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

摘要 现在，在9/11事件19年后，世界贸易中心(WTC)的反应人员中有很高比例的人表现出精神上的兴奋 以及对身体健康的影响，包括轻度认知障碍(MCI)的负担高于预期，以及 阿尔茨海默病(AD)或相关痴呆症(ADRD)的早期征兆。因为潜在的 MCI所示的神经退行性疾病令人担忧，迫切需要了解 疾病的发病机制和识别生物标志物，以便于在不可逆转的变化之前进行早期干预 对大脑的影响发生了。我们的试点工作显示，单核细胞亚群在 与MCI相关的转录组和差异表达(DE)基因在多种途径中得到丰富 与神经炎有关。这些发现与单核细胞在癌症中起关键作用的证据是一致的。 通过血脑屏障转导调节中枢和外周系统之间的接口。 拟议的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联系 转录组与24个月期间临床表型和神经病理学的变化。使用我们的银行 外周血单核细胞(PBMC)和血浆样本对n=250名有 经过基因分型(U01 OH011864)，我们将平均从PBMC中生成单核细胞转录组 每个样本150M读数的测序深度，以及经验证的脑神经病理血浆标记物 (包括pTau181、NFL、Aβ42、Aβ40)在两个时间点(基线和24个月随访)。在这250人中 应答者，我们也有来自以下的应答者(n=120)子集的结构和功能MRI神经成像 另一项研究(U01 OH011314)。在目标1中，我们将确定单核细胞转录组(基因和 选择性剪接(AS)水平)与临床表型的改变有关。在目标2中，我们将确定是否 单核细胞转录组的变化与每种血浆蛋白的变化有关。在基因和 与NFL相关，我们将通过整合 核磁共振数据。在目标3中，我们将通过eQTL识别与单核细胞转录组变化相关的遗传变异 和sQTL分析。这项拟议的研究将是第一次检查单核细胞转录组和替代方案。 在转化为痴呆症的个体中发生剪接(AS)。对生物过程的深入理解 MCI中单核细胞的动态变化及其与疾病进展的关系 可以帮助确定ADRD的新的基于血液的生物标志物和针对相关 疾病早期预防或减缓神经认知障碍进展的途径。

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.