# Postoperative Delirium and Alzheimer's Disease Related Dementias

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $709,656

## Abstract

Postoperative delirium (POD), a clinical phenomenon different from postoperative cognitive dysfunction, is
the most common postoperative complication among older patients and is associated with substantially
increased rates of morbidity and mortality, as well as an increased cost of care, and risk of developing
Alzheimer's disease and related dementias (ADRD). Specifically, people with ADRD are at an increased risk of
developing delirium, and dementia-free patients who experience delirium are at higher risk of developing
ADRD. However, the pathogenesis of POD is still largely unknown, and this gap in knowledge impedes current
efforts in preventing and treating POD. To further study the POD pathogenesis, we have established a rodent
model, called the Confusion Assessment Method (CAM) in mice, to assess the delirium-like behavior in mice.
Consistent with the notion that Tau phosphorylation and neuroinflammation are part of ADRD
neuropathogenesis and are associated with cognitive impairments, our preliminary studies showed that open
abdominal surgery under general anesthesia (anesthesia/surgery) induced neuroinflammation and POD-like
behavior in aged mice which had elevated levels of brain phosphorylated Tau (pTau). Thus, the proposed
research will extend these studies to define a potential multifactorial model of POD pathogenesis by testing the
following hypothesis: anesthesia/surgery-induced neuroinflammation is exacerbated by aging- or AD gene
mutation-associated accumulation of brain pTau, leading to neuronal dysfunction and POD-like behavior in
mice. We will employ biochemical and genetic tools through both in vivo (mice) and in vitro (neuron and
microglia) approaches to accomplish three Specific Aims: 1) We will evaluate the effects of abdominal surgery
under anesthesia with 1.4% isoflurane, 3% sevoflurane or 9% desflurane for two hours on plasma and brain
levels of IL-6 and pTau, microglia activation, neuronal dysfunction, and POD-like behavior in mice. 2) We will
perform in vitro studies to determine the trafficking of neuronal pTau and microglia IL-6, and their effects on
each other's generation and consequent neuronal dysfunction, using the neurons and microglia harvested from
wild-type, IL-6 knockout and Tau knockout mice. 3) We will assess whether knockout of IL-6 or Tau, anti-
inflammatory treatments (naproxen and parecoxib) or Tau phosphorylation inhibitor (lithium) can mitigate the
anesthesia/surgery-induced neuronal dysfunction and POD-like behavior in mice. We will include adult wild-
type (3 months-old) mice versus age matched (3 months-old) AD transgenic and aged wild-type (18 months-
old) mice (with higher pTau levels), and employ a label-free nano-biosensing system for biomolecular analysis
(nanobeam technology), calcium imaging, in vitro electrophysiology, microdialysis, and CAM in mice. This
proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses.
Our efforts could ultimately h...

## Key facts

- **NIH application ID:** 10113503
- **Project number:** 5R01AG062509-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhongcong Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $709,656
- **Award type:** 5
- **Project period:** 2019-04-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113503

## Citation

> US National Institutes of Health, RePORTER application 10113503, Postoperative Delirium and Alzheimer's Disease Related Dementias (5R01AG062509-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113503. Licensed CC0.

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