Delirium, Long-Term Cognition and the Dementia Pathological Trajectory

谵妄、长期认知和痴呆病理轨迹

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要/摘要脓毒症是急性疾病住院的常见原因，每年影响超过 2000 万患者年。它的死亡率高达40%，并且幸存者认知障碍的负担很高。下列的危重疾病时，26%没有预先存在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) 是该国最大的残疾原因和第六大死亡原因。年度费用接近1万亿美元。谵妄是一种突然的混乱状态，常见于败血症和相关疾病随着发病率、死亡率的增加和获得性长期认知能力下降。虽然有谵妄和 ADRD 都会给个人、财务和社会这两种情况带来巨大的损失疗法。痴呆与谵妄之间存在双向临床倾向，反之亦然；然而，这种效应的潜在机制尚不清楚。研究相关病理变化谵妄症提供了一个独特的机会来了解神经退行性和精神错乱的急性积累是如何发生的。 tau 蛋白病理可能导致疾病发病机制并导致长期认知能力下降。我们将研究急性脑功能障碍与谵妄、认知能力下降和 ADRD 的相互关系病理学。我们将研究神经元损伤的血浆生物标志物（神经丝光）或磷酸化 tau 蛋白疾病（阿尔茨海默病的生物标志物）与急性脑功能障碍有关脓毒症相关危重疾病期间的谵妄或认知能力下降。我们还将研究炎症（和临床因素）在驱动神经元损伤和 tau 蛋白变化中的作用疾病，当我们研究谵妄和 ADRD 病理累积的机制时。这些调查将从根本上阐明导致谵妄的机制危重疾病，可能导致认知能力下降，并为发病机制提供新的见解谵妄。我们解决了我们领域中最关键的问题：谵妄如何加剧认知能力衰退？我们利用 NIH 资助的 MENDS2 研究以可行且可行的方式解决这些问题有效的方法，分析 1526 个已经生物库的样本。所需的所有必要的临床数据为此项目收集并准备进行分析。通过了解谵妄的机制和 ADRD，包括神经退行性病变和 tau 病理学以及炎症的相互作用，我们将确定潜在的治疗方法，以防止 ADRD 相关病理的增加。我们还将提供重要信息，说明在急性疾病期间筛查 ADRD 病理是否可以识别受试者有认知能力下降的风险，并确定新的方法来减轻病理学的增加。我们的长期目标是限制急性和危重疾病的认知负担，从而减轻负担 ADRD 在我们社区中的应用。