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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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、神经认知迟缓恢复和术后神经认知障碍 - 与发病率和死亡率增加相关，高额护理费用以及阿尔茨海默病和阿尔茨海默病相关痴呆症 (AD/ADRD)。与最近的研究结果一致，即血液 Tau-PT217 和 Tau-PT181 是早期疾病的特异性生物标志物。 AD阶段，我们的初步数据表明，术后继续出现谵妄的患者术前血液中 Tau-PT217 和 Tau-PT181 的浓度比术前高出五倍和两倍以上术后无谵妄的患者分别检测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，该前瞻性队列的目标是。研究的目的是确定血液 Tau-PT217 和 Tau-PT181 是否可以作为生物标志物（主要目标） PND 和炎症与 PND 之间关联的增强剂（次要目标）假设。血液生物标志物仅在血液水平较高的参与者中与 PND 相关 Tau-PT217 或 Tau-PT181 的量，因为很难测量低浓度的 pTau。血液，我们将采用新开发的创新纳米针技术，一种超高灵敏度方法检测低浓度分子，测定血液中的Tau-PT217和Tau-PT181。将招募 40 名参与者（> 70 岁），建立一个未来学习系统，这些参与者将具有非全身麻醉下心脏手术的两个具体目标在目标 1 中，我们将建立一个测量系统。 Tau-PT217 和 Tau-PT181（同时使用纳米针和 Simoa 进行比较）以及 IL-6 和 CRP（同时使用纳米针和 Simoa）纳米针和 ELISA 进行比较）浓度，我们将确定它们与发病率的关系。在目标 2 中，我们将使用招募的患者。目标 1 的参与者调查这些血液生物标志物与延迟之间的关联神经认知恢复（术后21天）和术后神经认知障碍（术后9个月） PND 将使用 3D 混淆评估方法 (3D-CAM) 和 CAM-Severity 来定义术后谵妄，以及神经认知恢复延迟和术后的神经心理学测试这项针对老年人的高影响力前瞻性队列研究可以提供重要的信息。 R01 应用的信息，以进一步确定血液中的 Tau-PT217 和 Tau-PT181 作为生物标志物，这些结果将有助于识别具有较高风险的患者。 PND，能够确定减少 PND 的干预措施的效果，并针对 PT217 和 Tau- 血液中的 PT181 作为 PND 的潜在干预措施，促进预防和治疗策略的制定治疗 PND，最终减轻 AD/ADRD 的发生。