# Neurovascular dysfunction in delirium superimposed on dementia

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $561,845

## Abstract

ABSTRACT
Impaired cognitive function after common surgical procedures is a growing concern especially among over 5
million people in the United States who suffer from dementia, including Alzheimer's disease (AD), and thus
have a 3-fold increased risk for fracture requiring surgical repair. After orthopedic surgery, acute changes in
cognitive function, often referred to as postoperative delirium, occur in up to 89% of patients with preexisting
dementia, and associate with poorer prognosis and even 2-fold greater risk for 1-year mortality compared to
patients without dementia or delirium. Our long-term goal is to define the mechanisms that underlie surgery-
induced cognitive dysfunction, and to provide safe and effective approaches to reduce this potentially
devastating complication. In the proposed study, we will model postoperative delirium superimposed on
dementia by subjecting mice with cerebral amyloid angiopathy (CAA), which is common in AD patients, to
orthopedic surgery (tibial fracture). Our overall objective is to determine the role of the blood–brain interface
(the neurovascular unit (NVU) and the blood-brain barrier (BBB) within) and vascular β-amyloid deposition in
cognitive function after orthopedic surgery in CAA mice. The central hypothesis is that surgery-induced
BBB/NVU dysfunction is worsened in the presence of CAA, and that this is potentially preventable by
regulating microglial function, which in turn, can impact postoperative cognitive outcomes. This hypothesis is
based on preliminary data acquired in the applicants' laboratories, and will be tested by pursuing 3 specific
aims: 1) Analyze BBB/NVU dysfunction in a CAA mouse model after orthopedic surgery; 2) Define the extent
to which systemic inflammation and monocyte infiltration impact microglial function in CAA mice after
orthopedic surgery; and 3) Determine the effects of an MLK3 inhibitor on microglial function, vascular β-
amyloid deposition, and cognition in CAA mice after orthopedic surgery. 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 unbiased profiling of the neurovasculature and novel
behavioral assays to define delirium-like changes in dementia-prone mice. The rationale for the proposed
research is that successful completion will advance and expand our understanding of how surgery affects the
blood-brain interface, and will provide new molecular mechanisms of relevance to delirium, neurodegeneration,
and aging. Such knowledge is highly significant because it has the potential to improve surgical outcome and
quality of life for millions of elderly vulnerable patients in the United States.

## Key facts

- **NIH application ID:** 9919475
- **Project number:** 5R01AG057525-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Niccolo Terrando
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $561,845
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919475

## Citation

> US National Institutes of Health, RePORTER application 9919475, Neurovascular dysfunction in delirium superimposed on dementia (5R01AG057525-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9919475. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*