Molecular Basis of Postoperative Delirium in the Elderly

描述（由申请人提供）：术后谵妄是老年人常见的并发症，发生率范围为10%-70%。 它与几种不良结局相关，包括住院时间延长、功能恢复不良以及在某些情况下死亡率增加。 由于老年手术患者的比例正在增加，因此了解术后谵妄的病理生理学至关重要。 几种神经递质系统似乎参与了谵妄，拟议中的研究将测试这一假设，即术后谵妄与特定基因和蛋白质表达的变化有关。这些基因和蛋白质的鉴定将导致诊断、治疗和可能预防术后谵妄的新策略。第一个目标是使用DNA微阵列检测外周血单个核细胞（PBMC）中基因表达的变化。这一目标是基于我们的初步数据，表明手术导致PBMC中466个基因表达的两倍或更大变化，其中329个上调，137个下调。 这种手术诱导的基因表达变化的幅度是前所未有的，并提高了这些基因中的一些是术后谵妄的标志物和/或原因的可能性。 我们将招募250名接受髋关节或膝关节置换术的老年患者（>65岁），这一手术导致约20%的术后谵妄发生率，并使用一组仪器评估术后谵妄。 将使用含有12，000个人类基因的DNA微阵列芯片测定来自50名谵妄患者和50名非谵妄患者的术前和术后PBMC中的基因表达。 基因表达数据的统计分析将确定与术后谵妄相关的基因簇。 第二个具体目标是通过使用二维凝胶电泳/质谱法检查整体蛋白质表达来识别随着谵妄而变化的血清蛋白。 PI和co-PI组建了一支跨学科团队，拥有麻醉学、生物信息学、老年病学、分子药理学、护理学、精神病学、心理学、整形外科和统计学方面的专业知识。 此外，顾问可在谵妄，DNA微阵列和质谱的专业知识。 因此，我们的团队处于一个独特的位置，成功完成拟议的研究。

DESCRIPTION (provided by applicant): Postoperative delirium is a frequent complication in the elderly, with an incidence rate ranging from 10% to 70%. It is associated with several adverse outcomes, including prolonged hospitalizations, poor functional recovery, and in some cases increased mortality. Because the proportion of elderly surgical patients is increasing, it is critical to understand the pathophysiology of postoperative delirium. Several neurotransmitter systems appear to be involved in delirium, and the proposed studies will test the hypothesis that postoperative delirium is associated with changes in the expression of specific genes and proteins Identification of these genes and proteins will lead to novel strategies for diagnosing, treating, and possibly preventing postoperative delirium. The first aim will be to examine changes in gene expression in peripheral blood mononuclear cells (PBMCs) using DNA microarrays. This aim is based on our preliminary data indicating that surgery causes a twofold or greater change in the expression of 466 genes in PBMCs, with 329 getting up-regulated and 137 getting down-regulated. The magnitude of this surgery-inducing change in gene expression is unprecedented and raises the probability that some of these genes are the markers of and/or the cause of postoperative delirium. We will enroll 250 elderly patients (>65 years old) undergoing hip or knee replacement-a procedure that causes about 20% incidence of postoperative delirium-and assess postoperative delirium using a battery of instruments. Gene expression in pro- and post-surgery PBMCs from 50 delirious and 50 non-deledous patients will be determined using a DNA microarray chip containing 12,000 human genes. Statistical analysis of the gene expression data will identify the cluster of genes associated with postoperative delirium. The second specific aim will be to identify serum proteins that change with delirium by examining global protein expression using 2D-gel electrophoresis/mass spectrometry. The PI and the co-PI have assembled an interdisciplinary team with expertise in anesthesiology, bioinformatics, geriatrics, molecular pharmacology, nursing, psychiatry, psychology, orthopedic surgery, and statistics. In addition, consultants are available with expertise in delirium, DNA microarrays, and mass spectrometry. Our team is therefore in a unique position to successfully complete the proposed studies.