The National Institutes of Health’s National Institute on Aging has awarded Duke Anesthesiology’s Niccolò Terrando, PhD, and University of Rochester’s Harris Gelbard, MD, PhD, a $239,843 multi-PI R21 grant for their project, “Immunoprofiling Postoperative Delirium During Aging and Neurodegeneration.”
Millions of elderly Americans live with cognitive impairment and require common surgical interventions, such as orthopedic surgery, that are frequently accompanied by delirium in the postoperative period. The proposed research will address this serious public health concern by providing key data about immune cell populations that are the likely cause of this type of delirium. This will help Terrando and Gelbard develop new therapies that target these immune cells for these high-risk patients.
With the R21 award, they will explore the use of the technique of mass cytometry (CyTOF) that is available through the Gelbard lab to identify immune cell subsets that mediate neuroinflammation in the central nervous system (CNS) using a well- established orthopedic mouse model of postoperative delirium developed by Terrando’s Neuroinflammation and Cognitive Outcomes Laboratory. This represents an ever-growing collaboration between these two labs, which over the past five years have been tackling questions on how surgery, and more recently infection akin to COVID-19, affect the vulnerable brain. “We are thrilled to be working with Dr. Gelbard and his team to expand our understanding on how surgery engages the immune system in contributing to complications such as delirium,” says Terrando, associate professor in anesthesiology.
Dysregulated immunity is a hallmark of normal aging; it is also recognized as a key feature of many neurological disorders, including dementia and perioperative complications like delirium as recently reviewed in Nature Immunology. No study has yet attempted to unbiasedly profile the immune subset specific response to orthopedic surgical trauma in the CNS. Terrando and Gelbard will conduct two specific aims: (1) to define how age differences between young adult and elderly male and female mice modulate immune cell subsets in the CNS and blood after orthopedic surgery; and (2) to determine the impact of Alzheimer’s (AD)-like pathologic features using 5xFAD transgenic male and female mice (an accelerated model to study key aspects of neurodegeneration) on immune cell subsets in the CNS and blood after orthopedic surgery. The ability to resolve immune cell subsets and align them with discrete repertoires of pro-inflammatory signaling molecules with CyTOF will be key to understanding whether delirium results from neuroinflammation due to peripherally migrating and/or CNS-resident immunocytes.
Findings from this research are expected to have an important, positive impact on the ADRD field to reduce the impact of delirium and dementia in the aging population by helping identify patients at greater risk for developing delirium and delirium superimposed on dementia. “We are grateful for the continuous support by the National Institute on Aging to advance this field of research,” adds Terrando.