Neural Circuits Underlying Post-operative Delirium in Early Stage Alzheimer's Disease

早期阿尔茨海默病术后谵妄的神经回路

• 批准号: 10590280
• 负责人: Kathleen Frances Vincent
• 金额: $ 13.52万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10590280
• 关键词: Acute; Address; Adult; Advisory Committees; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid; Anesthesia procedures; Anesthetics; Animals; Attention; Attentional deficit; Attenuated; Automobile Driving; Award; Basic Science; Behavioral; Brain; Brain Pathology; Chronic; Clinical; Clinical Research; Cognitive deficits; Communication; Communities; Complication; Confusion; Curiosities; Dementia; Development; Development Plans; Elderly; Environment; Functional disorder; General Anesthesia; General Hospitals; General anesthetic drugs; Genetic; Genetic Techniques; Goals; Grant; Healthcare; Histopathology; Hospitalization; Hour; Human; Impairment; Intervention; Lead; Linear Models; Massachusetts; Mediating; Mentors; Mentorship; Neurocognitive; Neurons; Operant Conditioning; Outcome; Pathologic; Pathology; Phase; Positioning Attribute; Postoperative Complications; Pre-Clinical Model; Rattus; Reaction Time; Research; Research Personnel; Risk; Rodent Model; Role; Severities; Symptoms; Techniques; Testing; Therapeutic Intervention; Time; Training; Transgenic Organisms; Translational Research; Unconscious State; Variant; Ventral Tegmental Area; Viral; Work; Writing; behavior test; brain tissue; career; career development; career networking; clinically relevant; cognitive function; cognitive recovery; cognitive testing; cost; dopaminergic neuron; inattention; insight; locus ceruleus structure; medical schools; mortality risk; neural circuit; neuropathology; noninvasive brain stimulation; noradrenergic; novel; novel therapeutics; postoperative delirium; pre-clinical; prevent; prodromal Alzheimer' s disease; programs; skills; statistics; sustained attention; tau Proteins; tau aggregation; therapeutic target; tool; touchscreen; transgenic model of alzheimer disease

Postoperative delirium (POD) is a common and serious postoperative complication among the elderly, especially those with Alzheimer’s disease (AD), and has no available treatments. Interestingly, the risk for POD begins at preclinical AD stages when mild sustained attention deficits emerge. For this K99/R00, I will investigate the role of the locus coeruleus and ventral tegmental area – two regions affected by AD pathology and inhibited by general anesthetics – on the development of sustained attention deficits and POD using the rodent model of AD, TgF344-AD. I have developed a variant of the 5-choice serial reaction time task, a touchscreen sustained attention task, in which real-time cognitive recovery is assessed in rats following general anesthesia to capture the severity and duration of POD symptoms. In Aim 1 (K99), I will characterize the progression of sustained attention deficits in TgF344-AD and aging rats and its association with POD and AD histopathology. In Aim 2.1 (K99), I will use a novel dual-viral mediated chemogenetic targeting technique to establish the role of ventral tegmental area dopaminergic neurons in AD-related attentional impairments. With these skills, I will be well- equipped to independently pursue Aim 2.2 (R00), which applies the same techniques to investigate noradrenergic locus coeruleus neurons in AD-related attention impairments, and Aim 3 (R00), where chronic and acute activation of the ventral tegmental area and locus coeruleus will be used to mitigate AD-associated POD. My overall career goal is to lead an independent research group examining the underlying neural circuits impacting POD in AD with the long-term goal of creating interventional therapeutic strategies against dementia- associated POD. To accomplish this goal, I will need additional training in chemogenetic techniques, transgenic rodent models of AD, and AD neuropathology. For the K99 phase, I will have the guidance of my mentor, Dr. Ken Solt, who will train me in chemogenetics, and co-mentor, Dr. Zhongcong Xie, an expert in AD and POD research. My Advisory Committee, Drs. Christiane Wrann (AD transgenic model expertise) and Timothy Houle (statistics expertise), will provide research and professional guidance as I near independence. My career development plan integrates didactics in AD pathology and neuroengineering; training in communication, lab management, and grant writing; and professional networking opportunities. Massachusetts General Hospital and Harvard Medical School provide the ideal environment to conduct the proposed research, providing all the facilities necessary within a supportive, collaborative team of researchers and clinicians. The protected time and mentorship provided by this K99/R00 will allow me to acquire the technical and conceptual skills required to lead a focused research program on POD and AD research as an independent investigator. The outcome of this work will yield important insight into the role of neural circuits implicated in prodromal AD and aging and how they may be targeted to prevent and treat POD.

术后谵妄（POD）是老年人尤其是老年人常见且严重的术后并发症。 患有阿尔茨海默病（AD）的人，并且没有可用的治疗方法。有趣的是，POD 的风险始于 临床前 AD 阶段出现轻度持续注意力缺陷。对于这款K99/R00，我来考察一下作用 蓝斑和腹侧被盖区——这两个区域受 AD 病理影响并受到抑制 全身麻醉 – 使用 AD 啮齿动物模型研究持续注意力缺陷和 POD 的发展， TgF344-AD。我开发了 5 个选择的串行反应时间任务的变体，一个持续的触摸屏 注意力任务，其中评估全身麻醉后大鼠的实时认知恢复情况以捕获 POD 症状的严重程度和持续时间。在目标 1 (K99) 中，我将描述持续性的进展 TgF344-AD 和衰老大鼠的注意力缺陷及其与 POD 和 AD 组织病理学的关系。瞄准2.1 （K99），我将使用一种新型的双病毒介导的化学遗传学靶向技术来建立腹侧的作用 AD 相关注意力障碍中的被盖区多巴胺能神经元。有了这些技能，我就能很好地—— 具备独立追求目标 2.2 (R00) 的能力，该目标采用相同的技术进行调查 AD 相关注意力障碍中的去甲肾上腺素能蓝斑神经元和目标 3 (R00)，其中慢性 腹侧被盖区和蓝斑的急性激活将用于减轻 AD 相关性 荚。我的总体职业目标是领导一个独立的研究小组检查潜在的神经回路 影响 AD 中的 POD，长期目标是制定针对痴呆症的介入治疗策略 相关的 POD。为了实现这一目标，我需要在化学遗传学技术、转基因技术方面进行额外的培训 AD 啮齿动物模型和 AD 神经病理学。 K99阶段，我将得到我的导师Dr. Ken Solt 将对我进行化学遗传学方面的培训，共同导师谢中聪博士是 AD 和 POD 方面的专家 研究。我的顾问委员会，博士。 Christiane Wrann（AD 转基因模型专家）和 Timothy Houle （统计专业知识），将在我接近独立时提供研究和专业指导。我的职业生涯 发展计划整合了 AD 病理学和神经工程方面的教学法；沟通、实验室培训 管理和拨款写作；和专业的社交机会。马萨诸塞州综合医院和 哈佛医学院提供了进行拟议研究的理想环境，提供了所有 由研究人员和临床医生组成的支持性协作团队内所需的设施。受保护的时间和 K99/R00 提供的指导将使我能够获得领导所需的技术和概念技能 作为独立研究者开展 POD 和 AD 研究的重点研究项目。这项工作的成果 将深入了解神经回路在前驱 AD 和衰老中的作用以及它们如何发挥作用 有针对性地预防和治疗POD。