# Immunoprofiling postoperative delirium during aging and neurodegeneration

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $198,489

## Abstract

This R21 application uses the high risk, high reward technique of mass cytometry (abbreviated as CyTOF) to
identify immune cell subsets that mediate neuroinflammation in the central nervous system (CNS) in a well-
established orthopedic mouse model of postoperative delirium (POD). Dysregulated immunity is a hallmark of
normal aging; it is also recognized as a key feature of many neurological disorders including dementia and
perioperative complications like delirium. POD is common, occurring in up to 50% of older patients after a fracture
repair. The strongest risk factors for POD are advanced age and dementia. Interestingly, the postoperative
emergence of delirium may presage dementia. In fact, delirium superimposed on dementia (DSD) contributes to
a faster trajectory of cognitive decline as well as significant mortality. This is significant because of the millions
of elderly patients that routinely undergo orthopedic or other surgeries every year. The biologic mechanisms that
drive POD and DSD during aging are unknown and without approved drugs to treat or prevent it. We have
pioneered a clinically-relevant orthopedic surgery murine model that displays systemic inflammation, alters
microglial activation, and causes memory deficits in mice. In our model, surgery mobilizes discrete immune cell
populations with pro-inflammatory signaling responses that mediate damage to the blood-brain barrier, damage
the neurovascular unit (NVU) and impair normal synaptic transduction. Translationally, similar immune
signatures with the same pro-inflammatory markers have now been described in fluid biomarkers of delirious
patients. However, current immunophenotyping is limited to selected non-specific cytokines and pro-
inflammatory molecules such as TNF, IL-1, IL-6, MCP-1 and S100b in brain tissue (rodents) and cerebrospinal
fluid (humans). No study has yet attempted to unbiasedly profile the immune subset specific response to
orthopedic surgical trauma in the CNS. We propose two specific aims: (1) to define how age differences between
young adult (6mos) and elderly (22mos) male and female mice modulate immune cell subsets in the CNS and
blood after orthopedic surgery; and (2) to determine the impact of Alzheimer’s (AD)-like pathologic features using
5xFAD transgenic male and female mice at 6mos of age (when AD and postoperative neuroinflammation
become pathologically significant) on immune cell subsets in the CNS and blood after orthopedic surgery. The
ability to resolve immune cell subsets and align them with discrete repertoires of pro-inflammatory signaling
molecules with CyTOF will be key to understanding whether POD results from neuroinflammation due to
peripherally migrating and/or CNS-resident immunocytes. These experiments will provide the foundation for
future RO1 studies in which we pursue key findings focused on dysfunction of the NVU associated with
neurodegeneration in Alzheimer’s disease as sought by NOT-AG-19-033. We expect our findings to have an...

## Key facts

- **NIH application ID:** 10456947
- **Project number:** 5R21AG074232-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** HARRIS A GELBARD
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $198,489
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456947

## Citation

> US National Institutes of Health, RePORTER application 10456947, Immunoprofiling postoperative delirium during aging and neurodegeneration (5R21AG074232-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10456947. Licensed CC0.

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