Mechanisms of Risk and Resilience to Age-Related Cognitive Decline: A 60-Year Prospective Prenatal Cohort

与年龄相关的认知衰退的风险和恢复力机制：60 年预期产前队列

基本信息

批准号：
10063316
负责人：
STEPHEN L BUKA
金额：
$ 104.98万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10063316
关键词：
7 year old Address Adolescence Adult Affect Age Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid beta-42 Amyloid beta-Protein Anatomy Apolipoprotein E Birth Brain Brain Pathology Child Childhood Clinical Cognition Cognitive Cognitive aging Cohort Studies Data Collection Development Economic Burden Economics Education Elderly Equilibrium Etiology Failure Family Functional Magnetic Resonance Imaging Genotype Health Status Healthcare Systems Impaired cognition Incidence Income Individual Individual Differences Investigation Lead Life Life Experience Link Longevity Longitudinal cohort Measures Neurocognitive Neuropsychology Occupational Onset of illness Outcome Participant Pathology Pathway interactions Pattern Perinatal Phase Physical activity Plasma Population Pregnancy Prevention strategy Race Research Risk Saliva Sampling Studies Social Behavior Structure System Therapeutic Time age related childhood adversity cognitive ability cognitive control cognitive function cognitive neuroscience cognitive testing cohort early childhood effective therapy ethnic diversity indexing insight lifestyle factors member middle age neural network neuroimaging novel novel strategies pre-clinical prenatal prevent programs prospective racial and ethnic resilience social

项目摘要

PROJECT SUMMARY/ABSTRACT The failure to find any effective treatment for Alzheimer’s disease (AD) despite over four decades of research underscores the critical need for new strategies to prevent or delay disease onset. The proposed investigation aims to examine mechanisms of risk and resilience to age-related cognitive decline by leveraging recent advances in cognitive neuroscience and a unique 60-year longitudinal prenatal cohort. The concept of reserve has been developed to account for the large individual differences in cognitive aging trajectories, with nascent understanding of potential modifiable determinants of reserve. However, fundamental questions remain regarding, for instance, the impact of education, cognitively stimulating activities in adulthood, or early childhood enrichment on reserve mechanisms and cognitive decline. Previous investigations have been hampered by a number of limitations, including the lack of: 1) prospective measures of early childhood cognition, needed to address critical issues of reverse causation plaguing this field; 2) indices of adult cognitive decline over a large time window; 3) measures of relevant sociobehavioral factors across the entire lifespan; and 4) economic and racial/ethnic diversity of study samples. This proposal addresses these limitations by extending our continued study of the Providence RI cohort of the US Collaborative Perinatal Project (CPP). The original CPP involved systematic data collection from pregnancy through age 7 years, including measures of three key early life factors thought to influence cognitive trajectories in later life: early childhood IQ, family SES, and childhood adversity. We conducted a comprehensive cognitive assessment of 720 members of this cohort at age 35. We propose to reassess these participants (now approaching age 60) with a detailed neuropsychological battery to examine cognitive decline over a 25-year period. We will also assess engagement in cognitively stimulating activities, physical activity, occupational complexity, income, and health status. Participants will provide biosamples for plasma beta-amyloid (Aβ) 42/40 ratio and apolipoprotein E (APOE) genotype, and will undergo structural and functional MRI, providing operationally-defined brain measures of reserve. Finally, we propose a novel conceptual framework linking lifespan factors to cognitive outcomes through distinct brain mechanisms. This framework drives our aims which are: (1) Determine the relative influence of educational attainment, early life, and adult lifestyle factors on cognitive level and decline in late middle-aged adults; (2) Determine the relative contributions of specific brain reserve mechanisms to cognitive decline; and (3) Identify major determinants of brain reserve mechanisms in later life. A projected doubling of the elderly population by 2050 will place tremendous AD-related burden on the U.S. healthcare system. By providing novel insights into mechanisms of risk and resilience, findings may lead to new strategies to significantly reduce this burden by delaying cognitive decline and the onset of Alzheimer’s Disease.

项目概要/摘要尽管经过四十多年的研究，仍未找到治疗阿尔茨海默病（AD）的任何有效方法研究强调迫切需要新的策略来预防或延缓疾病的发生。调查旨在通过以下方式研究与年龄相关的认知能力下降的风险和恢复力机制：利用认知神经科学的最新进展和独特的 60 年纵向产前队列。储备概念的提出是为了解释认知老化的巨大个体差异然而，对潜在的可改变的储备决定因素的了解刚刚起步。基本问题仍然存在，例如，教育的影响、认知刺激成年期或幼儿期的活动丰富了储备机制和认知能力下降的情况。以前的调查受到许多限制的阻碍，包括缺乏：1) 早期儿童认知的前瞻性测量，需要解决反向因果关系的关键问题困扰这一领域的问题；2) 成人认知能力在较长时间内下降的指数；3) 相关措施；整个生命周期的社会行为因素；4) 学习的经济和种族/民族多样性该提案通过扩展我们对普罗维登斯 RI 的持续研究来解决这些限制。美国围产期合作项目 (CPP) 的队列最初的 CPP 涉及系统数据收集。从怀孕到 7 岁，包括对被认为影响的三个关键的早期生命因素的测量晚年的认知轨迹：幼儿期智商、家庭社会经济地位和童年逆境。对这个队列中 720 名 35 岁成员进行的全面认知评估。我们建议重新评估这些参与者（现已接近 60 岁）需要进行详细的神经心理学研究我们还将评估 25 年内认知能力下降的情况。体力活动、职业复杂性、收入和健康状况参与者将提供生物样本。用于血浆 β-淀粉样蛋白 (Aβ) 42/40 比率和载脂蛋白 E (APOE) 基因型，并将进行结构分析和功能性 MRI，提供可操作定义的大脑储备测量。通过不同的大脑机制将寿命因素与认知结果联系起来的概念框架。该框架推动我们的目标是：（1）确定教育程度的相对影响， (2) 确定早期生活和成年生活方式因素对中年晚期认知水平和衰退的影响；特定大脑储备机制对认知能力下降的相对贡献；以及 (3) 确定主要因素晚年大脑储备机制的决定因素预计老年人口将增加一倍。到 2050 年，美国医疗保健系统将面临与 AD 相关的巨大负担。深入研究风险和复原力的机制，研究结果可能会导致新的策略来显着减少这种情况通过延缓认知能力下降和阿尔茨海默病的发作来减轻负担。