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Dr. Terrando NIH Grant Renewed to Advance Delirium Research

by Stacey Hilton

The National Institutes of Health’s National Institute on Aging has awarded Duke Anesthesiology’s Niccolò Terrando, PhD, a five-year $4,311,630 R01 renewal grant for his project titled, “Microglia-Amyloid Interactions in Delirium Superimposed on Dementia.” Dysregulated immunity is a hallmark of many neurological disorders, including delirium and dementia. Delirium superimposed on dementia remains a poorly understood, life threatening complication that has no available therapeutics. Terrando’s research will address this serious public health concern by clarifying molecular and cellular mechanisms that drive the onset of delirium.

More than five million people in the United States suffer from dementia, including Alzheimer’s disease (AD), and commonly require surgical interventions, such as orthopedic surgery. After a common fracture repair, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89 percent of patients with preexisting dementia. Delirium after surgery is associated with poorer prognosis and even two-fold greater risk for one-year mortality compared to patients without dementia or delirium. The mechanisms underlying this complication remain unknown and without effective therapies

Immunovascular interactions in the brain
Immunovascular interactions in the brain after surgery (red: microglia cells; green: endothelial cells; blue: nuclei). Photo courtesy: the Terrando lab.

“We have established an innovative, multidisciplinary and collaborative program at Duke University to advance fundamental understanding on the pathophysiology of postoperative delirium, focusing on common risk factors such as aging and neurodegeneration,” says Terrando, associate professor of anesthesiology, cell biology, immunology and director of the Duke Neuroinflammation and Cognitive Outcomes Laboratory. “Work from our team has advanced new knowledge on the impact that surgery exerts on the vulnerable brain, which we are translating into more targeted ways to prevent this common complication."

The long-term goal of this study is to develop new tools to comprehensively understand how surgery impacts the vulnerable brain and to advance novel therapeutics to safely and effectively treat delirium. Terrando will serve as the project’s principal investigator. Co-investigators include Katerina Akassoglou, PhD, senior investigator and director of the Center for Neurovascular Brain Immunology at Gladstone Institutes, and professor of neurology at the University of California, San Francisco.

Over the previous course of this R01, the scientists discovered that orthopedic surgery triggers an acute deposition of amyloid-β, a key hallmark of AD, as well as vascular dysfunction in the brains of Alzheimer’s-like mice. This work has also uncovered putative targets that may lead to novel strategies to treat delirium superimposed on dementia. A key target discovered in the brain after orthopedic surgery in collaboration with the Akassoglou laboratory is fibrinogen, which drives neuroinflammation and cognitive decline in AD mice. In this R01 renewal, the teams will continue to characterize neuro-immune-vascular interactions and changes in blood-brain function using multiple models and technologies. Finally, the investigators will test if novel therapeutics aimed at restoring neuro-immune-vascular dysfunction after surgery prevent neuroinflammation in the attempt to advance much needed strategies for the millions of older adults at risk to develop delirium superimposed on dementia.

“It’s critical to understand the relationships between vascular, neuronal and immune dysfunction,” says Akassoglou. "This work will be invaluable in the design of novel therapies for postoperative delirium and dementia.”