AD/ADRD and biological aging proteomic signatures in the etiopathology of delirium and its associated long-term cognitive decline

项目摘要/摘要 精神错乱(急性精神错乱)是老年患者手术的主要并发症，与长期的 术语认知功能减退(LTCD)和阿尔茨海默病及相关痴呆(AD/ADRD)。预防 如果我们能更好地识别危险因素，术后精神错乱及其长期并发症将会进一步发展。 如果可以实施有针对性的基于病理生理的干预措施。至 针对这些空白，我们开展了由NIA资助的《促进对术后妄想的认识》 R01项目和资助SAGES(成功老龄化后)的方案项目 择期手术)I和II研究。我们鉴定和验证了手术前后的妄想蛋白。 信号，表明促炎蛋白、急性期反应物、血管生成和神经元 在出现精神错乱的患者中，损伤标记物会升高。一种精神错乱的病理生理学模型 规定全身炎症前状态易导致过度活跃的炎症反应的研究出现 从大手术，导致精神错乱，以及潜在的LTCD和AD/ADRD的易损性个体 大脑。虽然耐人寻味，但这个模型并没有完全解决精神错乱和精神错乱之间的复杂相互关系。 AD/ADRD。对于我们的R01更新，我们假设AD/ADRD易感性和加速的生物老化 是导致精神错乱和长期精神错乱的关键诱因，这反过来又可能增加患上 AD/ADRD。基于SomaScan的血浆蛋白质组特征在发病前20年预测AD/ADRD， 以及蛋白质组衰老时钟，即测量相对于时间顺序的生物衰老的血浆蛋白质面板 年龄，已经开发，并在大型队列中得到广泛验证。我们将使用最先进的 SomaScan蛋白质组学平台，测量7,000个蛋白质来测试我们的假设AD/ADRD蛋白质组 信号(目标1)和蛋白质组衰老时钟(目标2)预测LTCD术后精神错乱和精神错乱。 我们将利用SAGE I(N=560)手术前和手术后的标本，用连续的 对大型定期手术后72个月的随访，以及最近获得的第二个独立队列， SAGES II(N=400)，特征相似，随访18个月。我们将结合来自 AD/ADRD和老化蛋白质组特征，以及来自7,000蛋白SomaScan的其他蛋白质 涵盖许多生物途径，以深入了解血浆蛋白质组的病因学特征 SAGES I中的精神错乱和伴有LTCD的精神错乱(目标3)和蛋白质组签名的独立验证 使用SomaScan和用SAGES II的血浆进行的ELISAGE试验(目标4)。我们的R01续订目标将 提供了新的见解，揭示了精神错乱发病的分子机制及其与 AD/ADRD和生物老化。这个项目很有希望开发准确的血液生物标记物。 术前、术后对术后LTCD的预测、术前、术中、术后的临床研究 有针对性的干预措施的基础，以改善有精神错乱风险的老年人的预后。

Project Summary/Abstract Delirium (acute confusion), is a major complication of surgery in older patients, strongly associated with long term cognitive decline (LTCD) and Alzheimer's Disease and Related Dementias (AD/ADRD). Prevention of postoperative delirium and its long-term complications would be advanced if we could better identify at-risk patients preoperatively, and if targeted pathophysiologically-based interventions could be implemented. To address these gaps, we conducted the NIA-funded “Advancing the Understanding of Postoperative Delirium Mechanisms via Multi-Omics” R01 project and program project that funded the SAGES (Successful Aging after Elective Surgery) I and II studies. We identified and validated pre- and post-operative delirium protein signatures, demonstrating that pro-inflammatory proteins, acute phase reactants, angiogenic, and neuronal injury markers are elevated in patients who develop delirium. A model of delirium pathophysiology has emerged that stipulates a systemic pre-inflammatory state predisposes to a hyperactive inflammatory response from major surgery, leading to delirium, and potentially LTCD and AD/ADRD in individuals with a vulnerable brain. While intriguing, this model does not fully address the complex inter-relationship between delirium and AD/ADRD. For our R01 renewal, we hypothesize that AD/ADRD susceptibility and accelerated biological aging are key predisposing factors for delirium and delirium with LTCD, which in turn may increase risk for AD/ADRD. SomaScan-based plasma proteomic signatures predicting AD/ADRD up to 20 years before onset, and proteomic aging clocks, panels of plasma proteins measuring biological aging relative to chronological age, have been developed and extensively validated in large cohorts. We will use the state-of-the-art SomaScan proteomics platform that measures 7,000 proteins to test our hypotheses that AD/ADRD proteomic signatures (Aim 1) and proteomic aging clocks (Aim 2) predict postoperative delirium and delirium with LTCD. We will capitalize upon the pre- and post-operative banked specimens from SAGES I (N=560) with continuous follow-up to 72 months after major scheduled surgery, and a second, recently accrued independent cohort, SAGES II (N=400), with similar characteristics and follow-up to 18 months. We will combine proteins from the AD/ADRD and aging proteomic signatures, along with additional proteins from the 7,000 protein SomaScan covering many biological pathways, for a deep etiopathological characterization of the plasma proteome for delirium and delirium with LTCD in SAGES I (Aim 3) and independent validation of the proteomic signature for delirium using both SomaScan and ELISA with plasma from SAGES II (Aim 4). Our R01 renewal Aims will provide new insights into molecular mechanisms underlying delirium pathogenesis and its association with AD/ADRD and biological aging. This project holds great promise to develop accurate blood-based biomarkers for preoperative delirium risk prediction, postoperative prognostication of LTCD following delirium, and to lay the groundwork for targeted interventions to improve outcomes of older adults at risk of delirium.