# Delirium, Long-Term Cognition and the Dementia Pathological Trajectory

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $87,145

## Abstract

Project Summary/Abstract
Sepsis is a common cause of acute illness hospitalization affecting more than 20 million patients each
year. It has a mortality rate of up to 40% and a high burden of cognitive impairment in surviors. Following
critical illness, 26% of patients without pre-existing cognitive deficits will have cognitive function
scores similar to mild Alzheimer's disease. Alzheimer's Disease and Related Dementias (ADRD) are the
greatest cause of disability, and the sixth leading cause of death, in the country. Annual costs
approach $1 trillion. Delirium is a sudden state of confusion that is common in sepsis and associated
with increased morbidity, mortality and acquired long-term cognitive decline. Although there are
substantial costs to both conditions - personal, financial and societal - delirium and ADRD are bereft of
therapies. There is an established bidirectional clinical predisposition of dementia to delirium and vice-versa;
however, the underlying mechanisms for this effect are unknown. Studying pathological changes associated
with delirium offers a unique opportunity to understand how acute accumulations of neurodegenerative and
tau pathologies may contribute to disease pathogenesis and lead to long-term cognitive decline. We will
investigate the inter-relationship of acute brain dysfunction and delirium, cognitive decline and ADRD
pathologies. We will investigate whether plasma biomarkers for neuronal injury (neurofilament light) or
phosphorylated tau disease (a biomarker of Alzheimer's disease) are associated with acute brain dysfunction
and delirium during, or cognitive decline following, sepsis-associated critical illness. We will also
investigate the role of inflammation (and clinical factors) to drive changes in neuronal injury and tau
disease, as we investigate the mechanisms of delirium and accumulation of ADRD pathologies. These
investigations will fundamentally illuminate the mechanisms through which delirium, resulting from
critical illness, may lead to cognitive decline as well as provide novel insights into the pathogenesis
of delirium. We address the most critical question in our field: how does delirium exacerbate cognitive
decline? We leverage our NIH-funded MENDS2 study to address these questions in a feasible and
efficient way, analysing 1526 samples that are already biobanked. All the necessary clinical data required
for this project are collected and ready to be analysed. Through understanding the mechanisms of delirium
and ADRD, including the interaction of neurodegenerative and tau pathologies and inflammation, we will
identify potential therapeutic approaches to prevent increases in ADRD-related pathology. We will also
provide important information on whether screening for ADRD pathologies during acute illnesses may identify
subjects at risk for cognitive decline and identify novel approaches to mitigate the increases in pathology.
Our long-term aim is to limit the cognitive burden of acute and critical il...

## Key facts

- **NIH application ID:** 10757413
- **Project number:** 5R21AG080420-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Christopher Hughes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $87,145
- **Award type:** 5
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10757413

## Citation

> US National Institutes of Health, RePORTER application 10757413, Delirium, Long-Term Cognition and the Dementia Pathological Trajectory (5R21AG080420-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10757413. Licensed CC0.

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