The National Institutes of Health’s National Institute on Aging has awarded Duke Anesthesiology’s Dr. Niccolo Terrando a five-year $3,465,825 multi-PI R01 grant for the project titled, “Impact of Hypertension and Aging on Postoperative Delirium.”
Millions of Americans suffer from cardiovascular disorders, including high blood pressure, and undergo routine surgical operations that pose high risks for neurologic complications such delirium and ADRD. The mechanisms whereby high blood pressure contributes to cognitive decline after surgery remain unknown. Terrando’s research, with multi-PI Dr. Ting Yang of Duke Medicine, aims to help solve this common public health concern by investigating how immune and vascular targets can lead to brain pathology and inflammation in postoperative delirium superimposed on hypertension.
“Although emerging epidemiological evidence associates hypertension with delirium, the mechanisms whereby chronic hypertension contributes to neuroimmune dysregulation after surgery remain poorly understood,” says Terrando, professor of anesthesiology.
Terrando and Yang’s research demonstrates that blood-brain barrier (BBB) dysfunction and postoperative neuroinflammation are exacerbated in mice with Angiotensin II (AngII)-dependent hypertension. This pathological brain response to surgical stress is accompanied by upregulation of the Ang II type 1 receptor and induction of perivascular macrophages (PVMs) in the hippocampus. The ultimate goal of this research program is to ascertain the causal role of these targets as potential contributors to vascular impairments in postoperative delirium and ensuing ADRD onset.
The primary objective of this study is to elucidate the specific contributions of endothelial cells and PVMs to surgery-induced neuroinflammation, BBB disruption, and delirium-like behavior in aging and hypertension. Their central hypothesis is that BBB dysfunction in hypertension primes the neurovascular unit (NVU) by worsening border-associated immune activation and vascular dysfunction, thus exacerbating delirium-like behavior after orthopedic surgery and aging.
This study involves an innovative approach, including specific contributions of endothelial cells and PVMs to surgery-induced neuroinflammation, as well as comprehensive behavioral testing to evaluate cognitive decline in hypertensive mice following surgery and aging. The latter will be conducted in collaboration with the Mouse Behavioral and Neuroendocrine Analysis Core Facility and a long-term collaboration with Dr. William Wetsel of Duke Psychiatry and Behavioral Sciences. This project will also integrate a microphysiologic BBB platform developed by Dr. James McGrath at the University of Rochester, New York, that will be used to further identify signaling and key targets at the BBB.
“We are grateful for this award from the NIA that brings together an interdisciplinary team of investigators and provides a unique opportunity to understand how vascular and immune risk factors contribute to postoperative delirium during chronic hypertension. These efforts are timely given how common these complications are for vulnerable older patients and direct impact on AD/ADRD,” adds Terrando.