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.

项目摘要/摘要 痴呆症是美国第六大死亡原因，并因生活质量和生活的丧失而陷入困境 独立；它不能阻止，咖喱甚至放缓。 与病态增加，死亡率和长期认知受损有关。 这两种情况的巨额成本 - 财务，社交和个人 - del妄和痴呆症丧失 疗法，很大程度上是由于对病原体的有限理解。 彼此的痴呆症和del妄提供了一个独特的机会，可以理解其重叠的病理 机制并确定新的治疗方法。 用淀粉样蛋白沉积表示，与额叶α功率的增加有关，表明类似的变化 在两种疾病开始之前，在大脑动力学中都是明显的。 认知变化，del妄和痴呆症的电生理标志 了解影响所有这些条件的清醒中的SWA，将导致新颖的，相互的信息 洞悉这些内容的发病机理。 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的电生理学障碍并受损 连通性，导致此应用中的del妄。 倾向于（特定的目标1），并因（特定目标3）发作而加剧 研究炎症诱导del妄，SWA和连通性的机理作用 与淀粉样蛋白病理学和神经变性的相互作用（特定目标2）。 ir妄与两种痴呆病理的轨迹相互作用，同时了解SWA，因此 ir妄的认知变化 密度脑电图（HD-EEG）通过行为来跟踪电生理变化 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对受试者的磁共振成像（MRI）或正电子发射断层扫描 （PET）淀粉样蛋白的数据。 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。 del妄和痴呆症，突出显示（i）淀粉样蛋白终点的新途径 del妄的病理或风险（额叶α功率）和（ii）针对机械的治疗发育 对这些认知变化的基础，将皮质SWA理解为基础。

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

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

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

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