A Nonhuman Primate Model for Postoperative Delirium and Working Memory Impairment

项目摘要/摘要： 在R21的应用中，我们建议在老年非人灵长类动物(NHP)中建立一个新的临床前模型， 目的是长期使用它来研究术后痴呆(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， NHPS是唯一更好的动物模型，可以用来同时确定神志不清的行为， 来自相当于人类的新皮质的侵入性神经记录，以及在功能正常的动物中进行的血液生物标记物测试。 既不是人类(不能进行侵入性记录和频繁干预)，也不是啮齿类动物(有限的新皮质， 有限的人类相关性)可以提供与NHP一样有用的模型。因此，建立的国家惠普模式将 使我们能够进行更好的精神错乱研究，包括机械性的洞察和有针对性的干预，这将 更好地指导未来POD的临床研究。扩展我们最近的NHP研究，我们将使用挥发性 七氟醚复合GABA介导的丙泊酚静脉麻醉用于POD系统的建立 在卫生保健计划方面的研究。据报道，在不同年龄的患者中，七氟醚与POD有关。 异丙酚还没有被证明能促进患者的POD。与文献中的直肠疗法相一致 是AD神经发病机制的一个标志，我们以前的工作表明，全身麻醉药可能促进tau 小鼠体内的磷酸化，而发生POD的患者术前和术后可能有更高的 术后血tau和磷酸化tau(p-tau)水平。因此，我们假设七氟醚，但不是 异丙酚促进精神错乱样行为和工作记忆障碍，诱导特定的皮质 与青年猴相比，老年猴的神经生理学改变和血浆p-tau水平升高 猴子。具体的目的是：(1)确定七氟醚是否会促进神志不清的行为。 (注意力不集中、意识水平改变、幻觉和运动刻板印象)、工作中的缺陷 记忆(延迟匹配到样本任务)和老年猴子皮层神经变化的比较 以及(2)评估七氟醚和异丙酚对老年猴子血浆p-tau水平的影响。我们 将在中央(额顶叶)执行网络(额叶背外侧前额叶)直接进行皮质内记录 大脑皮质、顶叶后皮质)，这些活动被认为与精神错乱和工作记忆有关。 我们将使用一种新的纳米技术来测量神经元损伤的血液生物标记物，血浆tau和p-tau (P-tau217，p-tau181)水平。这些测量将在麻醉前和麻醉后进行，最长达3个月。 建议的研究将为POD的研究建立一个新的NHP模型，并有助于验证 精神错乱的神经生理学和血液生物标志物。使用这项研究的数据，我们将申请R01 用AD病理系统研究老年NHP患者POD的病理生理学机制 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.