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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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年人的常见症状，也是一个主要指标。载脂蛋白-E epsilon4 (APOE-ε4) 等位基因是唯一明确确定的阿尔茨海默病 (AD) 的致病基因。迟发性 AD 的候选基因，与认知能力下降和大脑的较早发病年龄相关然而，APOE-ε4 等位基因遗传并不能完美地预测谁会患上 AD。可改变的生活方式因素，如体力活动 (PA) 和代谢健康指标，如心肺健康（CRF）可能会随着年龄的增长而影响认知轨迹，但目前尚不清楚。 CRF 改变遗传风险增加的健康无症状老年人的神经网络完整性指数对于 AD，为了响应 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 MR 成像数据为了确定 CRF 对认知功能和人脑网络完整性的调节作用，我们将使用。两种创新方法来研究 CRF 如何随年龄影响神经连接和大脑微结构我们还将确定 CRF 为老年人提供神经保护的潜在神经机制。检验更大的 CRF 可以保护情景记忆性能、记忆网络连接性的假设，以及通过利用所有可用的方法，保护大脑微结构的完整性，免受 APOE-4 等位基因的有害影响。 HCP-Aging 数据集中的功能数据（提高我们工作的可重复性和影响力），我们将定义海马皮层记忆系统内的神经网络完整性指数已知会降低随着年龄和认知能力的下降，包括网络隔离——网络内相关性比较的指数网络间相关性；以及聚类系数 - 网络节点的邻居的分数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且对与传统的扩散张量成像相比，我们将计算底层组织的微观结构和功能。灰质中的神经突密度指数和白质中的方向分散指数来检查关联我们勇敢地认为 CRF 会缓和与年龄相关的情景记忆、神经衰退的关系。网络连接性和神经突密度（以及与年龄相关的方向分散度增加）使得高 CRF 会随着年龄的增长而减弱。此外，我们发现高 CRF 会减弱组合的效果。 APOE-4 等位基因和年龄对认知、网络连接和微观结构完整性的影响随着时间的推移，高 CRF 与低 CRF ε4 载体的结果预计将产生巨大影响。通过使用来自 HCP-Aging 的高质量神经影像数据，以及确定证实 CRF 与老年人大脑健康之间的关联将为我们提供信息。针对健康老龄化和 AD 遗传风险增加人群的循证实践和预防工作。