# Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach

> **NIH NIH P01** · HEBREW REHABILITATION CENTER FOR AGED · 2022 · $2,716,296

## Abstract

ABSTRACT
 Delirium is a common, costly, life-threatening, and potentially preventable problem for older persons, yet its
pathophysiology remains poorly understood. The development of delirium is considered to be a marker of brain
vulnerability; however, its relationship to dementia remains unclear. During the first cycle, we successfully
completed 4 projects centered around a cohort of >560 older surgical patients (SAGES I), which documented:
an accelerated trajectory of long-term cognitive decline following delirium (Project 1); and important risk
markers for delirium, related to inflammation (Project 2), structural dysconnectivity (Project 3), and impairment
in global cognitive performance (Project 4). These important findings have paved the way for us to move
forward to extend our pathophysiologic understanding through innovative probes of brain vulnerability.
 We now propose a series of 5 interlinked projects applying innovative approaches to deepen our
exploration of pathophysiologic pathways potentially contributing to delirium and its associated cognitive
decline. We will examine the role of inflammation with state-of-the-art approaches in Project 2; Alzheimer's
disease (AD) biomarkers (cerebrospinal fluid, CSF) in Project 1,and neuroimaging markers in Project 3); and
measures of brain plasticity/connectivity (transcranial magnetic stimulation and evoked potentials) in Project 5.
These approaches were chosen based on their innovation, potential to probe vulnerability, and ability to
advance our mechanistic understanding. Project 4 will identify and validate predictors of complicated delirium,
i.e., delirium associated with long-term cognitive decline. All of these studies will utilize both the original
SAGES I cohort, and a new prospectively enrolled cohort, SAGES II (N=400), which will include CSF sampling
obtained prior to spinal anesthesia. All projects will be supported by our effective infrastructure of 3 cores:
Administrative (Core A), Field (Core B), and Data Management and Statistical Analysis (Core C).
 This Program Project renewal proposal brings together an expert, interdisciplinary group in a supportive
environment to address a highly clinically relevant area in an integrated and coordinated fashion. The proposal
is truly innovative with novel pathophysiologic approaches, extensive cross-linking aims, and multiple
methodologic innovations. Furthermore, the large, well-defined cohort created in the first cycle (SAGES I)
presents an unprecedented opportunity to explore long-term the relationship of delirium, cognitive decline, and
Alzheimer's disease, lending some urgency to this renewal. The highly integrated nature of all the projects
could not be achieved without this program project infrastructure, representing a major strength and source of
efficiency. This infrastructure provides the capacity to execute five projects and cross-linking aims, expanding
the breadth of our pathophysiologic investigation in far-reaching directio...

## Key facts

- **NIH application ID:** 10405113
- **Project number:** 5P01AG031720-10
- **Recipient organization:** HEBREW REHABILITATION CENTER FOR AGED
- **Principal Investigator:** SHARON K. INOUYE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,716,296
- **Award type:** 5
- **Project period:** 2018-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405113

## Citation

> US National Institutes of Health, RePORTER application 10405113, Delirium, Dementia, and the Vulnerable Brain: An Integrative Approach (5P01AG031720-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10405113. Licensed CC0.

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