NEURAL PHENOTYPES OF RESISTANCE AND RESILIENCY TO AD AND ADRD IN THE OLDEST OF THE OLD

最古老的老年人对 AD 和 ADRD 的抵抗和恢复的神经表型

• 批准号: 10283071
• 负责人: DAVID H SALAT
• 金额: $ 11.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10283071
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-42; Atrophic; Autopsy; Biological; Biological Markers; Blood Vessels; Brain; Brain Pathology; Centenarian; Cerebrovascular Circulation; Cerebrovascular Physiology; Clinical; Cognition; Cognitive; Cognitive aging; Dementia; Development; Diffusion; Disease; Education; Elderly; Exhibits; Frequencies; Future; Genetic Risk; Health; Hippocampus (Brain); Human; Hypertension; Image; Impaired cognition; Impairment; Incidence; Individual; Infrastructure; Lesion; Life; Life Style; Light; Longevity; Measures; Memory; Menopause; Mental Depression; Nerve Degeneration; Obesity; Organ; Parietal; Pathology; Pattern; Performance; Phenotype; Physical activity; Physiology; Plasma; Population; Prevalence; Reading; Research; Resistance; Risk; Risk Factors; Sampling; Social Network; Socioeconomic Status; Sociology; Structure; Survivors; Symptoms; Time; Underrepresented Populations; Vasomotor; Work; aged; allostatic load; base; cerebrovascular health; cognitive ability; cognitive function; cognitive performance; cohort; connectome; density; entorhinal cortex; hippocampal atrophy; human old age (65+); indexing; insight; middle age; neurochemistry; neurofilament; neuroimaging; neuromechanism; non-demented; preservation; protective factors; relating to nervous system; resilience; segregation; skills; sleep quality; social health determinants; socioeconomics; tau Proteins; tau-1; white matter; young adult

ABSTRACT FOR PROJECT 4 Prior work has described several factors that confer vulnerability for or protection against risk for the development of Alzheimer's disease (AD) and related disorders (ADRD), including demographic and social determinants of health, (e.g., socioeconomic status and education quality/skill), systemic and organ health (including conditions beginning at midlife, e.g. hypertension and obesity; examined in Project 1), lifestyle and wellness factors (e.g. physical activity and sleep quality; examined in Project 2), manifestations of menopause (e.g. vasomotor symptoms; examined in Project 3), as well as psychiatric (e.g. depression), and sociological (e.g. social network density) domains1. Some factors begin to influence risk for ADRD early in young adulthood and mid-life and promote cognitive impairment in relatively early old age. Thus, older adults vary greatly in function, with certain `unsuccessful' individuals exhibiting a reduction of cognitive abilities earlier in life. These individuals are in stark contrast to individuals in the latest decades of life who harbor cognitive risk factors but have successfully resisted pathology or exhibit resilience against cognitive impairment when pathology is present. Findings from the large autopsy cohort in the Rush Memory Aging Project demonstrated frequent discordance between cognition and pathology and noted the need to examine mechanisms of cognitive resilience2. Here, we aim to elucidate factors related to `successful aging' (minimal brain pathology and optimal cognition) in the latest stages of life. Studies have identified neural factors that contribute to relatively preserved functioning in the very-old3,4. In cohorts with AD pathology, high performing individuals have relatively larger hippocampal volumes than lower performing individuals5. This preservation in brain structure may confer cognitive resilience in certain individuals. We and others have found that vascular lesions modulate the level of AD pathology necessary for a given level of clinical impairment6,7 and that vascular lesion burden is associated with hippocampal atrophy8. It is therefore possible that superior vascular health (i.e., preserved vascular physiology and low vascular lesion burden) protects against impairment from early AD pathology. In the proposed work, we will examine the impact of advanced aging on structural and functional brain connectivity, neurochemistry, and cognitive abilities in groups stratified by cognitive performance (high/typical performance on a cognitive composite index), and cognitive risk (high/typical based on known risk factors; `allostatic load'). Aim 1. To determine patterns of brain connectivity and neurochemistry that confer superior cognitive performance in very-old (80+) adults. Aim 2. To determine associations among cerebrovascular health, connectivity, performance and lifespan risk and protective factors. Aim 3. To further define superior performance in the very-old based on patterns of `resistance' against the development of pathology (amyloid, tau, and neurodegeneration `A-T-N'; indexed via plasma amyloid β 42/40, p-tau, NfL, and hippocampal atrophy), or cognitive `resilience' in the face of existing pathologies. Successful completion of this work would uncover neural mechanisms associated with intact cognition in advanced aging.

项目4摘要 先前的工作描述了几个因素，赋予脆弱性或保护免受风险的发展 阿尔茨海默病（AD）和相关疾病（ADRD），包括人口统计学和社会决定因素， 健康，（例如，社会经济地位和教育质量/技能）、全身和器官健康（包括条件 从中年开始，例如高血压和肥胖;在项目1中进行了研究），生活方式和健康因素（例如， 体力活动和睡眠质量;在项目2中检查），更年期的表现（如血管痉挛 症状;在项目3中检查），以及精神病学（例如抑郁症）和社会学（例如社交网络 密度）领域1.一些因素开始影响ADRD的风险在青年和中年早期， 在相对较早的老年时期促进认知障碍。因此，老年人在功能上差异很大， “不成功”的人在生命早期表现出认知能力下降。这些人在斯塔克 与最近几十年生活中具有认知风险因素但成功抵制的人形成对比 病理或表现出对认知障碍的恢复力时，病理存在。大型调查结果 拉什记忆老化项目中的尸检队列表明，认知和 病理学，并指出需要检查认知能力的机制2。在这里，我们旨在阐明因素 与生命最后阶段的“成功衰老”（最小的大脑病理和最佳认知）相关。 研究已经确定了有助于老年人相对保留功能的神经因素3，4。在 与AD病理学队列相比，高表现个体的海马体积相对较大， 表演者5.这种大脑结构的保存可能会赋予某些个体认知弹性。 我们和其他人已经发现，血管病变调节AD病理学水平所需的给定水平 临床损伤的6，7和血管病变负荷与海马萎缩相关8。因此 可能的是上级血管健康（即，保留血管生理学和低血管病变负荷） 保护免受早期AD病理损害。在拟议的工作中，我们将研究 老龄化对大脑结构和功能连接、神经化学和认知能力的影响 按认知表现（认知综合指数的高/典型表现）和认知风险分层 (high/基于已知风险因素的典型;“非稳态负荷”）。目标1。为了确定大脑连接的模式 和神经化学，赋予非常老（80岁以上）的成年人上级认知能力。目标2.以确定 脑血管健康、连通性、性能和寿命风险与保护因素之间的关联。 目标3.为了进一步确定基于“抵抗”模式的老龄化的上级表现， 病理学的发展（淀粉样蛋白、tau和神经变性“A-T-N”;通过血浆淀粉样蛋白β 42/40， p-tau、NfL和海马萎缩），或面对现有病理的认知“恢复力”。成功 这项工作的完成将揭示与晚期衰老中完整认知相关的神经机制。