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

摘要： 早期生活压力/逆境(ELS/ELA)与年龄相关疾病(如心脏代谢紊乱)之间的强烈联系 疾病，认知和精神/神经障碍，主要是基于回顾而建立的 人类报告。然而，跨生命周期的前瞻性、纵向研究对于确定糖尿病的生物标志物至关重要。 ELA风险嵌入在生活的早期，在中年期间制定早期干预策略。动物模型 由于寿命短(无脊椎动物、啮齿动物)，对人类衰老和 从这些模型开发的治疗方法在临床试验中失败了。纵向非人灵长类(NHP) 研究可以为ELA相关认知的早期生物学和神经标记物提供重要信息 由于他们的长寿和逐渐衰老相关的认知障碍和大脑病理相似而导致的衰退 对那些出现在中年的人类来说。这项建议建立在我们的数据基础上，将猕猴的ELA与 细胞老化加速的早期标志(DNA甲基化年龄加快，端粒长度缩短)， 炎症和神经认知改变，从婴儿期到成年期都可以检测到。我们的目标是使用 在NHP中进行前瞻性的纵向设计，以确定早期生物标志物/途径和潜在的机制 从青壮年到中年，ELA相关的加速神经老化轨迹和认知能力下降。 这一独特的成年雌性猕猴种群患有ELA(社会从属压力)，目前生活在 耶尔克斯国家灵长类动物研究中心的社会团体，从出生起就具有纵向特征 作为美国国立卫生研究院资助的研究的一部分。这些动物(高ELA：从属；低ELA：优势) 将在7岁(成年早期)到11岁(中年)之间进行纵向研究。Aim 1将检查 控制认知和压力/情绪的大脑区域中ELA加速神经老化的轨迹 在AIM 2中研究的功能(前额叶皮质-PFC-，海马-HIPP-，杏仁核)；它将使用(A)MRI，DTI 和静息状态功能磁共振检查髓鞘丢失、皮质变薄和失去远程连接；(B) 用磁共振波谱(N-乙酰天冬氨酸减少)和标记物检测神经病理 人类痴呆症(脑脊液中淀粉样蛋白β(Aβ42)/tau比率降低)；以及(C)神经炎症和 神经毒性(脑脊液中犬尿氨酸途径代谢物的水平)。目标2将测试ELA是否加速衰老- PFC-杏仁核回路(HPA轴，人类入侵者)介导的应激/情绪调节的相关缺陷 和点探测任务)和认知：注意(连续操作任务)、执行功能和认知 由PFC电路(传统/外部辨别)和空间关系调节的灵活性 由HIPP-PFC电路调节的记忆(空间记忆广度)。目标3将研究两者之间的关联 神经测量的纵向轨迹(目标1)和认知结果(目标2)；我们将使用创新 纵向统计方法开发个性化的风险和弹性轨迹生物标记物 超越关联，建立统计因果关系。假设ELA小组将会表现出 压力的早期生物标记物以及中年生物和神经认知老化的加速轨迹。

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.