Clarifying the overlapping pathology of delirium and dementia

澄清谵妄和痴呆的重叠病理学

• 批准号: 10202478
• 负责人: ROBERT A PEARCE
• 金额: $ 74.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202478
• 关键词: Acute; Address; Affect; Aging; Alzheimer' s Disease; Amyloid; Amyloid deposition; Anatomy; Anterior; Atrophic; Behavior; Biological; Biological Markers; Brain; Cause of Death; Characteristics; Chronic; Cognition; Cognitive; Cognitive aging; Confusion; Data; Data Collection; Delirium; Dementia; Elderly; Electrodes; Electroencephalogram; Electrophysiology (science); Fostering; Health; Image; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; Light; Longitudinal cohort study; Magnetic Resonance Imaging; Methodology; Mission; Morbidity - disease rate; Nerve Degeneration; Neuronal Injury; Operative Surgical Procedures; Pathogenesis; Pathologic; Pathology; Patients; Perioperative; Perioperative Care; Pilot Projects; Plasma; Positron-Emission Tomography; Postoperative Period; Predisposition; Preventive; Public Health; Quality of life; Research; Risk; Role; Screening procedure; Severities; Source; Testing; Therapeutic; Time; United States; United States National Institutes of Health; Wakefulness; amyloid pathology; base; cerebral atrophy; cingulate cortex; cognitive change; cohort; cost; cytokine; density; entorhinal cortex; improved; innovation; insight; ischemic injury; ischemic lesion; longitudinal positron emission tomography; medical complication; mortality; neurofilament; novel; novel marker; novel therapeutic intervention; novel therapeutics; postoperative delirium; prevent; primary outcome; screening; serial imaging; systemic inflammatory response; therapeutic development

Project Summary/Abstract Dementia is the sixth leading cause of death in the United States and is associated with loss of quality of life and independence; it cannot be prevented, cured, or even slowed. Delirium is a sudden state of confusion that is associated with increased morbidity and mortality and impaired long-term cognition. Although there are substantial costs to both conditions – financial, societal and individual – delirium and dementia are bereft of therapies, largely due to the limited understanding of their pathogeneses. The bidirectional predisposition of dementia and delirium to each other offers a unique opportunity to understand their overlapping pathological mechanisms and to identify new therapeutic approaches. For example, predisposition to delirium and dementia, denoted by amyloid deposition, is associated with increased frontal alpha power, suggesting that similar changes in brain dynamics are evident before the onset of either condition. Cortical slow wave activity (SWA) is a shared electrophysiological hallmark of cognitive changes in aging, delirium and dementia. We propose that understanding SWA in wakefulness, which affects all these conditions, will lead to novel, mutually informative insights into the pathogenesis of those conditions. Our overarching hypothesis is that delirium results from an interaction between inflammation and two key dementia pathologies, amyloid and neurodegeneration, leading to the electrophysiological disturbance of cortical SWA and impaired connectivity, which results in delirium. In this application, we will test how amyloid and neurodegeneration predispose to (Specific Aim 1) and are exacerbated by (Specific Aim 3) an episode of delirium. We will also investigate the mechanistic role of inflammation to induce delirium, SWA, and connectivity changes through interaction with amyloid pathology and neurodegeneration (Specific Aim 2). In this way, we can understand how delirium interacts with the trajectory of two dementia pathologies, while understanding how SWA, and therefore the cognitive changes of delirium, can arise so abruptly. Our technical innovation is to use 256 channel high- density electroencephalogram (HD-EEG) to track the electrophysiological changes with behavior. We will source reconstruct the SWA to individual subject anatomy using state-of-the-art electrode digitization to allow correspondence of the SWA to a subject's magnetic resonance imaging (MRI) or positron emission tomography (PET) amyloid data. Mapping spatial overlap in pathologies is our methodological innovation, which enhances biological plausibility for any relationship. We will track how delirium contributes to neuropathological changes that may account for the cognitive decline after surgery. Our data will illuminate the pathological overlap of delirium and dementia, highlighting (i) new avenues for screening/novel biomarker endpoints for amyloid pathology or risk of delirium (frontal alpha power) and (ii) therapeutic development targeted to a mechanistic understanding of cortical SWA as an underpinning for those cognitive changes.

项目摘要/摘要 痴呆症是美国第六大死亡原因，与生活质量丧失和 独立;它无法预防，治愈，甚至放慢速度。 ir妄是一种突然的混乱状态 与发病率和死亡率增加以及长期认知受损有关。虽然有 这两种情况的大量成本 - 财务，社会和个人 - del妄和痴呆症是 疗法，很大程度上是由于对病原体的理解有限。双向倾向 彼此的痴呆症和del妄提供了一个独特的机会来了解其重叠的病理 机制并确定新的治疗方法。例如，偏爱del妄和痴呆症， 用淀粉样蛋白沉积表示，与额叶α功率增加有关，表明类似的变化 在脑动力学中，这是两种疾病发作之前的证据。皮质慢波活动（SWA）是共享 衰老，妄想和痴呆症认知变化的电生理标志。我们提出了这一点 了解所有这些条件的清醒中的SWA将导致新颖的，相互的信息 洞悉这些条件的发病机理。我们的总体假设是ir妄来自 炎症与两种关键痴呆病理学，淀粉样蛋白和 神经变性，导致皮质SWA的电生理灾难并受损 连通性，导致del妄。在此应用中，我们将测试淀粉样蛋白和神经变性 倾向于（特定目标1），并因（特定目标3）del妄而加剧。我们也会 研究炎症在诱导ir妄，SWA和连通性的机理作用。 与淀粉样病理和神经变性的相互作用（特定目标2）。这样，我们可以理解如何 ir妄与两种痴呆病理的轨迹相互作用，同时了解SWA，因此 del妄的认知变化可能会如此突然出现。我们的技术创新是使用256频道高级 密度脑电图（HD-EEG）以行为跟踪电生理变化。我们将来源 使用最先进的电极数字化将SWA重建为单个主题解剖结构，以允许 SWA与受试者的磁共振成像（MRI）或正电子发射断层扫描的对应关系 （PET）淀粉样蛋白数据。绘制病理学的空间重叠是我们的方法论创新，它增强了 任何关系的生物合理性。我们将跟踪ir妄如何对神经病理学变化做出贡献 这可能是手术后的认知能力下降。我们的数据将阐明 del妄和痴呆，突出显示（i）筛查/新型生物标志物淀粉样蛋白的新途径 del妄的病理或风险（额叶α功率）和（ii）针对机械的治疗发育 理解皮质SWA是这些认知变化的基础。