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.

摘要 现在9/11事件已经过去了19年，很大一部分世界贸易中心（WTC）的反应者表现出精神状态的提高。 和身体健康影响，包括轻度认知障碍（MCI）的负担高于预期， 阿尔茨海默病（AD）或相关痴呆（ADRD）的早期体征。因为潜在的 神经退行性疾病，如MCI所示的关注，有一个关键的需要，以了解 疾病的发病机制，并确定生物标志物，以促进不可逆变化之前的早期干预 大脑发生。我们的初步工作表明，单核细胞亚群在 与MCI相关的转录组和差异表达（DE）基因在途径中富集 与神经炎症有关。这些发现与证据一致，即单核细胞在 通过血脑屏障转导介导中枢和外周系统之间的界面。 这项研究建立在我们的试点工作的基础上，通过评估单核细胞变化之间的关联， 在24个月的时间内，临床表型和神经病理学的变化与转录组。使用我们的银行 外周血单核细胞（PBMC）和血浆样本，n=250个应答者的子集， 基因分型（U 01 OH 011864），我们将从PBMC中产生单核细胞转录组谱，平均 测序深度为每个样本150 M读数，以及经验证的脑神经病理学血浆标志物 （包括pTau 181、NfL、Aβ42、Aβ40）。其中250 响应者，我们也有结构和功能MRI神经成像的一个子集的响应者（n=120），从 一项单独的研究（U 01 OH 011314）。在目标1中，我们将确定单核细胞转录组（基因和转录水平）的变化是否与单核细胞的转录水平有关。 可变剪接（AS）水平）与临床表型的变化相关。在目标2中，我们将确定 单核细胞转录组的变化与每种血浆蛋白的变化相关。在基因和 由于与NfL相关，我们将通过整合 MRI数据。在目标3中，我们将通过eQTL鉴定与单核细胞转录组变化相关的遗传变异 sQTL分析。这项拟议的研究将是第一个检查单核细胞转录组和替代转录组的研究。 剪接（AS）在个人转化为痴呆症。对生物过程的深入了解 MCI中单核细胞动力学的基础以及这些过程如何与疾病进展相关 可以帮助确定ADRD的新型血液生物标志物和针对相关疾病的干预策略。 在疾病早期的通路，以防止或减缓神经认知障碍的进展。