The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction.
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BACKGROUND/OBJECTIVES:Every year, up to 40% of the more than 16 million older Americans who undergo anesthesia/surgery develop postoperative cognitive dysfunction (POCD) or delirium. Each of these distinct syndromes is associated with decreased quality of life, increased mortality, and a possible increased risk of Alzheimer's disease. One pathologic process hypothesized to underlie both delirium and POCD is neuroinflammation. The INTUIT study described here will determine the extent to which postoperative increases in cerebrospinal fluid (CSF) monocyte chemoattractant protein 1 (MCP-1) levels and monocyte numbers are associated with delirium and/or POCD and their underlying brain connectivity changes. DESIGN:Observational prospective cohort. SETTING:Duke University Medical Center, Duke Regional Hospital, and Duke Raleigh Hospital. PARTICIPANTS:Patients 60 years of age or older (N = 200) undergoing noncardiac/nonneurologic surgery. MEASUREMENTS:Participants will undergo cognitive testing before, 6 weeks, and 1 year after surgery. Delirium screening will be performed on postoperative days 1 to 5. Blood and CSF samples are obtained before surgery, and 24 hours, 6 weeks, and 1 year after surgery. CSF MCP-1 levels are measured by enzyme-linked immunosorbent assay, and CSF monocytes are assessed by flow cytometry. Half the patients will also undergo pre- and postoperative functional magnetic resonance imaging scans. 32-channel intraoperative electroencephalogram (EEG) recordings will be performed to identify intraoperative EEG correlates of neuroinflammation and/or postoperative cognitive resilience. Eighty patients will also undergo home sleep apnea testing to determine the relationships between sleep apnea severity, neuroinflammation, and impaired postoperative cognition. Additional assessments will help evaluate relationships between delirium, POCD, and other geriatric syndromes. CONCLUSION:INTUIT will use a transdisciplinary approach to study the role of neuroinflammation in postoperative delirium and cognitive dysfunction and their associated functional brain connectivity changes, and it may identify novel targets for treating and/or preventing delirium and POCD and their sequelae.
Published Version (Please cite this version)
Berger, Miles, Deborah Oyeyemi, Mobolaji O Olurinde, Heather E Whitson, Kent J Weinhold, Marty G Woldorff, Lewis A Lipsitz, Eugene Moretti, et al. (2019). The INTUIT Study: Investigating Neuroinflammation Underlying Postoperative Cognitive Dysfunction. Journal of the American Geriatrics Society. 10.1111/jgs.15770 Retrieved from https://hdl.handle.net/10161/17958.
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My research team focuses on 3 areas:
1) We are interested in the mechanisms of postoperative neurocognitive disorders such as delirium, and the relationship between these disorders and Alzheimer's Disease and Related Dementias (ADRD). Towards these ends, we use a combination of methods including pre and postoperative CSF and blood sampling, functional neuroimaging, EEG recordings, rigorous biochemical assays, and cognitive testing and delirium screening. In the long run, this work has the potential to help us improve long term neurocognitive outcomes for the more than 20 million Americans over age 60 who undergo anesthesia and surgery each year.
2) We are interested in the idea that altered anesthetic-induced brain EEG waveforms can serve as indicators of specific types of preclinical/prodromal neurodegenerative disease pathology, specific cognitive domain deficits, and postoperative delirium risk. We are studying this topic in the ALADDIN study, a 250 patient prospective cohort study in older surgical patients at Duke. Many people have viewed anesthesia and surgery as a "stress test" for the aging brain; we hope that this work will help us learn how to develop a real-time EEG readout of this "perioperative stress test" for the aging brain, just as ECG analysis can provide a real-time readout of cardiac treadmill stress tests.
3) We are interested in how the APOE4 allele damages brain circuitry throughout the adult lifespan, and how this contributes to increased risk of late onset Alzheimer's disease as well as worse outcomes following other acute brain disorders such as stroke and traumatic brain injury (TBI). In particular, we are investigating the hypothesis that the APOE4 allele leads to increased CNS complement activation throughout adult life, which then contributes to increased synaptic phagocytosis and long term neurocognitive decline. We are also studying whether acutely modulating APOE signaling in older surgical patients with the APOE mimetic peptide CN-105 is sufficient to block postoperative CSF neuroinflammation and complement activation.
Our work is transdisciplinary, and thus our team includes individuals with diverse scientific and clinical backgrounds, ranging from neuropsychology and neuroimaging to proteomics, flow cytometry and behavioral neuroscience in animal models. What unites us is the desire to better understand mechanisms of age-dependent brain dysfunction, both in the perioperative setting and in APOE4 carriers.
Dr. Whitson's research is focused on improving care options and resilience for people with multiple chronic conditions. In particular, she has interest and expertise related to the link between age-related changes in the eye and brain (e.g., How does late-life vision loss impact the aging brain or cognitive outcomes? Is Alzheimer's disease associated with distinctive changes in the retina, and could such changes help diagnose Alzheimer's disease early in its course?). Dr. Whitson leads a collaborative Alzheimer's Disease initiative that brings together investigators from Duke University and the University of North Carolina (UNC) at Chapel Hill, with a bold vision to transform dementia research and care across Eastern North Carolina. Dr. Whitson is also interested in improving health services to better meet the needs of medically complex patients. Within the Duke Aging Center, she leads research efforts aimed at promoting resilience to late-life stressors (e.g., surgery, sensory loss, infection). She has developed a novel rehabilitation model for people with co-existing vision and cognitive deficits, and she is part of a inter-disciplinary team seeking to improve peri-operative outcomes for frail or at-risk seniors who must undergo surgery. As a co-leader of a national resilience collaborative, she seeks to better understand the biological and psychological factors that determine how well we "bounce back" after health stressors.
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