The National Institutes of Health’s National Institute on Aging has awarded a multi-institutional, five-year $4,803,691 R01 grant to multi-PIs, Dr. Niccolò Terrando of Duke Anesthesiology and Dr. Mervyn Maze of the University of California, San Francisco, for their project titled "IL-6 Trans-signaling Increases Vulnerability to Postoperative Cognitive Decline in Aging and Alzheimer's Disease."
Aging and neurodegenerative conditions, including Alzheimer’s disease, are two well-established risk factors for developing perioperative neurocognitive disorders (PNDs), a spectrum of complications that range from acute delirium to longer-lasting cognitive deficits. With a steady increase in the aging population, more of these vulnerable patients are routinely exposed to surgical interventions, therefore becoming at increased risk for PNDs. Currently, there are no treatments available to slow down the increase in PNDs, which leads to a further decrease in quality of life, higher mortality, and significant health care costs of approximately $33 billion in the first year after diagnosis in the US alone.
This project brings together expertise from the Terrando laboratory that studies the impact of postoperative delirium with neurodegeneration and how systemic injury impacts the blood-brain barrier and the Maze laboratory that uncovered a specific role for IL-6 signaling using a mouse model of PND. The Duke team will study the effects of neuronal IL-6 signaling following anesthesia and surgery, and test the impact of sgp130Fc, a selective IL-6 trans-signaling blocker, on barrier function, neuroimmune endpoints, and cognitive outcomes during aging and neurodegeneration. Genetic models will be applied to ultimately inform on the application of critically needed therapies for safe prevention and/or reversal of postoperative cognitive impairments.
Duke co-investigators include Dr. William Wetsel of Duke Psychiatry and Behavioral Sciences and Dr. Ting Yang of Duke Medicine, who will contribute to the investigation of behavioral outcomes and the blood-brain barrier dysfunction after surgery and IL-6.
“Dysregulated innate immunity is a key hallmark of many neurologic conditions ranging from Alzheimer’s disease to postoperative delirium with cytokines such as IL-6 playing critical roles in mediating neuroinflammation and cognitive decline after systemic injury,” says Terrando, professor of anesthesiology, cell biology and integrative immunobiology and director of the Neuroinflammation and Cognitive Outcomes Laboratory at Duke Anesthesiology. “By studying the effects of a selective IL-6 trans-signaling blocker (gpr130Fc) on neuroimmune and cognitive outcomes this project will advance fundamental knowledge that may inform more targeted randomized clinical trials to safely reduce the incidence of PNDs in high-risk patients.”