Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study

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10.1016/j.bja.2021.08.012

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Browndyke, Jeffrey N, Mary C Wright, Rosa Yang, Ayesha Syed, John Park, Ashley Hall, Katherine Martucci, Michael J Devinney, et al. (2021). Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study. British Journal of Anaesthesia. 10.1016/j.bja.2021.08.012 Retrieved from https://hdl.handle.net/10161/23837.

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Scholars@Duke

Browndyke

Jeffrey Nicholas Browndyke

Associate Professor of Psychiatry and Behavioral Sciences

Dr. Browndyke is an Associate Professor of Behavioral Health & Neurosciences in the Department of Psychiatry & Behavioral Sciences.  He has a secondary appointment as Assistant Professor of Cardiovascular & Thoracic Surgery.

Dr. Browndyke's research interests involve the use of advanced neurocognitive and neuroimaging techniques for perioperative contributions to delirium and later dementia risk, monitoring of late-life neuropathological disease progression, and intervention/treatment outcomes.  His research also involves novel telehealth methods for remote neurocognitive evaluation and implementation of non-invasive neuromodulatory techniques to assist in postoperative recovery and dementia risk reduction.

Dr. Browndyke's clinical expertise is focused upon geriatric neuropsychology with an emphasis in the assessment, diagnosis, and treatment of dementia and related disorders in adults and US veteran patient populations.

Martucci

Katherine Martucci

Associate Professor in Anesthesiology

Katherine Martucci Ph.D. is a neuroscientist who specializes in human clinical research of chronic pain, reward and motivation behaviors, sensory and acute pain perception, and opioid use and addiction. Dr. Martucci serves as Director of the Human Affect and Pain Neuroscience Lab which uses a combination of neuroimaging techniques, including functional magnetic resonance imaging (fMRI) of the brain and cervical spinal cord, as well as sensory, behavioral and psychological tests to study acute and chronic pain in humans.

   As part of the Center for Translational Pain Medicine (CTPM), Dr. Martucci’s lab is part of Duke University’s Department of Anesthesiology, conducting research in collaboration with the Brain Imaging and Analysis Center (BIAC) and Duke Institute for Brain Sciences (DIBS).

   Dr. Martucci earned her Ph.D. in Neurobiology and Anatomy at Wake Forest School of Medicine and continued her training in clinical research with a postdoctoral fellowship at Stanford University. While at Stanford, Dr. Martucci obtained a prestigious NIH K99 “Pathway to Independence Award”. Since joining Duke University in 2018, Dr. Martucci has acquired funding via multiple NIH grants to continue her line of neuroimaging clinical research of the central nervous system in chronic pain.

Devinney

Michael Devinney

Assistant Professor of Anesthesiology

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).

Moretti

Eugene William Moretti

Professor of Anesthesiology

Research efforts are focused primarily in the area of functional genomics. Work has centered on investigating genetic polymorphisms in the surgical intensive care population that would predispose one to the development of the sepsis syndrome. As an extension of this work, there is ongoing investigation working to identify genetically susceptible populations at risk for developing various types of perioperative organ dysfunction. Parallel studies involve identification of a panel of biomarkers that would enable early diagnosis and intervention for those patients, both surgical and non-surgical that develop the sepsis syndrome. There is also active investigation in the human pharmacology laboratory in the department of anesthesiology involving the phase 1 testing of novel pharmaceutical agents in healthy volunteers.

Whitson

Heather Elizabeth Whitson

Duke School of Medicine Distinguished Professor in Neuroscience

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.  

Mathew

Joseph P. Mathew

Jerry Reves, M.D. Distinguished Professor of Cardiac Anesthesiology

Current research interests include:
1. The relationship between white matter patency, functional connectivity (fMRI) and neurocognitive function following cardiac surgery.
2. The relationship between global and regional cortical beta-amyloid deposition and postoperative cognitive decline.
3. The effect of lidocaine infusion upon neurocognitive function following cardiac surgery.
4. The association between genotype and outcome after cardiac surgery.
5. Atrial fibrillation following cardiopulmonary bypass.

Berger

Miles Berger

Associate Professor of Anesthesiology

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. 


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