# Immunovascular interactions in postoperative delirium superimposed on dementia (DSD).

> **NIH NIH RF1** · DUKE UNIVERSITY · 2022 · $2,244,681

## Abstract

ABSTRACT
Systemic inflammation triggered by surgical trauma can negatively impact brain function, particularly in older
adults and/or frail patients with pre-existing dementia. One frequent neurologic complication for these patients is
delirium, an acutely debilitating change in brain function that precedes an adverse prognosis. Indeed, patients
that develop delirium superimposed on dementia (DSD) have significiantly worse outcomes with mortality rates
as high as 92% two years after surgery, compared to a 7% post-surgical mortality in patients without dementia
or delirium. Damage to the blood-brain barrier (BBB), a key interface that regulates neuroimmune interactions
between the periphery and the brain, may play a role in DSD. Using a clinically-relevant mouse model of delirium-
like behavior as a result of orthopedic surgery, we have identified a prominent role for the innate immune
response in promoting BBB dysfunction, and neuroinflammation. Notably, BBB breakdown has been reported in
many neurodegenerative conditions, including Alzhemeir’s disease (AD) as well as during aging via altered
transcellular permeability and trafficking of blood-derived factors into the brain parenchyma. Yet, the
mechanisms by which surgery impacts the BBB and the specific role(s) of vascular dysfunction in DSD remain
unknown. Our overall objective is to identify postoperative mechanisms for BBB dysfunction in DSD. Our central
hypothesis is that systemic factors impair structure and function of discrete brain vasculature and BBB leading
to neuroinflammation, neurodegeneration, and delirium-like behavior in AD mice after surgery. We propose two
Specific Aims: 1) to characterize how the postoperative systemic milieu impacts the BBB using organ-on-chip
technology comprised of μSiM (microphysiologic system with nanoporous silicon membranes) populated with
human iPSCs; and 2) to define cellular and molecular mechanisms mediating DSD-induced vascular dysfunction
after surgery. Feasibility for these models and techniques has been established in the applicants’ hands. In this
innovative approach, organ-on-chip technology will complement unbiased spatial profiling of vascular changes
in the brain of dementia-prone mice with delirium-like behavior. The rationale for the proposed research is that
successful completion will expand our understanding of how surgery affects the blood-brain interface, and will
provide new molecular mechanisms of relevance to delirium, and neurodegeneration. Such knowledge is highly
significant because it will implement new technologies to investigate immune-vascular interactions and inform
the advancement of safe therapies to limit postoperative neurocognitive complications in vulnerable patients.

## Key facts

- **NIH application ID:** 10524797
- **Project number:** 1RF1AG079138-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** HARRIS A GELBARD
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,244,681
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10524797

## Citation

> US National Institutes of Health, RePORTER application 10524797, Immunovascular interactions in postoperative delirium superimposed on dementia (DSD). (1RF1AG079138-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10524797. Licensed CC0.

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