Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study.
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Animal models suggest postoperative cognitive dysfunction may be caused by brain monocyte influx. To study this in humans, we developed a flow cytometry panel to profile cerebrospinal fluid (CSF) samples collected before and after major noncardiac surgery in 5 patients ≥60 years of age who developed postoperative cognitive dysfunction and 5 matched controls who did not. We detected 12,654 ± 4895 cells/10 mL of CSF sample (mean ± SD). Patients who developed postoperative cognitive dysfunction showed an increased CSF monocyte/lymphocyte ratio and monocyte chemoattractant protein 1 receptor downregulation on CSF monocytes 24 hours after surgery. These pilot data demonstrate that CSF flow cytometry can be used to study mechanisms of postoperative neurocognitive dysfunction.
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Berger, Miles, David M Murdoch, Janet S Staats, Cliburn Chan, Jake P Thomas, Grant E Garrigues, Jeffrey N Browndyke, Mary Cooter, et al. (2019). Flow Cytometry Characterization of Cerebrospinal Fluid Monocytes in Patients With Postoperative Cognitive Dysfunction: A Pilot Study. Anesthesia and analgesia. pp. 1–1. 10.1213/ane.0000000000004179 Retrieved from https://hdl.handle.net/10161/18624.
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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.
As a physician and researcher, my career has been driven by a passion for linking the basic and clinical sciences with the primary goal of understanding the disease pathogenesis. Through my training in epidemiology, basic science immunology, and clinical medicine, I have acquired a breadth of experience, knowledge, collaborators, and an adaptability which has culminated in a research focus on the reconstitution of immune responses and systemic inflammation in immunocompromised patients and vulnerable populations. My research focuses on T cell immunology utilizing a variety of platforms including polychromatic flow cytometry, cytokine multiplexing, and novel single cell assays. My initial research centered on the immune reconstitution syndrome (IRIS), with a focus on the mycobacterial precipitants of the disease, its epidemiology, and research efforts into elucidating the pathogenesis of the syndrome. Recently, I have translated my interest in co-infection immunology in the immunocompromised transplant population. With a career long interest in contrasting compartmental and peripheral immune responses, I have partnered with engineers in the Duke Pratt School of Engineering in order to develop novel single cell immune assays in order to comprehensively profile the immune response on limited specimens.
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