Phosphorylated Tau as Biomarkers of Perioperative Neurocognitive Disorder in Older Adults

围手术期神经认知障碍(PND)--包括术后精神错乱、神经认知迟缓 康复和术后神经认知障碍-与发病率和死亡率的增加有关， 护理费用高，以及阿尔茨海默病和阿尔茨海默病相关痴呆(AD/ADRD)。 与最近的研究结果一致，血液中的Tau-PT217和Tau-PT181是早期白血病的特异性生物标志物 在AD阶段，我们的初步数据显示，继续发展为术后精神错乱的患者 术前血液中Tau-PT217和Tau-PT181的浓度比 分别为无术后精神障碍的患者。此外，血液炎症生物标志物白细胞介素6 C反应蛋白(CRP)与PND相关。因此，拟议的预期队列的目标是 研究目的是确定血液中Tau-PT217和Tau-PT181是否可以作为高血压的生物标志物(主要目标)。 炎症和PND之间的联系的PND和增强剂(次要目标)。假说 血液炎症生物标记物仅在高血压者中与PND有关 Tau-PT217或Tau-PT181的量。因为很难测量出低浓度的ptau 血液，我们将采用一项新开发和创新的纳米针技术，一种超高灵敏度 方法检测低浓度分子，检测血液中Tau-PT217和Tau-PT181。我们 将通过招募40名参与者(70岁)为未来的研究建立一个系统，这些参与者将没有 心脏手术在全身麻醉下有两个特定的目的。在目标1中，我们将建立一个系统来衡量 Tau-PT217和Tau-PT181(同时使用纳米针和SIMOA进行比较)以及IL-6和CRP(两者都使用 纳米针法和ELISA法比较)浓度。我们将确定它们与发病率的关系 术后前3天及术后3天的幻觉严重程度。在目标2中，我们将使用招募的 目标1的参与者调查这些血液生物标记物和延迟之间的关系 神经认知功能恢复(术后21天)和术后神经认知障碍(术后9个月 手术)。将使用3D混淆评估方法(3D-CAM)和CAM-严重性来定义PND 术后神志不清和神经心理测试延迟神经认知恢复和术后 神经认知障碍。这项对老年人进行的高影响前瞻性队列研究可能会提供至关重要的 R01应用程序的信息，以进一步在血液中建立Tau-PT217和Tau-PT181作为生物标志物和 部分PND的发病机制。这样的结果将促进识别出具有更高风险的患者 PND，使得能够确定干预(S)降低PND的效果，并靶向PT217和Tau- 血液中的PT181作为PND的潜在干预措施，促进制定预防和治疗策略 治疗PND，最终减轻AD/ADRD的建立。

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.