Longitudinal Neurometabolic Outcomes of Traumatic Stress-Related Accelerated Cellular Aging

与年龄有关的疾病的早期发病，如心脏代谢紊乱、炎症综合征和 神经退行性疾病，造成巨大的个人、经济和社会损失，并导致缩短 健康寿命和寿命。创伤应激(创伤相关精神症状)和遗传因素增加 生物衰老潜在步伐加快的风险，如外周变化所示 DNA甲基化模式(例如，“表观遗传年龄”的估计)、炎症增加和代谢 病理学。这些过程的改变可能对随后的大脑健康具有预测价值。的目标是 该项目旨在研究外周创伤应激相关的加速衰老作为早期预测因子。 随着时间的推移，大脑的神经化学和神经认知能力的变化。这项研究还将 检查可能加剧这些关联的遗传因素。该项目将建立在两波 现有数据，包括基因分型、心理和神经心理评估，并储存 血浆样本，招募160名中晚期/老年早期参与者(他们都有创伤 暴露和创伤应激症状)返回进行第三次评估，即基线后5-15年。 参与者将接受尖端磁共振波谱检查，以评估前额叶的变化 神经代谢物(包括与神经炎症和神经元活性有关的物质，如肌醇 和N-乙酰天冬氨酸)，并检查神经认知表现，包括评估 轻度认知障碍。储存了最初两个时间点的DNA和血浆样本，以及新的 第三个时间点的外周样本将用于检查预测后续大脑的生物标记物 健康。这项研究将获得炎症(例如细胞因子)和神经病理(例如淀粉样蛋白)的测量结果 Beta和Total tau)使用最先进的SIMOA®技术，产生极其灵敏和精确的 每种分析物的估计值。将获得表观基因组范围的DNA甲基化以加速检查 表观遗传年龄(即，根据已建立的DNA甲基化算法估计的细胞年龄超过 按时间顺序排列)。使用三个时间点的纵向路径分析，这项研究将 检查外周生物标记物(表观遗传年龄加快、炎症、代谢和神经病理) 先前的创伤应激和随后的神经健康之间的联系的中介。这项研究将 检查遗传变量，例如阿尔茨海默病、心脏代谢疾病的全基因组风险得分 病理、炎症以及与痴呆症相关的基因类型(即载脂蛋白或载脂蛋白) 可能会缓和这些联系。最终，这项研究将确定早期的外周预后标志物。 随后大脑加速衰老，通过以下方式描绘出风险最高的亚群 精神、遗传和外周生物标志物图谱，并极大地促进了加速的科学 外周和大脑的细胞老化。

Early onset of age-related diseases, such as cardiometabolic disorders, inflammatory syndromes, and neurodegenerative conditions, exact a large personal, economic, and societal toll and lead to shortened healthspan and lifespan. Traumatic stress (trauma-related psychiatric symptoms) and genetic factors increase the risk for an acceleration in the underlying pace of biological aging, as indicated by changes in peripheral DNA methylation patterns (e.g., estimates of “epigenetic age”), increased inflammation, and metabolic pathology. Alterations in these processes may hold predictive value for subsequent brain health. The aims of this project are to examine traumatic stress-related accelerated aging in the periphery as an early predictor of alterations in the neurochemistry of the brain and in neurocognitive performance over time. The study will also examine genetic factors that may accentuate these associations. This project will build on two waves of existing data, which include genotypes, psychological and neuropsychological assessments, and banked plasma samples, by recruiting 160 participants in late middle age/early old age (all of whom have trauma exposure and symptoms of traumatic stress) to return for a third assessment that is 5-15 years after baseline. Participants will undergo cutting-edge magnetic resonance spectroscopy to asses for alterations in prefrontal neurometabolites (including those relevant to neuroinflammation and neuronal viability, such as myo-inositol and n-acetyl aspartate, respectively) and to examine neurocognitive performance, including assessment of mild cognitive impairment. Banked DNA and plasma samples from the initial two time points, and new peripheral samples from the third time point will be used to examine biomarkers that predict subsequent brain health. The study will obtain measures of inflammation (e.g., cytokines) and neuropathology (e.g., amyloid beta and total tau) using state-of-the-art Simoa® technology which yields extremely sensitive and precise estimates of each analyte. Epigenome-wide DNA methylation will be obtained to examine accelerated epigenetic age (i.e., when estimates of cellular age from established DNA methylation algorithms exceed chronological age). Using longitudinal path analyses across the three time points of data, the study will examine peripheral biomarkers (accelerated epigenetic age, inflammation, metabolic- and neuro-pathology) as mediators of the association between prior traumatic stress and subsequent neural health. The study will examine genetic variables, such as genome-wide risk scores for Alzheimer’s disease, cardiometabolic pathology, and inflammation as well as genotypes relevant to dementia (i.e., in apolipoprotein or APOE) that may moderate these associations. Ultimately, the study will identify early, peripheral prognostic markers of subsequent accelerated aging in the brain, delineate the subpopulations at greatest risk by virtue of psychiatric, genetic, and peripheral biomarker profiles, and substantially advance the science of accelerated cellular aging across the periphery and brain.