Changes in monocyte transcriptome as a predictor of cognitive decline in WTC responders: a longitudinal study

单核细胞转录组的变化作为世贸中心响应者认知能力下降的预测因子：一项纵向研究

• 批准号: 10459190
• 负责人: SEAN CLOUSTON
• 金额: $ 49.74万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459190
• 关键词: Changes; monocyte; transcriptome; predictor; cognitive

ABSTRACT Now nineteen years after 9/11, a high proportion of World Trade Center (WTC) responders show elevated mental and physical health effects that include a higher than expected burden of mild cognitive impairment (MCI), an early sign of Alzheimer’s disease (AD) or a related dementia (ADRD). Because the potential for neurodegenerative diseases as indicated by MCI are concerning, there is a critical need to understand the pathogenesis of the disorder and identify biomarkers to facilitate early intervention before irreversible changes to the brain occur. Our pilot work revealed that monocyte subpopulation showed the largest changes in transcriptome associated with MCI and the differentially expressed (DE) genes were enriched in pathways related to neuroinflammation. These findings are in line with evidence that monocytes play a pivotal role in mediating the interface between central and peripheral systems via transduction through the blood brain barrier. The proposed study builds on our pilot work by evaluating association between changes in monocyte transcriptome with changes in clinical phenotype and neuropathology over a 24-month period. Using our banked peripheral blood mononuclear cell (PBMC) and plasma samples on a subset of n=250 responders who have been genotyped (U01 OH011864), we will generate monocyte transcriptome profiles from PBMCs at an average sequencing depth of 150M reads per sample, as well as validated plasma markers of cerebral neuropathology (including pTau181, NfL, Aβ42, Aβ40) at both time points (baseline and 24-month follow up). Among these 250 responders, we also have structural and functional MRI neuroimaging for a subset of responders (n=120) from a separate study (U01 OH011314). In Aim 1, we will determine if changes in monocyte transcriptome (gene and alternative splicing (AS) levels) are associated with changes in clinical phenotype. In Aim 2, we will determine if changes in monocyte transcriptome are associated with changes in each plasma protein. Among the genes and AS associated with NfL, we will further determine if they are associated with cortical thickness by integrating the MRI data. In Aim 3, we will identify genetic variants associated with changes in monocyte transcriptome via eQTL and sQTL analyses. The proposed study will be the first to examine monocyte transcriptome and alternative splicing (AS) in individuals converting to dementia. The in-depth understanding of biological processes underlying the dynamics of monocytes in MCI and how the processes are associated with disease progression can help identify novel blood-based biomarkers for ADRD and intervention strategies that target relevant pathways early in the disease to prevent or slow the progression of neurocognitive disorders.

抽象的 在9/11之后的十九年之后，世界贸易中心（WTC）响应的很高比例显示了精神升高 和身体健康的影响包括轻度认知障碍的预期负担高于预期的负担（MCI） 阿尔茨海默氏病（AD）或相关痴呆症（ADRD）的早期迹象。 MCI所指出的神经退行性疾病是关于您的迫切需要了解的 该疾病的发病机理并识别生物标志物以促进早期干预之前 大脑发生。 与MCI相关的转录组和差异表达（DE）基因富含途径 与神经炎症有关。 通过转导血脑屏障来介导中央和周围系统之间的界面。 支撑研究通过评估单核细胞变化之间的关联建立在我们的试点工作的基础上 在24个月内，转录组随临床表型表型和神经病变的变化而变化 外周血单核细胞（PBMC）和血浆样品的n = 250响应的子集 已被基因分型（U01 OH011864），我们将平均从PBMC产生单核细胞转录组轮廓。 每个样品的测序深度读取150m，以及经过验证的脑神经病理的等离子体标记 （在这两个时间点中包含PTAU181，NFL，Aβ42，Aβ40）（基线和24个月的随访） 响应者，我们还具有结构和功能性MRI神经影像学 单独的研究（U01 OH011314）。 替代剪接（AS）水平与AIM 2中的临床表型变化有关。 单核细胞转录组的变化与每个血浆蛋白的变化有关。 与NFL相关，我们将进一步确定它们是否与皮质厚度相关联。 MRI数据在AIM 3中，我们将通过EQTL确定与变形的遗传变异 和SQTL分析。 对痴呆的个人的剪接（AS）。 MCI中单核细胞的动态以及在这里疾病计划的基础 可以帮助确定针对ADRD和国际策略目标目标的新型血液生物标志物 疾病早期的途径可防止或减慢神经认知障碍的进展。