Phosphorylated Tau as Biomarkers of Perioperative Neurocognitive Disorder in Older Adults

磷酸化 Tau 蛋白作为老年人围手术期神经认知障碍的生物标志物

• 批准号: 10645987
• 负责人: Feng Liang
• 金额: $ 26.99万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645987
• 关键词: 3-Dimensional; Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anesthesia procedures; Biological Markers; Blood; Blood specimen; C-reactive protein; Clinical Research; Data; Detection; Development; Diagnosis; Elderly; Eligibility Determination; Enhancers; Enzyme-Linked Immunosorbent Assay; Future; General Anesthesia; Incidence; Inflammation; Interleukin-6; Intervention; Knowledge; Measures; Medical Care Costs; Methods; Mission; Modeling; Morbidity - disease rate; Neurocognitive; Neuropsychological Tests; Operative Surgical Procedures; Outcome; Participant; Pathogenesis; Patient Recruitments; Patients; Perioperative; Plasma; Postoperative Period; Prospective, cohort study; Proteins; Protocols documentation; Recovery; Research; Risk; Safety; Sampling; Severities; System; Technology; Testing; Threonine; Time; United States National Institutes of Health; care costs; confusion assessment method; cost; early detection biomarkers; high risk; innovation; intervention effect; mortality; nanoneedle; neurocognitive disorder; novel; older patient; postoperative delirium; prevent; primary outcome; recruit; retention rate; specific biomarkers; tau-1

Perioperative neurocognitive disorders (PND) – including postoperative delirium, delayed neurocognitive recovery, and postoperative neurocognitive disorders – are associated with increased morbidity and mortality, high costs of care, and Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). Consistent with the recent findings that blood Tau-PT217 and Tau-PT181 are specific biomarkers for the early stage of AD, our preliminary data have shown that the patients who go on to develop postoperative delirium have more than five- and two-fold higher concentration of preoperative blood Tau-PT217 and Tau-PT181 than the patients without postoperative delirium, respectively. In addition, blood inflammation biomarker interleukin-6 and C-reactive protein (CRP) are associated with PND. Thus, the objective of the proposed prospective cohort study is to determine whether blood Tau-PT217 and Tau-PT181 can serve as biomarkers (primary objective) of PND and enhancers (secondary objective) of the association between inflammation and PND. The hypothesis is that blood inflammation biomarkers are associated with PND only in the participants with higher blood amounts of Tau-PT217 or Tau-PT181. Because it is difficult to measure the low concentrations of pTau in blood, we will employ a newly developed and innovative nanoneedle technology, an ultra-highly sensitive method to detect low concentrations of molecules, to measure the Tau-PT217 and Tau-PT181 in blood. We will establish a system for future studies by recruiting 40 participants (> 70 years old) who will have non- cardiac surgery under general anesthesia in two Specific Aims. In Aim 1, we will establish a system to measure Tau-PT217 and Tau-PT181 (using both nanoneedle and Simoa for comparison) and IL-6 and CRP (using both nanoneedle and ELISA for comparison) concentrations. We will determine their relationships with the incidence and severity of postoperative delirium on the first three days postoperatively. In Aim 2, we will use the recruited participants in Aim 1 to investigate the associations between these blood biomarkers and delayed neurocognitive recovery (21 days after surgery) and postoperative neurocognitive disorder (9 months after the surgery). PNDs will be defined using 3D Confusion Assessment Method (3D-CAM) and CAM-Severity for postoperative delirium, and neuropsychological tests for delayed neurocognitive recovery and postoperative neurocognitive disorders. This high-impact prospective cohort study in older adults could provide vital information for an R01 application to further establish Tau-PT217 and Tau-PT181 in blood as biomarkers and parts of pathogenesis of PND. Such outcomes will promote the identification of patients with a higher risk of PND, enable the determination of the effects of intervention(s) to reduce PND, and target PT217 and Tau- PT181 in blood as the potential intervention of PND, promoting the development of strategies to prevent and treat PND, ultimately mitigating the establishment of AD/ADRD.

围手术期神经认知障碍（PND）-包括术后谵妄、迟发性神经认知障碍 恢复和术后神经认知障碍-与发病率和死亡率增加有关， 高成本的护理，和阿尔茨海默病和阿尔茨海默病相关的痴呆症（AD/ADRD）。 与最近的发现一致，即血液Tau-PT 217和Tau-PT 181是早期糖尿病的特异性生物标志物。 我们的初步数据表明，在AD的第一阶段， 术前血液Tau-PT 217和Tau-PT 181的浓度比术前血液Tau-PT 217和Tau-PT 181的浓度高五倍和两倍以上。 术后未发生谵妄的患者。此外，血液炎症生物标志物白细胞介素-6 和C反应蛋白（CRP）与PND相关。因此，拟定的前瞻性队列的目的是 研究的目的是确定血液Tau-PT 217和Tau-PT 181是否可以作为以下疾病的生物标志物（主要目的）： PND和炎症与PND之间关联的增强子（次要目的）。的假设 血液炎症生物标志物仅在血液炎症指数较高的参与者中与PND相关， 量的Tau-PT 217或Tau-PT 181。因为难以测量细胞中pTau的低浓度， 血液，我们将采用新开发的创新纳米针技术，超高灵敏度， 检测低浓度分子的方法，以测量血液中的Tau-PT 217和Tau-PT 181。我们 将通过招募40名参与者（> 70岁）来建立未来研究的系统，这些参与者将具有非 心脏手术在全身麻醉下的两个特定目的。在目标1中，我们将建立一个衡量 Tau-PT 217和Tau-PT 181（使用纳米针和Simoa两者进行比较）和IL-6和CRP（使用纳米针和Simoa两者进行比较） 用于比较的纳米针和ELISA）浓度。我们将确定它们与发病率的关系 和术后前三天的术后谵妄的严重程度。在目标2中，我们将使用招募的 目标1的参与者，以调查这些血液生物标志物与延迟 神经认知恢复（术后21天）和术后神经认知障碍（术后9个月） 外科手术）。将使用3D混淆评估方法（3D-CAM）和CAM-严重度定义PND， 术后谵妄，以及神经认知恢复延迟和术后 神经认知障碍这项在老年人中进行的高影响力前瞻性队列研究可以提供重要的 R 01申请的信息，以进一步确定血液中的Tau-PT 217和Tau-PT 181作为生物标志物， PND发病机制的一部分。这些结果将促进识别具有较高风险的患者， PND，使得能够确定干预的效果以减少PND，并靶向PT 217和Tau-217。 血液中PT 181作为PND的潜在干预措施，促进了预防和治疗策略的发展。 治疗PND，最终减轻AD/ADRD的建立。