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.

项目摘要/摘要败血症是急性疾病住院的常见原因，每个患者都会影响超过2000万患者年。它的死亡率高达40％，幸存者的认知障碍负担很大。下列的重症疾病，有26％的没有预先存在认知缺陷的患者将具有认知功能与轻度阿尔茨海默氏病相似的评分。阿尔茨海默氏病和相关痴呆症（ADRD）是该国最大的残疾原因和第六大死亡原因。年成本进近1万亿美元。 ir妄是一种突然的混乱状态，在败血症和相关性中很常见随着发病率，死亡率的增加并获得了长期认知能力下降。虽然有两种条件的巨额成本 - 个人，财务和社会 - del妄和adrd丧失了疗法。痴呆症对痴呆症的双向临床倾向是del妄，反之亦然。但是，这种效果的基本机制尚不清楚。研究病理变化与 delirium提供了一个独特的机会，可以了解神经退行性的急性积累和 TAU病理可能导致疾病发病机理，并导致长期认知能力下降。我们将研究急性脑功能障碍和妄想，认知能力下降和ADRD的关系病理。我们将研究神经元损伤（神经丝光）的血浆生物标志物还是磷酸化的tau病（阿尔茨海默氏病的生物标志物）与急性脑功能障碍有关在随后或认知下降期间，与败血症相关的危害疾病。我们也会研究炎症（和临床因素）在驱动神经元损伤和TAU变化的作用疾病，当我们研究del妄的机制和ADRD病理的积累。这些调查将从根本上阐明del妄的机制危害疾病，可能导致认知能力下降，并提供对发病机理的新见解 del妄。我们解决我们领域中最关键的问题：del妄如何加剧认知衰退？我们利用NIH资助的Mends2研究来解决这些问题有效的方式，分析已经被生物群的1526个样本。所有必要的临床数据对于此项目，收集并准备好分析。通过了解ir妄的机制和ADRD，包括神经退行性和TAU病理和炎症的相互作用，我们将确定潜在的治疗方法，以防止与ADRD相关的病理增加。我们也会提供有关急性疾病期间ADRD病理筛查是否可以识别的重要信息有认知能力下降的风险的受试者并确定了减轻病理增加的新方法。我们的长期目标是限制急性和重症疾病的认知负担，从而减轻负担在我们社区中的阿德德。