Delirium, Long-Term Cognition and the Dementia Pathological Trajectory

谵妄、长期认知和痴呆病理轨迹

• 批准号: 10574994
• 负责人: Christopher Hughes
• 金额: $ 35.06万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10574994
• 关键词: Acute; Address; Admission activity; Affect; Age; Aging; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid; Axon; Biological Markers; Blood; Brain Injuries; Brain Pathology; Cause of Death; Cerebrospinal Fluid; Cerebrum; Clinical; Clinical Data; Cognition; Cognitive; Cognitive deficits; Collaborations; Coma; Communities; Complex; Complication; Confusion; Country; Critical Illness; Data; Delirium; Dementia; Development; Dexmedetomidine; Disease; Etiology; Fostering; Functional disorder; Funding; Health; Hospitalization; Hypotension; Hypoxia; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Intensive Care Units; Interleukin-8; Intervention Studies; Investigation; Light; Liquid substance; Manuscripts; Measures; Mediating; Mediation; Mediator; Mission; Morbidity - disease rate; Nerve Degeneration; Neurocognitive; Neuronal Injury; Neurons; Operative Surgical Procedures; Organ; Organ failure; Pathogenesis; Pathologic; Pathology; Patients; Perfusion; Plasma; Postoperative Period; Predisposition; Preventive; Propofol; Proteins; Public Health; Randomized, Controlled Trials; Research; Research Design; Risk; Risk Factors; Role; Sampling; Sedation procedure; Sepsis; Severities; Severity of illness; Stress; Telephone Interviews; Therapeutic; Time; United States National Institutes of Health; axon injury; biobank; blood-based biomarker; brain dysfunction; cognitive function; cognitive interview; cognitive load; cost; cytokine; disability; improved; innovation; insight; interest; modifiable risk; mortality; nervous system disorder; neurofilament; neuropathology; novel; novel strategies; novel therapeutics; postoperative delirium; prevent; prognostication; response; secondary analysis; sedative; septic; septic patients; sex; tau Proteins; tau-1; therapeutic target; therapy development; β-amyloid burden

Project Summary/Abstract Sepsis is a common cause of acute illness hospitalization affecting more than 20 million patients each year. It has a mortality rate of up to 40% and a high burden of cognitive impairment in surviors. Following critical illness, 26% of patients without pre-existing cognitive deficits will have cognitive function scores similar to mild Alzheimer's disease. Alzheimer's Disease and Related Dementias (ADRD) are the greatest cause of disability, and the sixth leading cause of death, in the country. Annual costs approach $1 trillion. Delirium is a sudden state of confusion that is common in sepsis and associated with increased morbidity, mortality and acquired long-term cognitive decline. Although there are substantial costs to both conditions - personal, financial and societal - delirium and ADRD are bereft of therapies. There is an established bidirectional clinical predisposition of dementia to delirium and vice-versa; however, the underlying mechanisms for this effect are unknown. Studying pathological changes associated with delirium offers a unique opportunity to understand how acute accumulations of neurodegenerative and tau pathologies may contribute to disease pathogenesis and lead to long-term cognitive decline. We will investigate the inter-relationship of acute brain dysfunction and delirium, cognitive decline and ADRD pathologies. We will investigate whether plasma biomarkers for neuronal injury (neurofilament light) or phosphorylated tau disease (a biomarker of Alzheimer's disease) are associated with acute brain dysfunction and delirium during, or cognitive decline following, sepsis-associated critical illness. We will also investigate the role of inflammation (and clinical factors) to drive changes in neuronal injury and tau disease, as we investigate the mechanisms of delirium and accumulation of ADRD pathologies. These investigations will fundamentally illuminate the mechanisms through which delirium, resulting from critical illness, may lead to cognitive decline as well as provide novel insights into the pathogenesis of delirium. We address the most critical question in our field: how does delirium exacerbate cognitive decline? We leverage our NIH-funded MENDS2 study to address these questions in a feasible and efficient way, analysing 1526 samples that are already biobanked. All the necessary clinical data required for this project are collected and ready to be analysed. Through understanding the mechanisms of delirium and ADRD, including the interaction of neurodegenerative and tau pathologies and inflammation, we will identify potential therapeutic approaches to prevent increases in ADRD-related pathology. We will also provide important information on whether screening for ADRD pathologies during acute illnesses may identify subjects at risk for cognitive decline and identify novel approaches to mitigate the increases in pathology. Our long-term aim is to limit the cognitive burden of acute and critical illness and hence, reduce the burden of ADRD in our communities.

项目摘要/摘要 败血症是急性疾病住院的常见原因，每个患者都有2000多万人受到影响。 年。它的死亡率高达40%，幸存者的认知障碍负担很高。跟随 危重疾病，26%的无认知缺陷的患者将具有认知功能 评分与轻度阿尔茨海默病相似。阿尔茨海默病和相关痴呆症(ADRD)是 这是导致残疾的最大原因，也是该国第六大死亡原因。年度成本 接近1万亿美元。精神错乱是一种突如其来的混乱状态，在脓毒症中很常见，并与 随着发病率、死亡率和获得性长期认知功能的下降而增加。尽管有 两种疾病--个人、经济和社会--都付出了巨大的代价，精神错乱和ADRD被剥夺了 治疗。痴呆症与神志不清之间存在双向临床易感性； 然而，这种效应的潜在机制尚不清楚。研究相关的病理变化 精神错乱提供了一个独特的机会来了解急性堆积的神经退行性和 Tau的病理改变可能参与疾病的发病机制，并导致长期的认知功能衰退。我们会 急性脑功能障碍与神志不清、认知功能减退及ADRD的相互关系 病理学。我们将调查神经元损伤的血浆生物标记物(神经丝光)或 磷酸化tau病(阿尔茨海默病的生物标志物)与急性脑功能障碍有关 以及败血症相关危重疾病期间的精神错乱或认知能力下降。我们还将 研究炎症(和临床因素)在神经元损伤和tau改变中的作用 疾病，因为我们调查了精神错乱和ADRD病理堆积的机制。这些 研究将从根本上阐明由精神错乱引起的 危重疾病，可能会导致认知能力下降，并为发病机制提供新的见解 精神错乱。我们解决了我们领域中最关键的问题：精神错乱如何加剧认知 拒绝？我们利用美国国立卫生研究院资助的MENDS2研究，以一种可行和 一种高效的方法，分析了1526个已经被生物库储存的样本。所有必需的临床数据 为这个项目收集并准备好进行分析。通过了解精神错乱的机制 和ADRD，包括神经退行性病变和tau病理与炎症的相互作用，我们将 确定潜在的治疗方法，以防止ADRD相关病理的增加。我们还将 提供有关在急性疾病期间筛查ADRD病理是否可以确定 有认知衰退风险的受试者，并找出新的方法来减轻病理上的增加。 我们的长期目标是限制急危重症的认知负担，从而减轻负担 ADRD在我们社区的传播。