Postoperative changes in cognition and cerebrospinal fluid neurodegenerative disease biomarkers.
Date
2022-02
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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
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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.
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Scholars@Duke
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
Daniel Todd Laskowitz
Our laboratory uses molecular biology, cell culture, and animal modeling techniques to examine the CNS response to acute injury. In particular, our laboratory examines the role of microglial activation and the endogenous CNS inflammatory response in exacerbating secondary injury following acute brain insult. Much of the in vitro work in this laboratory is dedicated to elucidating cellular responses to injury with the ultimate goal of exploring new therapeutic interventions in the clinical setting of stroke, intracranial hemorrhage, and closed head injury.
In conjunction with the Multidisciplinary Neuroprotection Laboratories, we also focus on clinically relevant small animal models of acute CNS injury. For example, we have recently characterized murine models of closed head injury, subarachnoid hemorrhage, intracranial hemorrhage and perinatal hypoxia-ischemia, in addition to the standard rodent models of focal stroke and transient forebrain ischemia. Recently we have adapted several of these models from the rat to the mouse to take advantage of murine transgenic technology. The objective of these studies are two-fold: to gain better insight into the cellular responses and pathophysiology of acute brain injury, and to test novel therapeutic strategies for clinical translation. In both cell culture systems and animal models, our primary focus is on examining the role of oxidative stress and inflammatory mechanism in mediating brain injury following acute brain insult, and examining the neuroprotective effects of endogenous apolipoprotein E in the injured mammalian central nervous system.
Our laboratory is committed to translational research, and has several active clinical research protocols, which are designed to bring the research performed in the Multidisciplinary Research Laboratories to the clinical arena. These protocols are centered around patients following stroke and acute brain injury, and are primarily based out of the Emergency Room and Neurocritical Care Unit. For example, we are currently examining the role of inflammatory mediators for use as a point-of-care diagnostic marker following stroke, intracranial hemorrhage, and closed head injury. We have recently translated a novel apoE mimetic from the preclinical setting to a multi center Phase 2 trial evaluating efficacy in intracranial hemorrhage. We are also examining the functional role of different polymorphisms of of inflammatory cytokines in the setting of acute brain injury and neurological dysfunction following cardiopulmonary bypass.
Heather Elizabeth Whitson
Dr. Whitson is a geriatrician, memory care specialist, and clinical researcher. Her career is focused on improving care options and resilience for people with multiple chronic conditions. In particular, she has interest and expertise related to how aging biology and comorbidities impact brain health and risk for Alzheimer's disease. She is co-director of the Duke/UNC Alzheimer's Disease Research Center (Duke/UNC ADRC), which aims to transform dementia care and research in Eastern North Carolina while developing novel preventions and treatment strategies for Alzheimer's disease by identifying aging-related factors across the lifespan that drive risk, progression, or experience of dementia. The Duke/UNC ADRC conducts the Memory and Aging Study, which is tracking brain and cognitive changes in over 400 individuals at risk for dementia in later life. Dr. Whitson also co-Chairs the Alzheimer's Association's Clinical Practice Guideline panel for the use of blood-based biomarkers in the diagnosis of Alzheimer's disease. As a thought leader in a national collaborative focused on the biomedical aspects of resilience, Dr. Whitson seeks to better understand biological, psychological, and contextual factors that determine how well we "bounce back" after acute health stressors and why our resilience capacity changes with age. Dr. Whitson has contributed to work examining resilience to many types of health stressors, including surgery, dialysis, infection, vascular events, and vision loss - often focused on how these stressors affect the brain. She has led multiple studies to examine how the aging brain responds to the late-life stressor of vision loss, and she has developed a rehabilitation model to improve independence in older adults living with comorbid impairments in vision and cognition.
Harvey Jay Cohen
Dr. Cohen's research program includes clinical research relating to aspects of the pathways to functional decline and reilience with aging, geriatric assessment, and cancer and anemia in the elderly.
Pathways to functional decline are being explored through the NIA funded Claude Pepper Older Americans Independence Center, and includes studies of the contributions of age related physiologic change, in particular changes in inflammatory parameters, comorbid diseases and conditions, environment, genetics, and the interactionas among them. Data are derived from several current studies as well as previously collected data sets from the Established Populations for Epidemiologic Studies of the Elderly (EPESE), National Long Term Care Survey, and the Chinese Longevity Study (with Dr. Zeng Yi). Previous work has demonstrated the important contributions of age related inflammation and coagulation activation to functional status. He is Co-PI of the Pepper Center Physical Performance Across the LifeSpan (PALS) study, which is a longitudinal cohort study of community dwelling adults from age 30-90+and includes functional measures and biomarkers on inflammation and metabolism.
Geriatric assessment approaches have been studied in a number of randomized and controlled studies and work is now concentrating on the application of Comprehensive Geriatric Assessment tools to the evaluation and treatment of elderly patients with cancer. This is an extension and continuation of a long standing interest in geriatric oncology. Previous studies have elucidated age-related patterns of disease presentation, treatment approaches, clinical trials, survivorship, quality of life, impact of comrobidities and functional outcomes. Dr. Cohen was co-chair, and now member of the Cancer in the Older Adult Committee of the Alliance for Clinical Trials in Oncology (ALLIANCE). A number of active studies and ongoing data bases aree being utilized to address these questions.
Anemia in the older adult is being addressed through an NIA funded U01 consortium (Dr. Cohen Co-PI). the current main study is an observational study followed by a pragmatic treatment trial for anemia in older adults with CHF, in collaboration with the Cardiovascular Research Network (CVRN) of the Health services research network (HSRN)
Joseph P. Mathew
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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