Molecular Basis of Postoperative Delirium in the Elderly

描述（申请人提供）：术后谵妄是老年人常见的并发症，发生率在10% - 70%之间。它与几种不良后果有关，包括住院时间延长、功能恢复不良，在某些情况下还会增加死亡率。由于老年外科患者的比例越来越大，因此了解术后谵妄的病理生理至关重要。一些神经递质系统似乎与谵妄有关，提出的研究将验证术后谵妄与特定基因和蛋白质表达变化相关的假设。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。第一个目标将是使用DNA微阵列检测外周血单核细胞（PBMCs）基因表达的变化。这一目标是基于我们的初步数据，该数据表明手术导致pbmc中466个基因表达发生两倍或更大的变化，其中329个基因表达上调，137个基因表达下调。这种手术诱导的基因表达变化的幅度是前所未有的，并且提高了其中一些基因是术后谵妄的标志和/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（50 - 65岁），该手术会导致20%的术后谵妄发生率，并使用一系列仪器评估术后谵妄。将使用包含12,000个人类基因的DNA微阵列芯片检测50例谵妄和50例非谵妄患者手术前后的pbmc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。第二个具体目标将是通过使用2d凝胶电泳/质谱法检测全局蛋白表达来鉴定随谵妄而变化的血清蛋白。PI和联合PI组建了一个跨学科团队，具有麻醉学、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，顾问在谵妄，DNA微阵列和质谱方面具有专业知识。因此，我们的团队在成功完成拟议研究方面处于独特的地位。

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.