# Neurovascular dysfunction in delirium superimposed on dementia

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $322,620

## Abstract

ABSTRACT
As many as 20-30% of all COVID-19 patients develop delirium during hospitalization, an estimate that increases
to 60-70% in those that develop severe illness. Delirium is a well-established risk factor for dementia, thus the
impact of the ongoing pandemic on neurodegeneration will be long-lasting. In particular, we hypothesize that
COVID-19 infection will accelerate the progression and emergence of Alzheimer’s Disease Related Dementias
(ADRD) in the elderly by increasing both peripheral and central inflammation as well as decreasing the ability of
the lungs to supply the brain with sufficient oxygen to maintain normal cognitive function. This supplement to
RO1AG057525 “Neurovascular dysfunction in delirium superimposed on dementia” seeks to model the systemic
impact of inflammation, akin to the pathology reported in patients with COVID-19 infection, on the central nervous
system (CNS) by focusing on the neurovascular unit (NVU) and delirium-like behavior as key endpoints from our
parent grant. Furthermore, we have recently reported on the protective effects of our drug in development,
URMC-099 on the NVU after orthopedic surgery in mice with ongoing neurodegeneration. We are well-positioned
to rapidly evaluate the effects of this therapy after lung injury using methodological approaches established for
our parent grant. Our overall objective for this supplement is to determine the impact of the inflammatory milieu
on the NVU and cognitive function after lipopolysaccharide (LPS) inhalation as a simplified model of COVID-19-
related delirium. The central hypothesis is that inhaled LPS induces platelet aggregation, neutrophil adhesion,
and neurovascular hypoxia — key pathologic hallmarks found in patients with COVID-19. We contend that these
sequelae are preventable by treatment with the brain penetrant mixed-lineage kinase (MLK) inhibitor URMC-
099. Our hypothesis is based on preliminary data acquired in the applicants’ laboratories and will be tested by
pursuing 2 specific aims: 1) To implement an inhaled LPS-based lung injury model to translate the clinical
features of systemic COVID-19 infection by quantifying indices of neutrophils, neutrophil extracellular traps
(NETs), platelets and cytokine release syndrome as the basis for CNS dysfunction; 2) To define inflammatory
events at the NVU and related cognitive impairment in mice treated with inhaled LPS and reposition URMC-099
to prevent these sequelae. Feasibility for these models and techniques has been established in the applicants’
hands. In this innovative approach, real-time in-vivo brain imaging and postmortem analyses will be combined
with novel behavioral assays to define delirium-like changes in mice. The rationale for the proposed research is
that successful completion will advance our understanding of how COVID-19 affects CNS function and provide
new molecular mechanisms of relevance to aging, delirium, neurodegeneration, and the Alzheimer's Disease
and Related Dementias at-l...

## Key facts

- **NIH application ID:** 10181377
- **Project number:** 3R01AG057525-04S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Niccolo Terrando
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $322,620
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181377

## Citation

> US National Institutes of Health, RePORTER application 10181377, Neurovascular dysfunction in delirium superimposed on dementia (3R01AG057525-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10181377. Licensed CC0.

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