A Nonhuman Primate Model for Postoperative Delirium and Working Memory Impairment

术后谵妄和工作记忆损伤的非人类灵长类动物模型

• 批准号: 10592515
• 负责人: Yumiko Ishizawa
• 金额: $ 23.95万
• 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: 2023-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592515
• 关键词: 10 year old; Address; Age; Age-associated memory impairment; Agonist; Altered Level of Consciousness; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s neuropathogenesis; Anesthesia procedures; Anesthetics; Animal Model; Animals; Attention; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Characteristics; Clinical Research; Crossover Design; Data; Delirium; Dementia; Dependence; Development; Dexmedetomidine; Electroencephalography; Functional disorder; Future; General anesthetic drugs; Hallucinations; Human; Intervention; Intravenous Anesthetics; Investigation; Ketamine; Literature; Measurement; Measures; Mediating; Memory impairment; Modeling; Monkeys; Mus; Nanotechnology; Neocortex; Neuronal Injury; Neurotransmitters; Parietal Lobe; Patients; Perioperative Care; Plasma; Postoperative Period; Pre-Clinical Model; Prefrontal Cortex; Propofol; Recovery; Reporting; Research; Research Personnel; Research Project Grants; Risk; Rodent; Sampling; Short-Term Memory; Surface; System; Tauopathies; Technology; Testing; Training; United States National Institutes of Health; Volatilization; Vulnerable Populations; Work; aged; behavior test; clinical investigation; cognitive testing; executive function; experimental study; gamma-Aminobutyric Acid; high risk; inattention; innovation; insight; multimodality; nanoneedle; neocortical; neural; neurophysiology; nonhuman primate; novel; older patient; postoperative delirium; sevoflurane; stereotypy; tau Proteins; tau-1; young adult; 10 year old; Address; Age; Age-associated memory impairment; Agonist; Altered Level of Consciousness; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s neuropathogenesis; Anesthesia procedures; Anesthetics; Animal Model; Animals; Attention; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Characteristics; Clinical Research; Crossover Design; Data; Delirium; Dementia; Dependence; Development; Dexmedetomidine; Electroencephalography; Functional disorder; Future; General anesthetic drugs; Hallucinations; Human; Intervention; Intravenous Anesthetics; Investigation; Ketamine; Literature; Measurement; Measures; Mediating; Memory impairment; Modeling; Monkeys; Mus; Nanotechnology; Neocortex; Neuronal Injury; Neurotransmitters; Parietal Lobe; Patients; Perioperative Care; Plasma; Postoperative Period; Pre-Clinical Model; Prefrontal Cortex; Propofol; Recovery; Reporting; Research; Research Personnel; Research Project Grants; Risk; Rodent; Sampling; Short-Term Memory; Surface; System; Tauopathies; Technology; Testing; Training; United States National Institutes of Health; Volatilization; Vulnerable Populations; Work; aged; behavior test; clinical investigation; cognitive testing; executive function; experimental study; gamma-Aminobutyric Acid; high risk; inattention; innovation; insight; multimodality; nanoneedle; neocortical; neural; neurophysiology; nonhuman primate; novel; older patient; postoperative delirium; sevoflurane; stereotypy; tau Proteins; tau-1; young adult

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.

项目摘要/摘要： 在此R21应用程序中，我们建议在老年非人类隐私（NHP）中建立一个新的临床前模型， 从长远来看，旨在研究术后del妄的病理生理（POD）， 已知会增加患阿尔茨海默氏病（AD）和相关痴呆症（ADRD）的风险。尤其， NHP是一种独特的更好的动物模型，可用于同时确定类似del妄的行为， 来自人类等效的新皮层的侵入性神经记录和功能性动物中的血液生物标志物测试。 人类既不是侵入性记录和经常干预的不可行），也不是啮齿动物（有限的新皮层， 有限的人类相关性）可以像NHP一样提供模型。那就建立的NHP模型将 允许我们进行更好的ir妄研究，包括机械洞察力和有针对性的干预措施，这将 更好地指导POD的未来临床研究。扩展了我们最近的NHP研究，我们将使用挥发性 麻醉二氟烷和GABA介导的静脉麻醉建议，以建立POD系统 NHP的研究。据报道，七氟醚与各种年龄患者的POD有关。 丙泊酚尚未被证明可以促进患者的POD。与tauopathy的文学一致 是AD神经病发生的标志，我们以前的作品表明，全身麻醉可以促进tau 小鼠的磷酸化和开发POD的患者可能具有较高的术前，并且 术后血液和磷酸化的tau（p-tau）水平。那我们假设那种七​​氟硫富 提案，促进类似ir妄的行为和工作记忆障碍，引起特定的皮质 与年轻人相比 猴子。具体目的是：（1）确定Sevoflurane是否促进了类似del妄的行为 （注意力不集中，意识水平改变，幻觉和运动刻板印象）定义了工作 与记忆（在延迟匹配样本任务中）和老年猴子的皮质神经变化相比 提案群体； （2）评估Sevoflurane和Proposalfol对老年猴子血浆P-TAU水平的影响。我们 将在中央（额叶）执行网络（背侧前额叶）中执行直接的物质记录 皮质，后顶叶皮层），认为这些活动与del妄和工作记忆有关。 我们将采用一种新型的纳米技术来测量神经元损伤，血浆TAU和P-TAU的血液生物标志物 （P-TAU217，P-TAU181）水平。这些测量将在最多3个月的麻醉前后进行。 拟议的研究将建立一个新的NHP模型，以研究POD并促进验证 del妄的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至 系统地研究具有AD病理学的老年NHP中POD的病理生理学，这是一个高级模型 最脆弱的人口。