Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings.
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OBJECTIVES: To look for changes in intrinsic functional brain connectivity associated with postoperative changes in cognition, a common complication in seniors undergoing major surgery, using resting-state functional magnetic resonance imaging. DESIGN: Objective cognitive testing and functional brain imaging were prospectively performed at preoperative baseline and 6 weeks after surgery and at the same time intervals in nonsurgical controls. SETTING: Academic medical center. PARTICIPANTS: Older adults undergoing cardiac surgery (n = 12) and nonsurgical older adult controls with a history of coronary artery disease (n = 12); no participants had cognitive impairment at preoperative baseline (Mini-Mental State Examination score >27). MEASUREMENTS: Differences in resting-state functional connectivity (RSFC) and global cognitive change relationships were assessed using a voxel-wise intrinsic connectivity method, controlling for demographic factors and pre- and perioperative cerebral white matter disease volume. Analyses were corrected for multiple comparisons (false discovery rate P < .01). RESULTS: Global cognitive change after cardiac surgery was significantly associated with intrinsic RSFC changes in regions of the posterior cingulate cortex and right superior frontal gyrus-anatomical and functional locations of the brain's default mode network (DMN). No statistically significant relationships were found between global cognitive change and RSFC change in nonsurgical controls. CONCLUSION: Clinicians have long known that some older adults develop postoperative cognitive dysfunction (POCD) after anesthesia and surgery, yet the neurobiological correlates of POCD are not well defined. The current results suggest that altered RSFC in specific DMN regions is positively correlated with global cognitive change 6 weeks after cardiac surgery, suggesting that DMN activity and connectivity could be important diagnostic markers of POCD or intervention targets for potential POCD treatment efforts.
Published Version (Please cite this version)
Browndyke, Jeffrey N, Miles Berger, Todd B Harshbarger, Patrick J Smith, William White, Tiffany L Bisanar, John H Alexander, Jeffrey G Gaca, et al. (2017). Resting-State Functional Connectivity and Cognition After Major Cardiac Surgery in Older Adults without Preoperative Cognitive Impairment: Preliminary Findings. J Am Geriatr Soc, 65(1). pp. e6–e12. 10.1111/jgs.14534 Retrieved from https://hdl.handle.net/10161/13329.
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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.
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.
John H. Alexander, MD, MHS is a cardiologist and Professor of Medicine in the Department of Medicine, Division of Cardiology at Duke University School of Medicine, as well as the Vice Chief, Clinical Research in the Division of Cardiology. He is the Director of Cardiovascular Research at the Duke Clinical Research Institute where he oversees a large group of clinical research faculty and a broad portfolio of cardiovascular clinical trials and observational clinical research programs. He is a member of the American Society of Clinical Investigation.
Dr. Alexander’s clinical interests are in acute and general cardiovascular disease, valvular heart disease, and echocardiology. His research is focused on the translation of novel therapeutic concepts into clinical data through clinical trials, specifically on the therapeutics of acute coronary syndromes, chronic coronary artery disease, and cardiac surgery and on novel methodological approaches to clinical trials. He was on the Executive Committee of the ARISTOTLE trial of apixaban in patients with atrial fibrillation and was the Principal Investigator of the APPRAISE-2 trial of apixaban in patients with acute coronary syndromes.
Dr. Alexander has published extensively and has served as the principal investigator of numerous multicenter clinical trials. He currently serves as the co-chair of the Clinical Trial Transformation Initiative (CTTI).
Dr. Kathleen Welsh-Bohmer is a Professor of Psychiatry with a secondary appointment in the Department of Neurology.
Clinically trained as a neuropsychologist, Dr. Welsh-Bohmer's research activities have been focused around developing effective prevention and treatment strategies to delay the onset of cognitive disorders occurring in later life. From 2006 through 2018 she directed the Joseph and Kathleen Bryan Alzheimer’s Center in the Department of Neurology. She also oversaw the neuropsychology scientific operations of a ground-breaking Phase III global clinical trial to delay the onset of early clinical symptoms of Alzheimer’s disease entitled the “TOMMORROW” study (Takeda Pharmaceutical Company funded) which concluded in 2018.
Currently, she directs the Alzheimer's disease therapeutic area within the Duke Clinical Research Institute and she collaborates actively with VeraSci, a Durham based company, to develop reliable digital cognitive and functional assessment tools of early Alzheimer's disease and related dementias. The methods her team is developing are informed by advances in neuroscience and technology and fill an information void in early pre-clinical Alzheimer's disease. Her work has implications for clinical practice and for the acceleration of global clinical trials aimed at the prevention of Alzheimer’s disease and related dementias.
Best known for his work in assessing and improving clinical outcomes and quality of life following cardiac surgery, Dr. Mark Newman is President of the Duke Private Diagnostic Clinic (The Duke Faculty Practice Organization) and the Merel H. Harmel Professor of Anesthesiology at Duke University Medical Center. In addition, Dr. Newman developed the Multicenter Perioperative Outcomes Research Group of the Duke Clinical Research Institute established at Duke in 2001 to further the study of strategies to improve the outcomes of patients undergoing surgery and anesthesia. Dr. Newman has received funding from the National Institute on Aging, the American Heart Association, the National Heart, Lung and Blood Institute, the Anesthesia Patient Safety Foundation, and the International Anesthesia Research Society to investigate the impact of perioperative outcomes (neurocognitive decline, stroke, myocardial infarction, renal injury) on quantity and quality of life following cardiac surgery and resulting in numerous seminal publications in the New England Journal of Medicine, JAMA and Lancet. Dr. Newman is a popular lecturer and speaker, having appeared on NBC Nightly News and The Today Show and having spoken at more than 200 national and international meetings. Dr. Newman recently stepped down as the Chairman of the Duke University Department after 13 years to assume the role of PDC President. During Dr. Newman’s tenure the department grew exponentially doubling its clinical and academic funding, and developing many outstanding individuals that have gone on to leadership roles at Duke and other key academic institutions across the country.
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.
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