Blood DNA Methylation Biomarkers of Alzheimer’s Disease and Postoperative Neurocognitive Disorder

摘要 影响老年人手术后最常见的并发症是围手术期的发展。 神经认知障碍。在60岁以上的患者中，高达30%会出现术后认知功能障碍(POCD)， 也称为神经认知功能障碍(NCD)，在手术后6周内。 POCD/NCD的特征是记忆力、注意力、学习、注意力和/或执行力的损害 在心理测试中起作用。POCD/NCD患者可能会经历持续性认知功能障碍 手术后7年，更多的人失去了独立性，离开了劳动力市场，更高的医疗费用，以及 发病率和死亡率增加。POCD/NCD的病因和发病机制尚不清楚。在… 目前，还没有POCD/NCD易感性的生物标志物可用于手术前或指导 POCD/NCD的诊断和治疗。轻度认知障碍和迟发性阿尔茨海默病是 手术后认知功能下降的危险因素提示存在重叠的病理生理学。最近，我们报道了 血液样本中超过450个区分阿尔茨海默病患者的DNA差异甲基化位置 来自年龄和性别相匹配的认知健康人的疾病。DNA甲基化调控基因的模式 通过协调环境因素和遗传编码序列的影响来表达。因此， 在此应用程序中，我们将测试手术前采集的血液样本是否提供DNA甲基化 阿尔茨海默病的生物标志物区分手术后有POCD/NCD风险的患者 那些不是(具体目标1)的人。此外，我们还将检测术后6周采集的血液样本 阿尔茨海默病的生物标记物与手术前基线水平不同的甲基化 有无POCD/NCD的患者(特定目标2)。我们的技术创新是使用了Illumina Infinium 甲基化EPIC珠芯片用于分类中国人群中超过850,000个候选胞嘧啶基因座的DNA甲基化状态 POCD/NCD患者和非POCD患者的纵向血样。这些数据将提供新的预测因素 对POCD/NCD易感性的研究有助于POCD/NCD患者的诊断、预后和护理。反过来, 在以前未知的基因座和通路上的差异甲基化位置将支持更完整的 理解POCD/NCD背后的可遗传和获得性机制，有可能识别新的 治疗靶点。

Abstract The most common complication to affect older adults after surgery is the development of a perioperative neurocognitive disorder. Up to 30% of patients over 60 develop postoperative cognitive dysfunction (POCD), also termed neurocognitive dysfunction (postoperative) (NCD), within 6 weeks after a surgical procedure. POCD/NCD is characterized by impairment of memory, attention, learning, concentration and/or executive function on psychometric testing. Patients with POCD/NCD may experience persistent cognitive dysfunction over 7 years after surgery, greater loss of independence, leaving the labor market, higher health care costs, and increased morbidity and mortality. The etiology and pathogenesis of POCD/NCD are poorly understood. At present, no biomarkers of susceptibility to POCD/NCD are available for use before surgery, or for guiding diagnosis and management of POCD/NCD. Mild cognitive impairment and late onset Alzheimer's disease are risk factors for cognitive decline after surgery suggesting overlapping pathophysiology. Recently, we reported over 450 differentially methylated positions in DNA from blood samples that distinguish persons with Alzheimer's disease from cognitively healthy persons matched for age and sex. Patterns of DNA methylation regulate gene expression by coordinating the influence of environmental factors and genetic coding sequences. Accordingly, in this application we will test whether blood samples acquired before surgery provide DNA methylation biomarkers of Alzheimer's disease that distinguish patients who are at risk for POCD/NCD after surgery from those who are not (Specific Aim 1). As well, we will test blood samples acquired 6 weeks after surgery for biomarkers of Alzheimer's disease that are differentially methylated from baseline levels before surgery in patients with and without POCD/NCD (Specific Aim 2). Our technical innovation is the use of the Illumina Infinium MethylationEPIC BeadChip to classify DNA methylation status at over 850,000 candidate cytosine loci in longitudinal blood samples from patients with and without POCD/NCD. These data will provide new predictors of susceptibility to POCD/NCD for the diagnosis, prognosis, and care of patients with POCD/NCD. In turn, differentially methylated positions at previously unknown loci and pathways will support a more complete understanding of heritable and acquired mechanisms that underlie POCD/NCD with potential to identify novel therapeutic targets.