Identifying ADRD intervention targets by characterizing neurobiological mechanisms of social isolation, loneliness, and social environment using novel imaging, molecular markers, and machine learning

使用新颖的成像、分子标记和机器学习来表征社会孤立、孤独和社会环境的神经生物学机制，从而确定 ADRD 干预目标

• 批准号: 10525514
• 负责人: Hugo Javier Aparicio
• 金额: $ 69.65万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525514
• 关键词: Address; Adult; Age; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anatomy; Automated Indexing; Biological; Biological Markers; Biological Process; Biology; Blinded; Blood; Brain; Brain imaging; COVID-19 pandemic; Censuses; Clinical; Clinical Trials; Cognitive; Cohort Studies; Communities; Complement; Computer Analysis; Computer Vision Systems; Computing Methodologies; Data; Data Set; Dementia; Dimensions; Enrollment; Funding; Future; Generations; Genetic; Genetic Risk; Health; Health Resources; Health behavior; Human; Image; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory; Information Networks; Intervention; Intervention Studies; Intervention Trial; Link; Loneliness; Long-Term Effects; Longevity; Machine Learning; Magnetic Resonance Imaging; Measures; Methods; Molecular; Molecular Profiling; Multiomic Data; Nerve Degeneration; Neurocognitive; Neuronal Plasticity; Neuropsychology; Participant; Pathway interactions; Pattern; Perfusion; Plant Roots; Population Study; Positron-Emission Tomography; Prevalence; Prevention; Process; Proteomics; Psychosocial Factor; Public Health; Research; Research Priority; Resources; Risk; Role; Social Environment; Social Network; Social isolation; Socioeconomic Factors; Stress; Structure; Time; Translating; Treatment/Psychosocial Effects; United States National Institutes of Health; Validation; Vascular Diseases; Vision; Work; aging brain; amyloid imaging; base; brain health; cognitive function; cohort; cytotoxic; data sharing; database of Genotypes and Phenotypes; dementia risk; ethnic diversity; follow-up; health equity; imaging biomarker; indexing; innovation; interest; machine learning method; method development; molecular marker; multi-ethnic; multiple omics; neurobiological mechanism; novel; open data; population health; pre-clinical; programs; psychosocial; public health relevance; racial and ethnic; racial diversity; repaired; resilience; response; social; social relationships; socioeconomic disparity; socioeconomics; tau Proteins; trend

PROJECT SUMMARY Social isolation, loneliness, and social environment continue to emerge as important factors in Alzheimer’s disease and related dementias (ADRD), more so with the COVID-19 pandemic and observed trends in the prevalence of social isolation, loneliness, and ADRD. Although there is increasing recognition these factors can impact the aging brain, represent early expression of ADRD neuropathological changes, and influence health behaviors and resource access, less is known about the biological mechanisms involved. Our overarching hypothesis is that social isolation, loneliness, and social environment are distinct factors that alter brain biology and influence trajectories of healthy neurocognitive aging and ADRD vulnerability. Because understanding causal pathways and the cumulative role of these critical psychosocial factors through decades-long human experimental trials is infeasible, here we propose a unique and innovative approach to comprehensively assess these psychosocial determinants and temporally relate them to dynamic profiles of ADRD vulnerability, leveraging one of the largest biologically well-characterized community-based cohorts in the US, the Framingham Study (FS). Since 1948, FS has enrolled 3 generations of participants (ages 20-50) and 2 multi- ethnic cohorts, examined them regularly for cognitive decline and dementia, and collected an exquisite array of in-depth and cutting-edge “multi-omic”, imaging, and other data over their lifespan and before clinical ADRD onset. The FS has a 70-year legacy of unique contributions to public health, and will continue make breakthroughs in ADRD through its Brain Aging Program (3U19AG068753-02S1). We seek to leverage these resources through the following specific aims: AIM 1 is to examine and explain associations of social isolation, loneliness, and social network structure with ADRD vulnerability over a lifetime. Our prior work in FS suggests a molecular pathway related to neural plasticity/repair and cognitive resilience might be involved in these mechanisms. We will collect a new wave of data on these factors—partially harmonized with the NIH Toolbox and integrate this data with relevant psychosocial information at multiple previous exams. AIM 2 is to identify and validate these biological pathways using causal inference analyses and machine-learning methods on the extensive multi-omics data available. AIM 3 is to characterize social environment’s cumulative role in psychosocial mechanisms of ADRD risk across the adult lifespan by developing a latent social environment index with a validated geocode-based method and conducting sophisticated analyses. We will validate our findings with other multi-ethnic cohort datasets and share all data through dbGaP and bioLINCC. We expect to meaningfully evaluate whether and how these psychosocial factors influence the biology of healthy neurocognitive aging and ADRD vulnerability and identify new pathways that may serve as targets for intervention in the preclinical stage of ADRD. This will advance our understanding of the long-term effects of psychosocial determinants, ADRD prevention, and how to address the root causes of disparities in ADRD.

项目总结 社交孤立、孤独和社交环境继续成为阿尔茨海默氏症的重要因素 疾病及相关痴呆症(ADRD)，新冠肺炎大流行和观察到的 普遍存在社会孤立、孤独和ADRD。尽管越来越多的人认识到这些因素可以 冲击老化的大脑，表现为ADRD神经病变的早期表现，影响健康 在行为和资源获取方面，人们对所涉及的生物学机制知之甚少。我们最重要的是 假设社交孤立、孤独和社会环境是改变大脑生物学的不同因素。 并影响健康的神经认知老化和ADRD脆弱性的轨迹。因为理解 因果路径和这些关键心理社会因素在人类数十年中的累积作用 实验试验是不可行的，在这里我们提出了一种独特的创新方法来全面评估 这些心理社会决定因素并在时间上将它们与ADRD脆弱性的动态概况相关联， 利用美国最大的生物特征良好的社区队列之一， 弗雷明汉研究(FS)。自1948年以来，FS已招募了3代参与者(20-50岁)和2名多代参与者 他们定期检查他们的认知能力下降和痴呆症，并收集了一系列精美的 在生命周期和临床ADRD之前的深度和尖端的“多组学”、成像和其他数据 开始了。财政司司长在公共卫生方面有70年的独特贡献，并将继续致力于 ADRD通过其大脑老化计划(3U19AG068753-02S1)取得的突破。我们寻求利用这些 通过以下具体目标提供资源：目标1是审查和解释 与世隔绝、孤独和具有终生ADRD脆弱性的社交网络结构。我们之前的工作 在FS中，可能涉及一条与神经可塑性/修复和认知弹性相关的分子途径 在这些机制中。我们将收集关于这些因素的新一波数据-部分与NIH协调 工具箱，并将这些数据与之前多项检查中的相关心理社会信息进行整合。目标2是 使用因果推理分析和机器学习来识别和验证这些生物通路 方法对现有的广泛的多组学数据进行分析。目标3是描述社会环境的特征 通过形成潜伏期，在成人一生中ADRD风险的心理社会机制中的累积作用 使用经过验证的基于地理编码的方法编制社会环境指数，并进行复杂的分析。我们 将使用其他多种族队列数据集验证我们的发现，并通过DBGaP和BioLINCC共享所有数据。 我们期望有意义地评估这些心理社会因素是否以及如何影响健康的生物学。 神经认知老化和ADRD脆弱性，并确定可能作为靶点的新途径 ADRD临床前阶段的干预。这将使我们更好地理解 心理社会决定因素、ADRD预防，以及如何解决ADRD差异的根本原因。