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: 10615795
• 负责人: MARIA C ALVARADO
• 金额: $ 115.71万
• 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/10615795
• 关键词: 11 year old; Acceleration; 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; Dimensions; Discrimination; Disease; Early Intervention; Early identification; Elderly; Epigenetic Process; Etiology; Female; Functional Magnetic Resonance Imaging; Funding; Goals; Health; Hippocampus; 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; biomarker identification; 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; longitudinal, prospective study; mathematical methods; men; middle age; negative affect; nervous system disorder; neural; neuroinflammation; neuropathology; neuroprotection; neurotoxic; neurotoxicity; nonhuman primate; novel; prospective; 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.

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