Early risk factors of accelerated neural aging trajectories and cognitive decline: a nonhuman primate longitudinal model

加速神经老化轨迹和认知能力下降的早期危险因素：非人类灵长类动物纵向模型

• 批准号: 10458748
• 负责人: MARIA C ALVARADO
• 金额: $ 117.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458748
• 关键词: 11 year old; Acids; Adult; Age; Age-Years; Aging; Amygdaloid structure; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animal Model; Animals; Attention; Biological; Biological Aging; Biological Markers; Birth; Brain; Brain Pathology; Brain region; Caenorhabditis elegans; Cardiometabolic Disease; Cell Aging; Clinical Trials; Cognition; Cognition Disorders; Cognitive; DNA Methylation; Data; Dementia; Development; Discrimination; Disease; Early Intervention; Elderly; Emotional Stress; Epigenetic Process; Etiology; Female; Functional Magnetic Resonance Imaging; Funding; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Inflammation; Intervention; Invertebrates; Kynurenine; Length; Life; Link; Longevity; Longitudinal Studies; Macaca; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Memory; Mental disorders; Methods; Modeling; Myelin; N-acetylaspartate; Neurocognitive; Outcome; Pathway interactions; Population; Predictive Factor; Prefrontal Cortex; Primates; Puberty; Quinolinic Acid; Reporting; Research; Rest; Risk; Risk Factors; Rodent; Statistical Methods; Statistical Models; Stress; Stress Tests; Synapses; Task Performances; Telomere Shortening; Testing; Therapeutic; Thinness; Time; United States National Institutes of Health; Woman; acute stress; age related; age related cognitive disorder; base; cognitive control; cognitive function; cohort; early detection biomarkers; early life stress; emerging adult; emotion dysregulation; emotion regulation; emotional functioning; executive function; flexibility; functional outcomes; healthy aging; hypothalamic-pituitary-adrenal axis; infancy; innovation; interest; longitudinal design; mathematical methods; men; middle age; negative affect; nervous system disorder; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; nonhuman primate; novel; prospective; relating to nervous system; relational memory; resilience; social; social group; spatial memory; statistics; tau Proteins; young adult

Abstract: A strong link between early life stress/adversity (ELS/ELA) and age-related disorders, such as cardiometabolic disease, cognitive and psychiatric/neurological disorders, have been established mostly based on retrospective human reports. Yet, prospective, longitudinal, studies across the life span are critical to identify biomarkers of ELA risk embedded earlier in life, during middle age to develop early intervention strategies. Animal models with short life spans (invertebrates, rodents) have significant limitations to inform about human aging and the therapeutics developed from those models have failed in clinical trials. Longitudinal nonhuman primate (NHP) studies could provide significant information on early biological and neural markers of ELA-related cognitive decline due to their long life span and gradual aging-related cognitive impairments and brain pathology similar to those in humans emerging in middle age. This proposal builds on our data linking ELA in macaques with early markers of accelerated cellular aging (accelerated DNA methylation age, shortened telomere length), inflammation, and neurocognitive alterations detectable from infancy to young adulthood. The goal is to use a prospective, longitudinal design in NHPs to identify early biomarkers/pathways and underlying mechanisms of ELA-related accelerated neural aging trajectories and cognitive decline from young adulthood to middle age. This unique population of adult female macaques with ELA (social subordination stress) are currently living in social groups at the Yerkes National Primate Research Center and were longitudinally characterized from birth through puberty as part of NIH-funded studies. These animals (High-ELA: subordinates; low-ELA: dominant) will be studied longitudinally between 7(early adulthood) and 11 (middle age) years of age. Aim 1 will examine trajectories of ELA-accelerated neural aging in brain regions that control cognitive and stress/emotional functions studied in Aim 2 (prefrontal cortex -PFC-, hippocampus -HIPP-, amygdala); it will use (a) MRI, DTI and resting state fMRI to examine myelin loss, cortical thinning and loss of long-range connectivity; (b) measures of neuropathology with MR spectroscopy (reductions in N-Acetylaspartate) and markers preceding dementia in humans (reduced amyloid β(Aβ42)/tau ratio in CSF); and (c) markers of neuroinflammation and neurotoxicity (CSF levels of kynurenine pathway metabolites). Aim 2 will test whether ELA accelerates age- related deficits in stress/emotional regulation mediated by PFC-amygdala circuits (HPA axis, Human Intruder and dot-probe tasks), and cognition: attention (continuous performance task), executive function and cognitive flexibility mediated by PFC circuits (Intradimensional/Extradimensional discrimination), and spatial relational memory mediated by HIPP-PFC circuits (spatial memory span). Aim 3 will examine associations between longitudinal trajectories of neural measures (Aim 1) and cognitive outcomes (Aim 2); we will use innovative longitudinal statistical approaches developing individualized trajectory biomarkers of risk and resilience that move beyond association to establishing statistical causation. The hypothesis is that the ELA group will show early biomarkers of stress and accelerated trajectories of biological and neurocognitive aging in middle age.

抽象的： 早期生活压力/逆境 (ELS/ELA) 与年龄相关疾病（例如心脏代谢疾病）之间存在密切联系 疾病、认知和精神/神经系统疾病，主要是基于回顾性研究确定的 人类报告。然而，跨生命周期的前瞻性、纵向研究对于识别生物标志物至关重要。 ELA 风险在生命早期、中年时期就已存在，以制定早期干预策略。动物模型 寿命短的动物（无脊椎动物、啮齿动物）在了解人类衰老和 从这些模型开发的疗法在临床试验中失败了。纵向非人灵长类动物 (NHP) 研究可以提供有关 ELA 相关认知的早期生物和神经标记的重要信息 由于寿命长而逐渐衰退，与衰老相关的认知障碍和大脑病理学相似 到中年时期的人类。该提案建立在我们将猕猴中的 ELA 与 加速细胞衰老的早期标志（加速 DNA 甲基化年龄、缩短端粒长度）， 从婴儿期到成年早期均可检测到炎症和神经认知改变。目标是使用一个 NHP 的前瞻性、纵向设计，以确定早期生物标志物/途径和潜在机制 ELA 相关的加速神经老化轨迹和从青年期到中年的认知能力下降。 这个独特的成年雌性猕猴群体目前生活在 ELA（社会从属压力）中。 耶克斯国家灵长类研究中心的社会群体从出生起就被纵向描述 作为 NIH 资助研究的一部分，贯穿青春期。这些动物（高 ELA：从属；低 ELA：主导） 将在 7 岁（成年早期）和 11 岁（中年）之间进行纵向研究。目标 1 将检查 ELA 加速控制认知和压力/情绪的大脑区域神经老化的轨迹 目标 2 中研究的功能（前额皮质 -PFC-、海马体 -HIPP-、杏仁核）；它将使用 (a) MRI、DTI 静息态功能磁共振成像检查髓磷脂损失、皮质变薄和远程连接丧失； (二) 使用 MR 波谱（N-乙酰天冬氨酸减少）和标记物进行神经病理学测量 人类痴呆（脑脊液中淀粉样蛋白 β(Aβ42)/tau 比率降低）； (c) 神经炎症标志物和 神经毒性（犬尿氨酸途径代谢物的脑脊液水平）。目标2将测试ELA是否会加速衰老—— PFC-杏仁核回路（HPA 轴、人类入侵者）介导的压力/情绪调节相关缺陷 和点探测任务）和认知：注意力（持续执行任务）、执行功能和认知 由 PFC 电路（维度内/维度区分）和空间关系介导的灵活性 由 HIPP-PFC 电路介导的记忆（空间记忆广度）。目标 3 将检查之间的关联 神经测量（目标 1）和认知结果（目标 2）的纵向轨迹；我们将用创新的 纵向统计方法开发风险和复原力的个性化轨迹生物标志物 超越关联来建立统计因果关系。假设 ELA 小组将显示 压力的早期生物标志物以及中年生物和神经认知衰老的加速轨迹。