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Clarifying the overlapping pathology of delirium and dementia

澄清谵妄和痴呆的重叠病理学

基本信息

批准号：
10408717
负责人：
ROBERT A PEARCE
金额：
$ 76.97万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10408717
关键词：
Acute Address Affect Aging Alzheimer&apos 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

项目摘要

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/文摘