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.

项目概要 认知障碍，特别是阿尔茨海默氏病，是机械通气和机械通气的已知后遗症。 尽管危重病后认知障碍的患病率很高。 随着我们的人口老龄化，预计会急剧增加，但我们对具体情况知之甚少 这一发现背后的机制，并且非常需要改善公众的治疗方法 先前的研究旨在了解机械通气之间的关联。 认知障碍与机械通气的潜在适应症相混淆，例如 败血症、手术或急性脑损伤，所有这些都可能独立导致认知障碍。 为了克服这一限制，我们开发了一种在野生型和 双转基因阿尔茨海默病模型小鼠研究机械作用的孤立后果 我们的初步数据表明，即使是短期机械通气。 通过增加大脑淀粉样蛋白-β的积累加速阿尔茨海默病的神经病理学， 然而，发生这种情况的确切机制仍然未知。 显示右心房压力升高与认知相关的神经病理学变化，现在建议 检查正压机械通气导致的右心房压力增加是否会损害 类淋巴清除率，增加血脑渗漏屏障，并增加大脑淀粉样蛋白-β的积累 ——从而促进了阿尔茨海默病的发病机制。 Lahiri 博士是本研究的 PI，是一位重症监护神经科医生，也是一位职业生涯早期的医生兼科学家， 开发了新的疾病模型并生成了 Lahiri 博士的提案中提出的初步数据。 先前的研究重点是机械通气对急性脑损伤的短期和长期临床效果 受伤，他现在将注意力转向与衰老相关的研究。 机构承诺将为拉希里博士提供时间、资源和培训，以成功启动 衰老研究的职业，重点关注老年人危重疾病的认知影响。