Molecular Basis of Postoperative Delirium in the Elderly

描述(申请人提供)：术后妄想是老年人常见的并发症，发生率从10%到70%不等。它与几种不良后果有关，包括延长住院时间，功能恢复不佳，在某些情况下增加了死亡率。由于老年手术患者的比例正在增加，因此了解术后精神障碍的病理生理学至关重要。几种神经递质系统似乎参与了妄想，拟议的研究将检验这一假说，即术后妄想与特定基因和蛋白表达的变化有关。对这些基因和蛋白的识别将导致诊断、治疗和预防术后妄想的新策略。第一个目标将是利用DNA微阵列检查外周血单核细胞(PBMC)中基因表达的变化。这一目标是基于我们的初步数据，该数据表明，手术导致PBMC中466个基因的表达发生两倍或更大的变化，其中329个基因上调，137个基因下调。这种由手术引起的基因表达变化的幅度是史无前例的，并增加了其中一些基因是术后精神错乱的标志和/或原因的可能性。我们将招募250名老年患者(65岁)接受髋关节或膝关节置换术--这一过程会导致约20%的术后精神错乱--并使用一系列仪器评估术后精神错乱。使用包含12,000个人类基因的DNA微阵列芯片，将测定50名精神错乱患者和50名非精神错乱患者手术前后PBMCs的基因表达。对基因表达数据的统计分析将确定与术后精神错乱相关的基因簇。第二个具体目标将是通过使用2D-Gel电泳法/质谱仪检测全球蛋白质表达来识别随着神志不清而改变的血清蛋白质。PI和联合PI组建了一个跨学科的团队，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，还提供在精神错乱、DNA微阵列和质谱学方面具有专业知识的顾问。因此，我们的团队处于一个独特的地位，可以成功地完成拟议的研究。

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.