# The Role of Inflammation in the Pathophysiology of Delirium and its Associated Long-Term Cognitive Decline

> **NIH NIH P01** · HEBREW REHABILITATION CENTER FOR AGED · 2020 · $418,997

## Abstract

ABSTRACT
The pathophysiology of delirium and the mechanisms underlying its epidemiological association with long-term
cognitive decline (LTCD) remain largely unknown. This important gap limits development of preventive and
disease-modifying therapies. To address this gap, we conducted the “Biomarker Discovery for Delirium” project
within the P01 “Interdisciplinary Study of Delirium and Its Long Term Outcomes”. Our results support a model
for delirium in which a predisposing, pre-inflammatory state results in a heightened inflammatory response to
surgery, leading to blood-brain barrier breakdown, microglial activation and neuro-inflammation, resulting in
neuronal injury and death. This model is intriguing, as inflammation could be the mechanism underlying the
epidemiological link between delirium, LTCD, and Alzheimer's Disease and Related Dementias (ADRD). For
the P01 renewal, Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach, our project will
leverage banked specimens from the first cycle's Successful Aging after Elective Surgery study (SAGES I),
which enrolled and followed 560 participants undergoing major scheduled surgery, and collected plasma at 4
time points relative to surgery. We add banked specimens from the Healthier Postoperative Recovery study
(HiPOR), which enrolled 242 participants undergoing total joint replacements under spinal anesthesia using a
similar protocol to SAGES I, with the additional collection of preoperative cerebrospinal fluid (CSF). Further, we
will collect new blood and CSF samples from a probability sample of 128 SAGES I participants, and from a
new cohort of 400 older patients undergoing total joint replacement under spinal anesthesia (SAGES II). We
will use two state-of-the-art approaches, SOMAscan, a next generation proteomics platform, to discover new
inflammatory proteins (Aim 1), and CyTOF, a single-cell mass cytometry platform, to characterize circulating
immune cells that regulate inflammation (Aim 2). We will also extend our prior work by examining CSF in
addition to plasma, and by quantifying a novel inflammatory index (Aim 3). Using these techniques, we will
compare inflammatory proteins and cells in patients who do and do not develop delirium, and in those who
have slower and faster rates of LTCD following delirium. Importantly, we will also independently validate all
SOMAscan and CyTOF results using standard laboratory methods. Our current Project represents the next in
a series of systematic studies extending important findings from the first P01 cycle, and leading to more
detailed understanding of the full inflammatory protein profile associated with delirium and LTCD, including
markers in the CSF, plus origins of the inflammatory response from immune cells. The Aims also represent an
initial step toward development of blood and CSF protein, and cytometry-based biomarker panels to refine
prediction of delirium and LTCD. Importantly, the proposed work will improve our understanding...

## Key facts

- **NIH application ID:** 9934083
- **Project number:** 5P01AG031720-08
- **Recipient organization:** HEBREW REHABILITATION CENTER FOR AGED
- **Principal Investigator:** EDWARD R MARCANTONIO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,997
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934083

## Citation

> US National Institutes of Health, RePORTER application 9934083, The Role of Inflammation in the Pathophysiology of Delirium and its Associated Long-Term Cognitive Decline (5P01AG031720-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934083. Licensed CC0.

---

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