# Neuropathology of Cognitive Impairment in Critical Illness

> **NIH NIH R03** · CEDARS-SINAI MEDICAL CENTER · 2020 · $127,500

## Abstract

PROJECT SUMMARY
Cognitive impairment, and specifically Alzheimer’s Disease, is a known sequela of mechanical ventilation and
critical illness in older individuals. Although the prevalence of cognitive impairment after critical illness is
expected to increase dramatically as our population ages, very little is understood about the specific
mechanisms that underlie this finding and there is a significant need for therapies that ameliorate the public
health impact of this condition. Prior research to understand the association between mechanical ventilation
and cognitive impairment has been confounded by the underlying indication for mechanical ventilation, such as
sepsis, surgery, or acute brain injury, all of which could independently contribute to cognitive impairment. To
overcome this limitation, we developed a novel model of short-term mechanical ventilation in wild-type and
double transgenic Alzheimer’s Disease-model mice to study the isolated consequences of mechanical
ventilation in older individuals. Our preliminary data suggest that even short-term mechanical ventilation
accelerates the neuropathology of Alzheimer’s Disease by increasing cerebral amyloid-β accumulation,
however the exact mechanism by which this occurs remains unknown. We obtained additional data that
show cognition-relevant neuropathological changes with elevated right atrial pressure, and now propose to
examine whether the increase in right atrial pressure due to positive pressure mechanical ventilation impairs
glymphatic clearance, increases blood-brain barrier leakiness, and increases cerebral amyloid-β accumulation
-- thus contributing to the pathogenesis of Alzheimer’s Disease.
Dr. Lahiri, the PI of this study, is a critical care neurologist and an early-career physician-scientist who
developed the novel disease model and generated preliminary data presented in this proposal. Dr. Lahiri’ s
previous research has focused on short- and long-term clinical effects of mechanical ventilation in acute brain
injury, and he is now transitioning his focus to aging-related research. The GEMSSTAR award and associated
institutional commitments would provide Dr. Lahiri with the time, resources, and training to launch a successful
career in aging-research that focuses on the cognitive effects of critical illness in older individuals.

## Key facts

- **NIH application ID:** 9987454
- **Project number:** 5R03AG064106-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Shouri Lahiri
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $127,500
- **Award type:** 5
- **Project period:** 2019-08-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987454

## Citation

> US National Institutes of Health, RePORTER application 9987454, Neuropathology of Cognitive Impairment in Critical Illness (5R03AG064106-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9987454. Licensed CC0.

---

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