Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.
Date
2022-02
Journal Title
Journal ISSN
Volume Title
Repository Usage Stats
views
downloads
Citation Stats
Abstract
Objective
Numerous investigators have theorized that postoperative changes in Alzheimer's disease neuropathology may underlie postoperative neurocognitive disorders. Thus, we determined the relationship between postoperative changes in cognition and cerebrospinal (CSF) tau, p-tau-181p, or Aβ levels after non-cardiac, non-neurologic surgery in older adults.Methods
Participants underwent cognitive testing before and 6 weeks after surgery, and lumbar punctures before, 24 h after, and 6 weeks after surgery. Cognitive scores were combined via factor analysis into an overall cognitive index. In total, 110 patients returned for 6-week postoperative testing and were included in the analysis.Results
There was no significant change from before to 24 h or 6 weeks following surgery in CSF tau (median [median absolute deviation] change before to 24 h: 0.00 [4.36] pg/mL, p = 0.853; change before to 6 weeks: -1.21 [3.98] pg/mL, p = 0.827). There were also no significant changes in CSF p-tau-181p or Aβ over this period. There was no change in cognitive index (mean [95% CI] 0.040 [-0.018, 0.098], p = 0.175) from before to 6 weeks after surgery, although there were postoperative declines in verbal memory (-0.346 [-0.523, -0.170], p = 0.003) and improvements in executive function (0.394, [0.310, 0.479], p < 0.001). There were no significant correlations between preoperative to 6-week postoperative changes in cognition and CSF tau, p-tau-181p, or Aβ42 changes over this interval (p > 0.05 for each).Interpretation
Neurocognitive changes after non-cardiac, non-neurologic surgery in the majority of cognitively healthy, community-dwelling older adults are unlikely to be related to postoperative changes in AD neuropathology (as assessed by CSF Aβ, tau or p-tau-181p levels or the p-tau-181p/Aβ or tau/Aβ ratios).Trial registration
clinicaltrials.gov (NCT01993836).Type
Department
Description
Provenance
Citation
Permalink
Published Version (Please cite this version)
Publication Info
Berger, Miles, Jeffrey N Browndyke, Mary Cooter Wright, Chloe Nobuhara, Melody Reese, Leah Acker, W Michael Bullock, Brian J Colin, et al. (2022). Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers. Annals of clinical and translational neurology, 9(2). pp. 155–170. 10.1002/acn3.51499 Retrieved from https://hdl.handle.net/10161/25543.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
Scholars@Duke
Miles Berger
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.
Jeffrey Nicholas Browndyke
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.
Leah Acker
William Michael Bullock
Michael Devinney
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).
Eugene William Moretti
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.
Judd Wendell Moul
Dr Judd Moul joined the Duke faculty in mid 2004 after a career in the US Army Medical Corps mainly at Walter Reed Army Medical Center. He is a retired colonel and a noted researcher and clinician in the area of prostate cancer and is a urologic oncologist. He served as the division chief of Duke Division of Urology from 2004 to 2011 and was named the James H Semans MD Professor of surgery in 2009 becoming Duke's first named endowed chair for urology. He was awarded the Gold Cystoscope Award from the American Urologic Association as well as Castle Connelly Physician of the year for Clinical Medicine in 2009. He has performed more than 1300 radical prostatectomies since joining the Duke faculty and is committed to outcomes research on this series and in other areas of prostate cancer. He served as the Editor for Prostate Cancer and Prostatic Dissease, a Nature Medicine journal, for more than a decade and is a popular speaker and lecturer having been visiting professor and keynote speaker throughout the US and the World. He is very committed to training residents and mentoring students and trainees.
Brian Joseph Ohlendorf
Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.