Neuropathology of Cognitive Impairment in Critical Illness

危重疾病认知障碍的神经病理学

• 批准号: 9810539
• 负责人: Shouri Lahiri
• 金额: $ 12.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810539
• 关键词: Abeta clearance; Acute Brain Injuries; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Award; Blood - brain barrier anatomy; Brain; Cerebral small vessel disease; Cerebrum; Cognition; Cognitive; Complication; Critical Care; Critical Illness; Data; Disease model; Drainage procedure; Enzyme-Linked Immunosorbent Assay; Functional disorder; Heart; Heart Atrium; Hour; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Intervention; Lung; Mechanical ventilation; Mechanics; Modeling; Mus; Neurobiology; Neurologic; Neurologist; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathway interactions; Physicians; Population; Positive-Pressure Respiration; Prevalence; Public Health; Rattus; Research; Research Proposals; Resources; Right atrial structure; Risk; Rodent; Scientist; Sepsis; Structure; Tail; Testing; Thoracic cavity structure; Tidal Volume; Time; Tracer; Tracheostomy Tube; Training; Transgenic Organisms; United States; Veins; Venous; Wild Type Mouse; abeta accumulation; career; clinical effect; endotracheal; fluorescence imaging; glymphatic system; improved; lung injury; mechanical pressure; mouse model; neuropathology; novel; pressure; transgenic model of alzheimer disease; trend

PROJECT SUMMARY Cognitive impairment, and specifically Alzheimer’s Disease, is a known sequela of mechanical ventilation and critical illness in older individuals. Although the prevalence of cognitive impairment after critical illness is expected to increase dramatically as our population ages, very little is understood about the specific mechanisms that underlie this finding and there is a significant need for therapies that ameliorate the public health impact of this condition. Prior research to understand the association between mechanical ventilation and cognitive impairment has been confounded by the underlying indication for mechanical ventilation, such as sepsis, surgery, or acute brain injury, all of which could independently contribute to cognitive impairment. To overcome this limitation, we developed a novel model of short-term mechanical ventilation in wild-type and double transgenic Alzheimer’s Disease-model mice to study the isolated consequences of mechanical ventilation in older individuals. Our preliminary data suggest that even short-term mechanical ventilation accelerates the neuropathology of Alzheimer’s Disease by increasing cerebral amyloid-β accumulation, however the exact mechanism by which this occurs remains unknown. We obtained additional data that show cognition-relevant neuropathological changes with elevated right atrial pressure, and now propose to examine whether the increase in right atrial pressure due to positive pressure mechanical ventilation impairs glymphatic clearance, increases blood-brain barrier leakiness, and increases cerebral amyloid-β accumulation -- thus contributing to the pathogenesis of Alzheimer’s Disease. Dr. Lahiri, the PI of this study, is a critical care neurologist and an early-career physician-scientist who developed the novel disease model and generated preliminary data presented in this proposal. Dr. Lahiri’ s previous research has focused on short- and long-term clinical effects of mechanical ventilation in acute brain injury, and he is now transitioning his focus to aging-related research. The GEMSSTAR award and associated institutional commitments would provide Dr. Lahiri with the time, resources, and training to launch a successful career in aging-research that focuses on the cognitive effects of critical illness in older individuals.

项目摘要 认知障碍，尤其是阿尔茨海默氏病，是机械通气和 老年人的重症疾病。尽管重病后认知障碍的患病率是 预计随着我们的人口年龄的增长，人们对特定的了解很少 这一发现的基础的机制以及对改善公众的疗法的重要需求 这种情况的健康影响。先前的研究以了解机械通气之间的关联 和认知障碍因机械通气的基本指示而感到困惑，例如 败血症，手术或急性脑损伤，所有这些都可能会导致认知障碍。到 克服了这一局限性，我们开发了一种新型的野生型机械通气的新型模型， 双转基因阿尔茨海默氏病模型小鼠研究机械的孤立后果 老年人的通风。我们的初步数据表明，即使是短期机械通气 通过增加脑淀粉样蛋白β的积累来加速阿尔茨海默氏病的神经病理学 但是，发生这种情况的确切机制仍然未知。我们获得了其他数据 显示与认知相关的神经病理学变化，右心房压力升高，现在建议 检查是否由于正压机械通气而导致的右心压增加是否增加 肾小球清除率，增加血脑屏障的泄漏，并增加脑淀粉样蛋白β的积累 - 因此有助于阿尔茨海默氏病的发病机理。 这项研究的PI Lahiri博士是一位重症监护神经病学家，也是早期的身体科学家 开发了新的疾病模型，并产生了本提案中介绍的初步数据。拉希里博士 先前的研究集中于急性大脑机械通气的短期和长期临床作用 受伤，他现在正在将重点转移到与衰老有关的研究中。 Gemsstar奖和关联 机构承诺将为Lahiri博士提供时间，资源和培训，以启动成功 衰老研究的职业专注于重症疾病对老年人的认知影响。