Dr. Terrando Awarded Grant for COVID-19 Related Research

Niccolò Terrando, BSc (hons), DIC, PhDThe National Institutes of Health has awarded Duke Anesthesiology’s Niccolò Terrando, BSc, DIC, PhD, a one-year, $322,620 supplement grant to his R01-funded project, titled “Delirium Superimposed on Dementia Intersects with COVID-19.”

Delirium has become a common complication of COVID-19 that further impairs the recovery of already debilitated patients, in particular older adults. Terrando and his co-investigators are studying the role of neuroinflammation as a putative driver of delirium pathogenesis. For this supplement, they will explore how lung injury, akin to COVID-19 infection, leads to delirium by impairing the blood-brain barrier and triggering immune cell trafficking into the brain.

Terrando aims to develop a model of COVID-19 lung injury that activates the immune system to damage the brain, affecting areas that serve attention, memory, and thinking, and reverse these changes with an experimental drug in development. Findings from this research supplement will address this serious public health concern by providing fundamental knowledge on the pathogenesis of delirium following COVID-19-like infection. Such work has the potential to reduce the health care burden of COVID-19 associated with delirium and related neurologic complications, such as Alzheimer’s disease and related dementias (ADRDs).

“We are thrilled to develop this project in collaboration with Dr. Purushothama Rao Tata in the Duke Department of Cell Biology, an expert in murine lung injury models, and Dr. Harris A. Gelbard in the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center that developed new therapeutics effective in resolving neuroinflammation, which we are currently testing in the R01 funded project,” says Terrando, associate professor in anesthesiology. “We are grateful for the National Institute on Aging’s continuous support, and we are looking forward to providing timely results that may curtail pathologic hallmarks of delirium and neurodegeneration resulting from COVID-19.”

Stacey HiltonDr. Terrando Awarded Grant for COVID-19 Related Research
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Duke Anesthesiology Awarded Program Project Grant

The National Institutes of Health (NIH) has awarded Duke Anesthesiology a five-year, $8,566,593 million Center of Excellence award that is supported via the NIH’s Program Project Grant (PPG) mechanism. This is of substantial significance to the department and university because it marks the funding of a new national center and represents the first PPG to the department in 40 years.

The designation as a Center of Excellence within Duke Anesthesiology’s Center for Translational Pain Medicine (CTPM) by the National Center for Complementary and Integrative Health (NCCIH) brings this department both national and international recognition; there are only 1-3 Centers of Excellence funded as PPGs by NCCIH in the country. The new center represents a new and unique resource to investigators world-wide who have interest in translational pain research; it represents a nidus that not only advances Duke Anesthesiology’s mission in translational pain research, but brings it increased visibility in the pain field, which will further expand international collaboration and increase its value and recognition as a leader in translational pain medicine.

William Maixner, DDS, PhDWe want to sincerely thank everyone who helped drive the Center of Excellence initiative that has resulted in this extraordinary outcome. This award and designation is the culmination of a nearly three-year effort by the CTPM, initiated by the center’s co-directors, including Dr. William Maixner, who worked closely to develop the proposal with the center’s members and affiliates (*see complete list of names below).

The title of the PPG is “Resolution of Neuroinflammation and Persistent Pain by Complementary Approaches.” The overarching aims of the PPG is to identify new and novel complimentary approaches to the treatment of pain conditions. The PPG will support the intellectual development of the Center of Excellence and the infrastructure for three scientific projects and three support cores. These units will further bring together Duke Anesthesiology’s basic science and clinical groups to advance translational pain research.

*P01 collaborators: William Maixner, Shad Smith, Andrey Bortsov, Andrea Nackley, Sven-Eric Jordt, Niccolo Terrando, Luis Ulloa (Anesthesiology), Wolfgang Liedtke and Yong Chen (Anesthesiology and Neurology), Fan Wang (Neurobiology), and Staci Bilbo (Psychology and Neuroscience)

Stacey HiltonDuke Anesthesiology Awarded Program Project Grant
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Study in Mice Suggests Post-Surgical Delirium Caused by Inflammation

Niccolò Terrando, BSc (hons), DIC, PhDAlzheimer’s disease patients who undergo orthopedic or other surgeries frequently develop post-surgical delirium, often leading to a poor recovery and a higher risk of dying.

The cause of this acute disruption in the patient’s mental status is largely unknown, but previous studies have suggested a link to some intrinsic response to surgical trauma itself, the multifaceted perioperative environment, and patient-specific factors that altogether contribute to post-surgical delirium.

In a study using mice led by Duke Health researchers, a new finding suggests that inflammation, especially as it impacts the blood-brain barrier in older and more frail subjects, amplifies neurodegenerative processes and drives the development of post-surgical delirium. The study published online April 15 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

“The blood-brain barrier has often been under-appreciated in the context of perioperative neurocognitive disorders, such as delirium,” said senior author Niccolò Terrando, Ph.D., associate professor in the Department of Anesthesiology at Duke University School of Medicine. “This study provides evidence that a systemic response to surgery triggers a series of events that enables inflammation to breach the brain’s gatekeeper.”

Terrando and colleagues studied the effects of orthopedic surgeries in older mice with the pathological features of human Alzheimer’s disease. These animals underwent an orthopedic fracture model and the researchers traced how post-surgical delirium unfolds.

Notably, inflammation disrupted the blood-brain barrier, especially in older and more vulnerable animals, and caused rapid accumulation of amyloid beta (a key protein dysregulated in the Alzheimer’s disease brain), which then altered the function of immune cells in the central nervous system, thus resulting in post-surgical delirium.

“We described a neurovascular pathology that drives the development of postoperative delirium as a result of surgical trauma, which contributes to a rapid accumulation of amyloid beta in the brain,” Terrando said. “This may represent a unique molecular signature of delirium superimposed on dementia and a potential target for interventions.”

Terrando said future studies will focus on how surgery impacts the blood-brain barrier and potential ways to curtail this neuroinflammatory response in older surgical patients and, particularly, those with Alzheimer’s disease.

In addition to Terrando, study authors include Ping Wang, Ravikanth Velagapudi, Cuicui Kong, Ramona M. Rodriguiz, William C. Wetsel, Ting Yang, Miles Berger, Harris A. Gelbard and Carol A. Colton.

The study received support from the National Institutes of Health (R01AG057525, R21 AG055877-01A1, R03 AG064260-01, K76-AG057022); the Duke Claude D. Pepper Older American Independence Center (P30AG028716); the Duke Anesthesiology Department; the Alzheimer’s Association. A full list of supporters is provided in the study.

Source: Duke Health news release (Durham, NC – April 15, 2020)

Stacey HiltonStudy in Mice Suggests Post-Surgical Delirium Caused by Inflammation
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Postdoctoral Associate Awarded Prestigious Grant

Ravikanth Velagapudi, PhDThe Network for Investigation of Delirium Unifying Scientists (NIDUS) has awarded Duke Anesthesiology’s Ravikanth Velagapudi, PhD, a 2019-2020 NIDUS Junior Investigator Pilot Award (12-month, $80,500 grant) for his proposal titled, “Profiling Postoperative Neuroinflammation in a Mouse Model of Delirium Superimposed on Parkinson’s Disease.”

Velagapudi’s proposal was selected through a rigorous review process from a pool of highly-competitive applications. His project will help gain fundamental knowledge on the impact of surgery on preclinical Parkinson’s disease (PD) models. Currently, millions of Americans live with PD and routinely undergo common surgical procedures, such as orthopedic surgery. Although lifesaving, surgery can increase the risk for cognitive complications like delirium, which in many cases associate with worse prognosis, increased health care costs, and even death. This is especially concerning in frail subjects and older adults who already suffer from ongoing neurodegeneration, such as Alzheimer’s disease, but also PD. This specific project will explore the effects of surgery-induced postoperative neuroinflammation in a genetic PD mouse model. Results from these experiments will provide novel understanding on how surgical trauma synergizes with PD pathology and may lead to novel therapeutic targets to treat delirium in subjects with ongoing PD pathology.

“It is a great opportunity to receive this pilot award from NIDUS under the junior investigator track to study delirium in PD,” says Velagapudi. “To date, this is a largely understudied subject, especially in the context of preclinical models and signaling mechanisms. In fact, few studies so far have addressed the effects of delirium on PD.” This pilot grant also provides a unique and timely opportunity to build a future career development research program for Velagapudi focusing on the interactions between postoperative delirium and PD-neurodegeneration.

Velagapudi is a postdoctoral associate in the Neuroinflammation and Cognitive Outcomes Laboratory in Duke Anesthesiology, led by Dr. Niccolò Terrando, who says this prestigious award is a remarkable accomplishment for his mentee. “I am very proud of Ravi’s achievement in just one year with my team. This award will provide an exceptional training opportunity and will further grow our collaboration with Dr. Laurie Sanders’ group in Duke Neurology, who are experts in PD pathogenesis.”

Velagapudi will present the findings of his project at the annual American Delirium Society meeting in 2021.

Stacey HiltonPostdoctoral Associate Awarded Prestigious Grant
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