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.

Public Health Relevance

The proposed research has direct public health implications given the major impact of delirium and dementia on the aging cognitive and health trajectory and the lack of therapeutic options for either condition. This present application is also immediately relevant to the NIH's mission of fostering innovative research strategies for improving health through identification of the causes, preventive approaches, and management of delirium and dementia. This application will result in novel insights into the inter-relationship of dementia pathologies, amyloid and neurodegeneration, with delirium, supporting therapeutic development and screening tools for both conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG063849-02
Application #
9988997
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Roberts, Luci
Project Start
2019-08-15
Project End
2024-05-31
Budget Start
2020-07-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715