 来自APOE-4等位基因有害影响的大脑微结构完整性。通过利用所有可用的 在HCP-Aging数据集中的功能数据(增加我们工作的再现性和影响)，我们将定义 海马皮层记忆系统内神经网络完整性指数已知降低 年龄和认知能力下降，包括网络隔离--一个比较网络内相关性的指数 网络之间的相关性；以及聚类系数-网络节点的邻居的分数 是彼此的邻居。我们还将利用高角分辨率扩散成像(HARDI)扩散- HCP提供的加权MRI方法，在组织学上更有意义，对 比传统的弥散张量成像更能显示组织的微结构和功能。我们将计算 灰质轴突密度指数与白质定向弥散指数的相关性研究 使用CRF。我们假设CRF将缓和与年龄相关的情景记忆、神经功能衰退的关系 网络连接性和轴突密度(以及与年龄相关的定向分散度增加) 随着年龄的增长，CRF会减弱这种减少。此外，我们假设高CRF将减弱合并的 载脂蛋白E-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携带者的结局。这个项目预计会产生很大的影响 通过使用来自HCP-Aging的高质量神经成像数据，并确定 慢性肾功能衰竭与老年人脑健康的关系。证实这些机制将使 健康老龄化和阿尔茨海默病遗传风险增加的循证实践和预防努力。

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.