Immunomodulatory lipid mediator profiling of cerebrospinal fluid following surgery in older adults.

My work uses translational neuroscience approaches, such as cerebrospinal fluid molecular assays, sleep EEG, cognitive testing, and delirium assessment to identify mechanisms of delirium. Delirium is a syndrome of disrupted attention and consciousness that occurs in ~20% of the >19 million older surgery patients and ~50% of the >5 million intensive care unit (ICU) patients in the United States every year. Delirium is also associated with increased risk for Alzheimer’s disease and related dementias (ADRD), yet there are no FDA-approved drugs to prevent it, due to a major gap in our understanding of its underlying mechanisms.  Our current work aims to discover potential mechanisms of delirium that could be targeted in future studies. We have recently found that increased blood-brain barrier dysfunction is associated with postoperative delirium, but it is unknown what inflammatory mediators actually cross the disrupted blood-brain barrier to drive delirium. Using mass spectrometry proteomics, we are examining the relationship of proteins and inflammatory markers found in the cerebrospinal fluid 24-hours following surgery with postoperative delirium. We are also interested in strategies that potentially protect the blood-brain barrier following surgery. Since sleep disruptions can cause blood-brain barrier dysfunction, we are conducting a study to determine the efficacy of suvorexant to improve postoperative sleep and reduce delirium severity in older surgical patients. Finally, we are working to extend these investigations to ICU patients, who are often more severely affected by delirium and more frequently develop long-term sequelae such as post-ICU long-term cognitive impairment (that is similar in magnitude to Alzheimer’s disease and related dementias).

Computational immunology (stochastic and spatial models and simulations, T cell signaling, immune regulation)
Statistical methodology for immunological laboratory techniques (flow cytometry, CFSE analysis, receptor-ligand binding and signaling kinetics)
Informatics of the immune system (reference and application ontologies, meta-programming, text mining and machine learning)

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.