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

AD/ADRD 和生物衰老蛋白质组特征在谵妄病因及其相关长期认知衰退中的作用

• 批准号: 10585942
• 负责人: TOWIA A. LIBERMANN
• 金额: $ 87.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585942
• 关键词: Acceleration; Acute; Acute-Phase Proteins; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Biological; Biological Aging; Biological Specimen Banks; Blood; Brain; Cessation of life; Characteristics; Chronology; Clinical; Clinical Data; Complex; Confusion; Delirium; Development; Elderly; Enzyme-Linked Immunosorbent Assay; Functional disorder; Funding; Future; Hyperactivity; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investments; Measures; Memory; Modeling; Molecular; National Institute on Aging; Neuronal Injury; Nursing Homes; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Plasma; Plasma Proteins; Postoperative Period; Predisposing Factor; Predisposition; Prevention; Proteins; Proteome; Proteomics; Risk; Schedule; Surgical complication; Techniques; Testing; Thinking; Validation; biomarker discovery; blood-based biomarker; cohort; follow-up; hospital readmission; improved outcome; insight; multiple omics; older patient; postoperative delirium; precision medicine; predictive panel; predictive signature; prognostication; programs; proteomic signature; risk prediction; tetrahydrobiopterin

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.

项目概要/摘要 谵妄（急性精神错乱）是老年患者手术的主要并发症，与长期昏迷密切相关。 术语认知衰退（LTCD）和阿尔茨海默病及相关痴呆（AD/ADRD）。预防 如果我们能够更好地识别高危人群，术后谵妄及其长期并发症将会进一步发展 术前对患者进行治疗，如果可以实施有针对性的基于病理生理学的干预措施。到 为了解决这些差距，我们进行了 NIA 资助的“增进对术后谵妄的理解”项目 Mechanisms via Multi-Omics”R01 项目和资助 SAGES（Successful Aging after 择期手术）I 和 II 研究。我们鉴定并验证了术前和术后谵妄蛋白 特征，证明促炎蛋白、急性期反应物、血管生成和神经元 发生谵妄的患者损伤标志物升高。谵妄病理生理学模型 出现规定全身性炎症前状态容易引起过度活跃的炎症反应 因大手术导致谵妄，并可能导致弱势群体出现 LTCD 和 AD/ADRD 脑。虽然很有趣，但这个模型并没有完全解决谵妄和谵妄之间复杂的相互关系。 AD/ADRD。对于我们的 R01 更新，我们假设 AD/ADRD 易感性和加速生物衰老 是谵妄和 LTCD 谵妄的关键诱发因素，这反过来又可能增加发生谵妄的风险 AD/ADRD。基于 SomaScan 的血浆蛋白质组学特征可在 AD/ADRD 发病前长达 20 年进行预测， 和蛋白质组衰老时钟，血浆蛋白组测量相对于时间顺序的生物衰老 年龄，已经在大群体中得到开发和广泛验证。我们将使用最先进的 SomaScan 蛋白质组学平台可测量 7,000 种蛋白质，以测试我们的 AD/ADRD 蛋白质组学假设 特征（目标 1）和蛋白质组老化时钟（目标 2）预测术后谵妄和 LTCD 引起的谵妄。 我们将利用 SAGES I (N=560) 的术前和术后储存样本，持续进行 大型预定手术后 72 个月的随访，以及最近建立的第二个独立队列， SAGES II (N=400)，具有相似的特征并随访 18 个月。我们将结合来自 AD/ADRD 和衰老蛋白质组特征，以及来自 7,000 种蛋白质 SomaScan 的其他蛋白质 涵盖许多生物学途径，对血浆蛋白质组进行深入的病因病理学表征 SAGES I 中的谵妄和 LTCD 的谵妄（目标 3）以及蛋白质组学特征的独立验证 使用 SomaScan 和 ELISA 以及 SAGES II 血浆检测谵妄（目标 4）。我们的 R01 更新目标将 为谵妄发病机制及其与谵妄的关联提供新的见解 AD/ADRD 和生物衰老。该项目有望开发准确的血液生物标志物 用于术前谵妄风险预测、术后谵妄后 LTCD 的预测，并制定 为改善有谵妄风险的老年人的结果而采取有针对性的干预措施奠定了基础。