Clarifying the overlapping pathology of delirium and dementia

澄清谵妄和痴呆的重叠病理学

• 批准号: 10632111
• 负责人: ROBERT A PEARCE
• 金额: $ 77.04万
• 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/10632111
• 关键词: Acceleration; 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; Electroencephalography; Electrophysiology (science); Fostering; Health; Image; Impaired cognition; Impairment; Incidence; Individual; Inflammation; Inflammatory; Interleukin-6; Light; Longitudinal cohort study; Magnetic Resonance Imaging; Maps; 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; Predisposition; Preventive; Public Health; Quality of life; Research; Risk; Role; Screening procedure; Severities; Sleep; Source; Temporal Lobe; Testing; Therapeutic; Time; United States; United States National Institutes of Health; Wakefulness; amyloid pathology; 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; mild cognitive impairment; mortality; neurofilament; neuropathology; 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.

项目总结/摘要 痴呆症是美国第六大死亡原因，与生活质量下降有关， 独立;它不能被阻止，治愈，甚至减缓。谵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相关。虽然有 这两种疾病--经济、社会和个人--都付出了巨大的代价， 治疗，很大程度上是由于其发病机制的了解有限。双向倾向 痴呆和谵妄彼此提供了一个独特的机会，了解他们的重叠病理 机制，并确定新的治疗方法。例如，易患谵妄和痴呆， 以淀粉样蛋白沉积表示，与额叶α功率增加有关，这表明类似的变化 在任何一种情况出现之前，大脑动力学的变化都很明显。皮层慢波活动（SWA）是一种共享的 在衰老、谵妄和痴呆中认知变化的电生理学标志。我们建议 了解影响所有这些条件的清醒状态下的SWA，将导致新的，相互信息 深入了解这些疾病的发病机制。我们的首要假设是谵妄是由 炎症和两种关键的痴呆病理学，淀粉样蛋白和 神经变性，导致皮层SWA的电生理紊乱和受损 连通性导致精神错乱在这个应用程序中，我们将测试淀粉样蛋白和神经变性 易患（特定目标1）并因（特定目标3）谵妄发作而加重。我们还将 研究炎症诱导谵妄、SWA和连接性变化的机制作用， 与淀粉样蛋白病理学和神经变性的相互作用（具体目标2）。这样，我们就可以理解 谵妄与两种痴呆病理学的轨迹相互作用，同时了解SWA如何，因此 精神错乱的认知变化会突然出现我们的技术创新是采用256通道高- 高密度脑电图（HD-EEG）跟踪行为的电生理变化。我们将源 使用最先进的电极数字化重建SWA到个体受试者解剖结构， 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性 (PET)淀粉样蛋白数据。映射病理学的空间重叠是我们的方法创新， 任何关系的生物相容性。我们将追踪谵妄如何导致神经病理学变化 可能导致术后认知能力下降的原因我们的数据将阐明 谵妄和痴呆，强调（i）淀粉样蛋白筛选/新生物标志物终点的新途径 病理学或谵妄风险（额叶α功率）和（ii）针对机制的治疗开发 理解皮层SWA作为这些认知变化的基础。

项目成果

Postoperative troponin increases after noncardiac surgery are associated with raised neurofilament light: a prospective observational cohort study.

非心脏手术后术后肌钙蛋白增加与神经丝光升高相关：一项前瞻性观察队列研究。

• DOI: 10.1016/j.bja.2020.10.012
• 发表时间: 2021
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: Sanders,RobertD;Craigova,Lenka;Schessler,Benjamin;Casey,Cameron;White,Marissa;Parker,Margaret;Kunkel,David;Blennow,Kaj;Zetterberg,Henrik;Pearce,RobertA;Lennertz,Richard
• 通讯作者: Lennertz,Richard

Resolution of elevated interleukin-6 after surgery is associated with return of normal cognitive function.

• DOI: 10.1016/j.bja.2023.05.023
• 发表时间: 2023-06
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: Jennifer Taylor;J. Wu;David Kunkel;Margaret Parker;Cameron A. Rivera;Cameron P. Casey;S. Naismith;A. Teixeira-Pinto;M. Maze;R. Pearce;R. Lennertz;Robert D. Sanders

Impact of postoperative delirium on days alive and at home after surgery: a prospective cohort study.

术后谵妄对术后存活天数和在家中的影响：一项前瞻性队列研究。

• DOI: 10.1016/j.bja.2021.08.027
• 发表时间: 2021
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: Kunkel,David;Parker,Margaret;Casey,Cameron;Krause,Bryan;Pearce,RobertA;Lennertz,Richard;Sanders,RobertD
• 通讯作者: Sanders,RobertD

Role of interleukin-18 in postoperative delirium: an exploratory analysis.

IL-18 在术后谵妄中的作用：探索性分析。

• DOI: 10.1016/j.bja.2021.12.037
• 发表时间: 2022
• 期刊: British journal of anaesthesia
• 影响因子: 9.8
• 作者: Wu,JustinG;Taylor,Jennifer;Parker,Maggie;Kunkel,David;Rivera,Cameron;Pearce,RobertA;Lennertz,Richard;Sanders,RobertD
• 通讯作者: Sanders,RobertD

The U-shaped curve predicting cognitive vulnerability to delirium severity.

U 形曲线预测谵妄严重程度的认知脆弱性。

• DOI: 10.1093/brain/awad115
• 发表时间: 2023
• 期刊: Brain : a journal of neurology
• 作者: Lennertz,RichardC;Sanders,RobertD
• 通讯作者: Sanders,RobertD