Neuroinflammation and Cognitive Outcomes Laboratory

Neurovascular Dysfunction in Delirium Superimposed on Dementia

Impaired cognitive function after common surgical procedures is a growing concern especially among over 5 million people in the United States who suffer from dementia, including Alzheimer’s disease. After orthopedic surgery, acute changes in cognitive function, often referred to as postoperative delirium, occur in up to 89% of patients with preexisting dementia, and associate with poorer prognosis and even 2-fold greater risk for 1-year mortality compared to patients without dementia or delirium. In this project, we will model postoperative delirium superimposed on dementia by subjecting mice with cerebral amyloid angiopathy (CAA), which is common in Alzheimer’s disease patients, to orthopedic surgery (tibial fracture). Our overall objective is to determine the role of the blood–brain interface (the neurovascular unit and the blood-brain barrier within), vascular β-amyloid deposition, and neuroinflammation in cognitive function after orthopedic surgery in CAA mice. Such knowledge is highly significant because it has the potential to improve surgical outcome and quality of life for millions of elderly vulnerable patients in the United States. This project is funded by the National Institute of Aging, 1R01AG057525-01.

Bioelectronic Regulation of Neuroinflammation and Memory Function

Aside from being fundamental organizational units of the nervous system and regulating a myriad of organ functions, neural reflexes are also capable of controlling inflammation. Our previous work revealed that pharmacological activation of a cholinergic anti-inflammatory reflex could mitigate surgery-induced neuroinflammation and cognitive dysfunction in mice. We are currently focusing on the interactions between the nervous and immune systems. Current efforts are aimed at developing novel strategies to activate these signaling pathways and regulate postoperative inflammation with electrical nerve stimulation. Bioelectronic medicine provides a novel therapeutic approach to possibly prevent perioperative neurocognitive disorders by harnessing neuronal circuits to better “tune” the immune response after surgery. This project brings together a multidisciplinary team of investigators from Duke University and is developed in close collaboration with Professor Warren Grill in Duke Biomedical Engineering. It was selected for a 2016 Duke Institute for Brain Sciences (DIBS) Incubator award and an R21 exploratory grant from the National Institute of Aging in 2018.

Pro-Resolving Strategies for Perioperative Neurocognitive Disorders

Resolution of inflammation is an active process where synthesis and release of anti-inflammatory molecules is required for balancing the overall immune response. Our lab first reported on the effects of resolvins, lipid mediators generated by omega-3 essential fatty acids, in preventing neuroinflammation and memory deficits after surgery. Current studies are looking into the mechanisms of actions of these molecules into the brain. Dr Zhiquan Zhang discovered a bioactive peptide from Annexin-A1 and ongoing efforts are evaluating the neuroprotective properties of this compound on the blood-brain barrier, immune cells trafficking after trauma, and postoperative pain. This is contributing to a holistic approach aimed at defining the role of endogenous pro-resolving mediators not only on the central nervous system, but also in a broader context of perioperative organ protection, healing, and resiliency. In collaboration with Dr Miles Berger in our Department we are attempting to translate preclinical evidence of neuroinflammation into surgical patients, and understand if these lipid mediators may aid diagnosing of postoperative delirium and cognitive decline in at-risk patients.

Alumni

1. Miller-Rhodes P, Li H, Velagapudi R, Wesley C, Terrando N*, Gelbard HA, URMC-099 Prophylaxis Repairs Hippocampal Vascular Damage in an Orthopedic Model of Delirium Superimposed on Dementia FASEB J, 2022;36(6):e22343. PMID:35535564
2. Zhang Z, Ma Q, Velagapudi R, Barclay W, Rodriguiz R, Wetsel W, Yang T, Shinohara M, Terrando N, Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome. Front Immunol, 2022;13:856254. PMID: 35603196
3. Yang T, Velagapudi R, Terrando N. Neuroinflammation after surgery: from mechanisms to therapeutic targets. Nat Immunol. 2020 Nov;21(11):1319-1326. doi: 10.1038/s41590-020-00812-1. Epub 2020 Oct 19. PMID: 33077953.
4. Wang P, Velagapudi R, Kong C, Rodriguiz R, Wetsel W, Yang T, Berger M, Gelbard HA, Colton C, Terrando N, Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia, Alzheimers Dement, 16(5):734-749, 2020. PMID: 32291962
5. Huffman W, Subramaniyan S, Rodriguiz R, Wetsel W, Grill W, Terrando N, Modulation of Neuroinflammation and Memory Dysfunction using Percutaneous Vagus Nerve Stimulation in Mice. Brain Stim, 12(1):19-29, 2019. PMID: 30337243

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