Tau is a microtubule-associated protein found in neuronal axons, and is released after neuronal injury. Increased cerebrospinal fluid (CSF) tau levels predict the development of Alzheimer's disease, and increased CSF tau levels also predict worsened outcomes after subarachnoid hemorrhage and traumatic brain injury. We have found increased CSF tau levels in patients after surgery and anesthesia, and numerous investigators have found that anesthesia and surgery increase tau levels and cause memory deficits in animal models (6-8). Taken together, these findings suggest the possibility that changes in CSF tau levels may also be associated with neurocognitive changes after anesthesia and surgery in our patients. Indeed, multiple studies have found neurocognitive changes (i.e. post-operative delirium and cognitive dysfunction) occur in a substantial fraction of patients after surgery and anesthesia, and a major risk factor for these disorders is age >60. Post-operative delirium and cognitive dysfunction are major complications in elderly patients: they are associated with decreased ability to perform IADLs, decreased quality of life, early exit from the work force, and increased one year mortality. Yet, the underlying pathophysiology of post-operative delirium and/or cognitive dysfunction is unclear, which impedes our ability to treat these syndromes and improve patient outcomes. In this application, we will extend our preliminary work demonstrating significant increases in CSF tau levels after anesthesia and surgery by determining the long-term trajectory of these perioperative CSF tau increases, and whether they are associated with delirium, cognitive dysfunction, or altered functional neural connectivity in elderly surgical patients vs age-matched controls. We will also obtain data on the relationship between changes in CSF tau levels, IADLs and quality of life in these patients' vs controls. This study is the first, adequately powered prospective clinical study to determine the long-term trajectory of perioperative changes in CSF tau levels, and to correlate these changes with changes in cognitive function, brain connectivity and functional status. Understanding these relationships could help develop strategies to prevent adverse effects of anesthesia and surgery in the elderly and to improve neurocognitive function for the millions of patients over age 60 who undergo perioperative care each year in the United States.

Public Health Relevance

Elderly patients are at risk for developing Alzheimer's disease (the most common cause of dementia in the elderly), animal studies suggest that anesthesia and surgery promote Alzheimer's disease pathways, and clinical studies have documented a high risk of thinking and memory problems (known as post-operative delirium and cognitive dysfunction) in elderly surgical patients. Thus, there is a critical need to determine whether anesthesia and surgery contribute to Alzheimer's disease risk in elderly surgical patients, and to understand what causes post-operative delirium and cognitive dysfunction. Our work aims to answer these questions, and has the potential to improve neurocognitive outcomes and quality of life for the millions of elderly patients who undergo anesthesia and surgery each year in the US.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1-ZIJ-3 (M1))
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Wagster, Molly V
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Duke University
Schools of Medicine
United States
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Berger, Miles; Terrando, Niccolò; Smith, S Kendall et al. (2018) Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms. Anesthesiology 129:829-851
Browndyke, Jeffrey N; Berger, Miles; Smith, Patrick J et al. (2018) Task-related changes in degree centrality and local coherence of the posterior cingulate cortex after major cardiac surgery in older adults. Hum Brain Mapp 39:985-1003
Devinney, Michael J; Mathew, Joseph P; Berger, Miles (2018) Postoperative Delirium and Postoperative Cognitive Dysfunction: Two Sides of the Same Coin? Anesthesiology 129:389-391
Giattino, Charles M; Gardner, Jacob E; Sbahi, Faris M et al. (2017) Intraoperative Frontal Alpha-Band Power Correlates with Preoperative Neurocognitive Function in Older Adults. Front Syst Neurosci 11:24
Browndyke, Jeffrey N; Berger, Miles; Harshbarger, Todd B 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:e6-e12
Berger, Miles; Nadler, Jacob W; Friedman, Allan et al. (2016) The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial. J Alzheimers Dis 52:1299-310
Berger, Miles; GarcĂ­a, Paul S (2016) Anesthetic Suppression of Thalamic High-Frequency Oscillations: Evidence that the Thalamus Is More Than Just a Gateway to Consciousness? Anesth Analg 122:1737-9