A Nonhuman Primate Model for Postoperative Delirium and Working Memory Impairment

项目总结/摘要： 在这个R21申请中，我们提出在老年非人灵长类动物（NHP）中建立新的临床前模型， 旨在长期使用它来研究术后谵妄（POD）的病理生理学， 已知会增加患阿尔茨海默病（AD）和相关痴呆症（ADRD）的风险。值得注意的是， NHP是唯一更好的动物模型，可用于同时确定谵妄样行为， 来自人类等效新皮层的侵入性神经记录，以及在功能动物中的血液生物标志物测试。 无论是人类（不适合侵入性记录和频繁干预）还是啮齿动物（有限的新皮层， 有限的人类相关性）可以提供与NHP一样有用的模型。因此，所建立的NHP模型将 使我们能够进行更好的谵妄研究，包括机械的洞察力和有针对性的干预，这将 更好地指导未来的POD临床研究。扩展我们最近的NHP研究，我们将使用一个挥发性的 麻醉剂七氟醚和GABA介导的静脉麻醉剂丙泊酚建立POD系统 研究NHPs。已报告七氟烷与不同年龄患者的POD相关。 尚未证明丙泊酚可促进患者的POD。与文献一致，tau蛋白病 是AD神经发病机制的标志，我们以前的工作表明，全身麻醉剂可以促进tau蛋白的表达， 在小鼠中，发生POD的患者可能具有更高的术前和术后磷酸化水平。 术后血液tau和磷酸化tau（p-tau）水平。因此，我们假设七氟烷，但不是 异丙酚，促进谵妄样行为和工作记忆障碍，诱导特定的皮质 神经生理学变化，并增加血浆p-tau水平在老年猴相比，年轻的成年 猴子具体目的是：（1）确定七氟烷是否促进谵妄样行为 （注意力不集中，意识水平改变，幻觉和运动刻板），工作能力缺陷 记忆（在延迟匹配到样本任务），和皮质神经的变化，在老年猴子相比， 丙泊酚;和（2）评估七氟烷和丙泊酚对老年猴血浆p-tau水平的影响。我们 将在中央（额顶叶）执行网络（背外侧前额叶）中执行直接皮质内记录 皮质，后顶叶皮质），这些活动被认为与谵妄和工作记忆有关。 我们将采用一种新的纳米技术来测量神经元损伤的血液生物标志物，血浆tau和p-tau （p-tau217，p-tau181）水平。这些测量将在麻醉前后进行，最长3个月。 本研究将为POD的研究建立一个新的NHP模型，并便于验证 神经生理学和血液生物标志物。使用本研究的数据，我们将申请R01， 系统地研究了老年NHP伴AD病理的POD病理生理学， 最脆弱的人群。

PROJECT SUMMARY/ABSTRACT: In this R21 application, we propose to establish a new preclinical model in aged nonhuman primates (NHP), aiming to use it in the long run to investigate the pathophysiology of postoperative delirium (POD), which is known to increase the risk of developing Alzheimer’s disease (AD) and related dementias (ADRD). Notably, NHPs are the uniquely better animal model that can be used to simultaneously determine delirium-like behaviors, invasive neural recording from human-equivalent neocortex, and blood biomarker testing in a functioning animal. Neither humans (infeasible for invasive recording and frequent interventions) nor rodents (limited neocortex, limited human relevance) can provide as useful of a model as NHPs can. Thus, the established NHP model will allow us to perform better delirium studies, including mechanistic insight and targeted interventions, which will better guide future clinical investigations of POD. Extended of our recent NHP studies, we will use a volatile anesthetic sevoflurane and a GABA-mediated intravenous anesthetic propofol to establish the system for POD research in NHPs. Sevoflurane has been reported for its association with POD in patients of various ages. Propofol has not been demonstrated to promote POD in patients. Consistent with the literatures that tauopathy is a hallmark of AD neuropathogenesis, our previous works show that general anesthetics may promote tau phosphorylation in mice and that the patients who developed POD might have higher preoperative and postoperative blood tau and phosphorylated tau (p-tau) levels. Thus, we hypothesize that sevoflurane, but not propofol, promotes delirium-like behaviors and working memory impairment, induces specific cortical neurophysiological changes, and increases plasma p-tau levels in aged monkeys as compared to young adult monkeys. The Specific Aims are: (1) to determine whether sevoflurane promotes delirium-like behaviors (inattention, altered level of consciousness, hallucinations, and locomotor stereotypies), deficits in working memory (in Delayed Matching-to-Sample task), and cortical neural changes in aged monkeys as compared to propofol; and (2) to assess the effect of sevoflurane and propofol on plasma p-tau levels in aged monkeys. We will perform direct intracortical recording in the central (frontoparietal) executive network (dorsolateral prefrontal cortex, posterior parietal cortex), which activities are thought to be associated with delirium and working memory. We will employ a novel nanotechnology to measure blood biomarkers for neuronal injury, plasma tau and p-tau (p-tau217, p-tau181) levels. These measurements will be performed before and after anesthesia up to 3 months. The proposed studies will establish a novel NHP model for the investigation of POD and facilitate validating neurophysiological and blood biomarkers of delirium. Using data from this study we will apply for a R01 to systematically study the pathophysiology of POD in aged NHPs with AD pathology, an advanced model for the most vulnerable population.