Surgery and Cognition: Delirium, Cognitive Decline, and Opportunities to Protect the Brain

Surgery and Cognition: Delirium, Cognitive Decline, and Opportunities to Protect the Brain

Tuesday, June 21, 2016

The New York Academy of Sciences

Surgery helps millions of Americans overcome illness to live longer, healthier lives. Yet for many of these people, surgery can lead to delirium, cognitive decline, and perhaps even a higher long-term risk of dementia. These risks are poorly understood and often under-recognized in the clinic. The level of risk to a patient depends on the individual and the surgery. For example, delirium is experienced in 15–80% of surgical patients who, in turn, may have a higher risk of long-term cognitive and functional decline. This one-day meeting will convene leading scientists to discuss the challenges and opportunities to create biomarkers and therapeutics for these vulnerable patients.

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This event will also be broadcast as a webinar; registration is required.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City where possible.

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Member (Student / Postdoc / Resident / Fellow)$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

Agenda

* Presentation times are subject to change.


Tuesday, June 21, 2016

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Howard Fillit, MD, The Alzheimer's Drug Discovery Foundation

9:15 AM

Plenary Address: Surgery and the Potential Intersections of Delirium, Cognitive Decline, and Dementia
Sharon Inouye, MD, MPH, Harvard Medical School

Session I: Anesthesia and Sedation

10:00 AM

Anesthesia, Neural Networks, and the Trajectory of Cognitive Recovery
Joshua Mincer, MD, PhD, Icahn School of Medicine at Mount Sinai

10:30 AM

Networking Coffee Break

11:00 AM

The Mechanistic Studies of Postoperative Delirium and Cognitive Dysfunction in Rodents
Zhongcong Xie, MD, PhD, Massachusetts General Hospital & Harvard Medical School

11:30 AM

Electroencephalography and Postoperative Delirium
Michael S. Avidan, MBBCh, FCASA, Washington University School of Medicine

12:00 PM

Networking Lunch Break and Poster Session

Session II: Clinical Biomarkers and Therapeutics

1:00 PM

CSF Alzheimer's Disease Biomarker Changes after Anesthesia and Surgery: Trajectory and Functional Significance
Miles Berger, MD, PhD, Duke University Medical Center

1:30 PM

Beta-amyloid Load as a Predictive Biomarker of Postoperative Cognitive Decline
Marek Brzezinski, MD, PhD, University of California, San Francisco

2:00 PM

BioCog: Biomarker Development for Postoperative Cognitive Impairment in the Elderly
Prof. Claudia Spies, Charité-University Medicine Berlin

2:30 PM

Networking Coffee Break

3:00 PM

Postoperative Delirium and Dementia: Is Inflammation the Connection?
Edward R. Marcantonio, MD, SM, Beth Israel Deaconess Medical Center

3:30 PM

Xenon for Protection from Ongoing Acute Neurologic Injury
Mervyn Maze, MB, ChB, University of California, San Francisco
* Presenter slides will not be included as part of the Webinar broadcast.

4:00 PM

Panel Discussion: Low Hanging Fruit for Therapeutic Interventions
Howard Fillit, MD (Moderator)

5:00 PM

Closing Remarks
Howard Fillit, MD, The Alzheimer's Drug Discovery Foundation

5:05 PM

Networking Reception

6:00 PM

Adjourn

Organizers

Howard Fillit, MD

The Alzheimer's Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF's mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer's disease, related dementias and cognitive aging. Dr. Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is a co-author of more than 250 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Previously, Dr. Fillit was the Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare managed care members in five regional markets. Dr. Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Penny Dacks, PhD

Alzheimer's Drug Discovery Foundation

Penny Dacks, PhD, directs the program on Aging and Alzheimer's Prevention at the Alzheimer's Drug Discovery Foundation. In this role, she leads efforts to evaluate, communicate, and accelerate the development of scientific evidence for proposed strategies to promote healthy aging and prevent Alzheimer's disease. A cornerstone of the program is CognitiveVitality.org, an online open resource on the state-of-the-science behind potential brain-health therapies. Dr. Dacks has authored over 20 peer-reviewed scientific articles. She trained in neuroscience at the Icahn School of Medicine at Mount Sinai and the University of Arizona with fellowships from the National Institute of Health, the Hilda and Preston Davis Foundation, the ARCS Foundation, and the Evelyn F. McKnight Brain Research Foundation.

Sonya Dougal, PhD

The New York Academy of Sciences

Keynote Speaker

Sharon Inouye, MD, MPH

Harvard Medical School

Dr. Inouye is Professor of Medicine at Harvard Medical School (Beth Israel Deaconess Medical Center), holder of the Milton and Shirley F. Levy Family Chair, and Director of the Aging Brain Center at the Institute for Aging Research, Hebrew SeniorLife. Dr. Inouye is board-certified in general internal medicine and geriatric medicine, and trained in clinical epidemiology and biostatistics. Dr. Inouye's research interests include the epidemiology and outcomes of delirium and functional decline in older persons, reversible contributors to cognitive decline with aging, the interrelationship of delirium and dementia, and improving measurement methods for cognition. Dr. Inouye developed the Confusion Assessment Method (CAM), a widely used method for identification of delirium, translated into over 19 languages; and the Hospital Elder Life Program (HELP) for delirium prevention, which has been implemented in over 200 hospitals worldwide. She currently directs the Successful AGing after Elective Surgery (SAGES) study, a large Program Project from the National Institute on Aging exploring innovative risk factors and long-term outcomes of delirium. Dr. Inouye has authored over 220 scientific articles, and was elected to the National Academy/Institute of Medicine in 2011. She recently received the 2015 M. Powell Lawton Award from the Gerontological Society of America. Her clinical practice includes dementia and functional assessment for geriatric and homeless populations. Dr. Inouye received the Harvard Medical School Barger Award in 2013 for excellence in mentoring. She has mentored over 90 students, fellows, and faculty in clinical research and aging.

Speakers

Michael S. Avidan, MBBCh, FCASA

Washington University School of Medicine

Michael S. Avidan, MBBCh, FCASA, the Dr. Seymour and Rose T. Brown Professor of Anesthesiology, is Professor of Anesthesiology and Surgery at Washington University School of Medicine. He is the Director of the Anesthesiology Department's Institute of Quality Improvement, Research and Informatics, and is the Chief of the Cardiothoracic Anesthesiology Division. He is a renowned investigator in the field of perioperative outcomes research, including large multi-center clinical trials. His major contributions to science have been in the fields of prevention of intraoperative awareness and explicit recall of surgical events; surgery and anesthesia and postoperative neurologic outcomes; and patient risk factors and postoperative outcomes publishing his work in prominent scientific journals including the New England Journal of Medicine, Science, Anesthesiology, Proceedings of the National Academy of Sciences and Journal of Alzheimer's Disease. His research has been generously funded by grants from the National Institutes of Health; the Foundation for Anesthesia Education and Research; the McDonnell Foundation for Neuroscience; the Institute of Clinical and Translational Sciences; the Barnes-Jewish Hospital Foundation; the American Society of Anesthesiologists; the University of Missouri Alzheimer's Disease and Related Disorders Program; the National Blood Authority, UK; and the British Journal of Anaesthesia/Royal College of Anaesthetists.

Miles Berger, MD, PhD

Duke University Medical Center

Dr. Miles Berger graduated from Columbia University Magna Cum Laude and Phi Beta Kappa with a major in biochemistry. His undergraduate research at Columbia's College of Physicians and Surgeons demonstrated that different human neutrophil Gi-coupled receptors induce differential cellular functions, from chemotaxis to hydrogen peroxide generation. Dr. Berger then completed the MD/PhD program at the University of California, San Francisco. His PhD work (published in the Proceedings of the National Academy of Sciences) led to the discovery that Gi-coupled serotonin receptors and other Gi-coupled receptors play a critical role in regulating perinatal pancreatic beta cell development, and thereby modulating adult beta cell mass, glucose homeostasis, and diabetes risk. Dr. Berger then completed a transitional internship, anesthesiology residency and neuroanesthesiology fellowship at Duke University Medical Center in Durham, NC, and then joined the Duke faculty as an assistant professor in 2014. His current research is funded by the National Institute of Aging, the Duke Translational Research Institute, the American Geriatrics Society, the Foundation for Anesthesia Education and Research, and the International Anesthesia Research Society. Dr. Berger's research group focuses on identifying biomarkers for postoperative cognitive dysfunction and delirium, as well as understanding the potential links between these disorders, anesthesia and surgery, and Alzheimer's disease pathogenesis.

Marek Brzezinski, MD, PhD

University of California, San Francisco

Marek Brzezinski, MD, PhD is a Professor in the Department of Anesthesia and Perioperative Care at University of California–San Francisco. He received his MD and PhD degrees from the Westfaelische Wilhelms- University in Muenster, Germany. He completed his anesthesia residency at University of Chicago. Subsequently, he went to Massachusetts General Hospital and Duke University where he completed fellowship training in critical care medicine and in cardiothoracic anesthesia, respectively. His research examines the effects of anesthesia and surgery on cognition and neuropsychiatric symptoms such as post-traumatic stress disorder. In addition, Dr. Brzezinski is a nationally recognized medical educator, and a member of the prestigious Haile T. Debas Academy of Medical Educators at UCSF.

Edward Marcantonio, MD, SM

Beth Israel Deaconess Medical Center

Dr. Edward Marcantonio is a Professor of Medicine at Harvard Medical School and serves as Section Chief for Research in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC), where he leads the Division's Aging Research Program. He is an internationally recognized expert and clinical investigator in the area of delirium (acute confusion), a common, morbid and costly condition in acutely ill older patients. Over the past 20 years, Dr. Marcantonio has conducted a series of observational and interventional studies designed to improve the diagnosis of delirium, target individuals at risk, identify modifiable risk factors, and test intervention strategies to reduce the incidence, severity and duration of delirium. Emerging research interests for Dr. Marcantonio are biomarker discovery for delirium, and the interrelationship between delirium and dementia, particularly Alzheimer's Disease. In addition to his administrative and research activities, Dr. Marcantonio is a clinical geriatrician and runs a Memory and Cognition consultation practice at BIDMC Senior Health.

Mervyn Maze, MB, ChB

University of California, San Francisco

Mervyn Maze, MB, ChB is William K. Hamilton Distinguished Professor of Anesthesia and Former Chair of the Department of Anesthesia and Perioperative Care at the University of California, San Francisco. He is currently the Acting Director of the Center for Cerebrovascular Research. His research interests include patient factors that increase the risk for postoperative cognitive decline, as well as neurotoxicity of anesthesia and surgery at the extremes of life. At the present time, the patient-related factors that are being investigated most intensively are the metabolic syndrome and obesity with and without insulin resistance. Dr. Maze is a long-time recipient of NIH and other federally funded agency support for his research that has resulted in the clinical translation of a new chemical entity (decks met atomic in). He holds 17 patents related to research performed in his laboratory while at Stanford University, Imperial College London, and UCSF.

Joshua Mincer, MD, PhD

Icahn School of Medicine at Mount Sinai

Joshua Mincer is an anesthesiologist and biophysicist whose interests center on the multiscale elucidation of mechanisms of general anesthetic action. His work builds on a record of computational study of problems of biological and clinical interest, with most recent application to the interactions of anesthetic ligands such as propofol with a model ion channel receptor target. He is currently a co-Investigator on the NIH funded TORIE (Trajectory of Recovery In the Elderly) project, employing functional neuroimaging to uncover the effects of anesthesia on the functional connectivity of the human brain, in addition to providing anesthesia to study participants. After completing his undergraduate studies at Princeton, Dr. Mincer entered the Medical Scientist Training Program at the Albert Einstein College of Medicine, where his PhD dissertation focused on the theory of enzyme catalysis. Prior to starting his post-graduate medical education, he was a research scientist at the Courant Institute of Mathematical Sciences at NYU where he employed agent-based simulation methods to model urban disaster and response scenarios. While a resident in anesthesiology at Mount Sinai, Dr. Mincer was a visiting fellow at Rockefeller University, where he developed a coarse-grained simulation model of transport in the nuclear pore complex, a process central to gene regulation. Dr. Mincer is currently an assistant professor in the department of anesthesiology at the Icahn School of Medicine at Mount Sinai. He is also attending anesthesiologist at Mount Sinai Hospital and section chief of thoracic anesthesia at the James J. Peters VA Medical Center.

Professor Claudia Spies

Charité-University Medicine Berlin

Professor Claudia D. Spies graduated in 1987 after training in Erlangen-Nuremberg and Boston. She became Head of the Department of Anaesthesiology and Intensive Care Medicine Campus Mitte and Campus Virchow-Klinikum at the Charité – Universitätsmedizin Berlin in 2005. In the CharitéCenter7 she is responsible for more than 300 anaesthesiologists (approximately 65,000 anaesthetics a year), more than 100 ICU beds, 2 pain clinics, and emergency medicine. She is member of the executive committee of the "German Association of the Scientific Medical Societies" (AWMF) and currently chairing the AWMF guideline committee. She was Vice Dean for Educational Affairs at the Charité from 2011–2014. In addition, she is elected Member of the "Leopoldina – National Academy of Science." Her scientific interest focusses on postoperative delirium and long-term cognitive dysfunctions.

Zhongcong Xie, MD, PhD

Massachusetts General Hospital & Harvard Medical School

Dr. Zhongcong Xie ("Z") graduated from Xuzhou Medical College in China in 1985. He started his research career in 1989 with graduate studies in behavioral pharmacology at Wayne State University, Detroit, Michigan, USA, and obtained PhD in 1994. He moved to Harvard Medical School, Boston, Massachusetts as a post-doctoral research fellow in both human and animal behavioral research. He returned to the clinical arena in 1997 as an Anesthesiology resident at Massachusetts General Hospital and Harvard Medical School. After completing anesthesia residency training, he decided to become a physician–scientist and continue his research in neuroscience. Dr. Xie's research works mainly focus on studying the cellular and molecular basis of the neuropathogenesis of Alzheimer's disease, postoperative cognitive dysfunction, and postoperative delirium in humans, animals and cultured cells using behavioral, genetic, molecular and cellular biological tools. Dr. Xie is a Professor of Anaesthesia at Harvard University and Attending Anesthesiologist at Massachusetts General Hospital, the affiliated hospital of Harvard Medical School. He is the director of the Geriatric Anesthesia Research Unit in the Department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital.

Abstracts

Surgery and the Potential Intersections of Delirium, Cognitive Decline, and Dementia
Sharon Inouye, MD, MPH, Harvard Medical School

This talk will cover the potential inter-relationships of post-operative delirium, cognitive decline, and dementia—their possible overlaps and distinctions. Current evidence will be reviewed in terms of epidemiology, risk factors, and pathophysiology. Future work to clarify these areas will be outlined.

Anesthesia, Neural Networks, and the Trajectory of Cognitive Recovery
Joshua S. Mincer, MD, PhD, Icahn School of Medicine at Mount Sinai

This talk focuses on functional neuroimaging, specifically the use of advanced resting state fMRI (rs-fMRI), to elucidate functional networks operative under anesthesia and changes of functional brain organization along the peri-anesthetic trajectory. We will present our ongoing study, the Trajectory of Recovery Project (TORIE), to demonstrate the effects of anesthesia on cognitive testing and functional neuroimaging. In this study, healthy volunteers are maintained under general anesthesia with sevoflurane, and fMRI imaging is obtained prior to, during, and after anesthesia, as well as at one day and one week later. Early results in our elderly subjects reveal a novel imaging biomarker for the brain's response to anesthesia, referred to as dimensionality. This statistical parameter is a measure of the brain's functional organization and connectivity at a given point in time. We demonstrate that along the peri-anesthetic trajectory there are least two different response profiles to anesthesia in the elderly. One subset of subjects shows an increase in dimensionality, corresponding to functional network fragmentation, whereas the other shows a decrease, corresponding to more global decrease in network activity. Future work will correlate dimensionality with network-specific changes in functional connectivity in the anesthetized brain, elucidate to what extent variations in dimensionality exist across age groups, and correlate this biomarker with cognitive testing.

The Mechanistic Studies of Postoperative Delirium and Cognitive Dysfunction in Rodents
Zhongcong Xie, MD, PhD, Massachusetts General Hospital & Harvard Medical School

Postoperative delirium and postoperative cognitive dysfunction (POCD) are the two most common postoperative complications in older adults, and increase morbidity, mortality, and cost of medical care in the patients. However, at the present time, both postoperative delirium and POCD are clinical phenomena and their pathogenesis remains largely to be determined, which impedes the progress of the research. This is mainly due to the lack of the animal model(s) to study postoperative delirium and POCD. We therefore set out to employ a battery of behavior tests, including nature and learning behaviors (buried food test, open field test and Y maze test) in mice, to investigate the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on the behaviors associated with postoperative delirium. We found that the Anesthesia/Surgery selectively impaired behaviors of mice, including latency to eat food in buried food test, time spent in the center in open field test, and entries and duration in novel arm of Y maze test, with acute onset and fluctuating course. The composite Z score further quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in the mice. The animal models (e.g., Morris Water Maze) to study POCD have been reviewed. In the mechanistic studies, we found that the Anesthesia/Surgery may induce the behavioral changes associated with postoperative delirium and POCD by causing energy deficits, blood brain barrier dysfunction and olfactory dysfunction in mice. The other underlying mechanisms of POCD, including apoptosis, Aβ accumulation, Tau phosphorylation, neuroinflammation, mitochondria dysfunction and NMDA receptor dysfunction, have also been reviewed.

Electroencephalography and Postoperative Delirium
Michael S. Avidan, MBBCh, FCASA, Washington University School of Medicine

Delirium is a clinical syndrome resulting from acute brain dysfunction or encephalopathy. Delirium is characterized by acute changes and fluctuations in attention, cognition, and consciousness. Emergence delirium typically presents and resolves within minutes to hours after termination of general anesthesia. Postoperative delirium, which occurs hours to days in a large number of older adults after major surgery, can herald poor outcomes. While more easily recognized when patients are hyperactive or agitated, delirium most commonly presents with hypoactivity and somnolence, and is frequently undiagnosed. Electroencephalography offers objective measurements to complement clinical assessment. The electroencephalographic signatures remain incompletely characterized for acute encephalopathies manifesting with delirium, but a shifting of electroencephalographic power into low frequencies is typical. Also when delirium is related to non-convulsive status epilepticus, electroencephalography is needed to confirm the diagnosis. New electroencephalographic approaches, including continuous recording and graph theoretical approaches are providing fresh insights into delirium. Based on preliminary data, evidence is emerging that electroencephalographic burst suppression, either during general anesthesia or with sedation on the intensive care unit, might be a risk factor for subsequent delirium. Currently, electroencephalographic features of evolving, established and resolving delirium, in the postoperative period specifically are poorly characterized. Future studies are needed to (1) clarify electroencephalographic features that can reliably predict or diagnose delirium in the postoperative period and (2) provide mechanistic insights into postoperative delirium, a pathologically diverse neurological disorder.

CSF Alzheimer's Disease Biomarker Changes after Anesthesia and Surgery: Trajectory and Functional Significance
Miles Berger, MD, PhD, Duke University Medical Center

Preclinical studies demonstrate that anesthesia and surgery accelerate Alzheimer's disease (AD) pathogenesis, and that isoflurane vs. propofol have differential effects on the AD biomarkers tau, phosphorylated tau (p-tau) and amyloid-beta. To examine the human relevance of these preclinical findings, we conducted the Markers of Alzheimer's Disease after Propofol or Isoflurane Anesthesia (MAD-PIA) trial: we randomized ENT and neurosurgery patients who needed CSF lumbar drain placement for surgery to receive isoflurane or propofol anesthesia, and measured the CSF tau/Amyloid beta ratio (the primary outcome) and individual AD biomarkers before, 10 and 24 hours after the start of surgery Surprisingly, we found no difference in the CSF tau/amyloid beta ratio over time among propofol- vs isoflurane-treated patients (p=1.000), although we found a ~3 fold increase in CSF tau levels from before to 24 hours after surgery among all patients (p=1.985 x 10-6), into the same range seen in Alzheimer's disease. To determine the long term trajectory and functional significance of these acute perioperative CSF tau increases, we then initiated the Markers of Alzheimer's Disease and neuroCognitive Outcomes after Perioperative Care (MADCO-PC) trial. Surgical patients age 60 and above undergo pre- and post-operative CSF sampling, cognitive testing and functional brain imaging, and the same procedures are performed in a matched cohort of non-surgical controls (i.e. community-dwelling older adults). As of 4/13/2016, we have enrolled 119 patients in this trial. Here we describe the baseline characteristics of this patient cohort, the statistical analysis plan for the study, and the timeline for study completion.

Beta-Amyloid Load as a Predictive Biomarker of Postoperative Cognitive Decline
Marek Brzezinski, MD, PhD, University of California, San Francisco

Recent evidence implicates Alzheimer's disease (AD) neuropathology as a risk factor for POCD. AD-neuropathology is readily detectable with PET imaging. This prospective study examined whether brain Aβ-burden at the preoperative baseline predicts short and long-term POCD in cognitively normal subjects, ≥65 years-old, scheduled for hip or knee replacement under general anesthesia. Preoperative PET with Aβ-specific tracer florbetapir-F18 was acquired. Cognitive testing was performed preoperatively, at hospital discharge, and 3 and 12 months after surgery. We analyzed data from 44 Surgical Group (SG) and 13 Control Group (CG) subjects with orthopedic problems who also underwent cognitive testing at similar time intervals (no PET). Of the 44 surgical subjects, 13 were Aβ positive(+) and 31 Aβ negative(−) (30% and 70%). Both groups were well matched at the preoperative baseline. The incidence of POCD in the Aβ(+) group was higher at all 3 time points tested compared to the Aβ(−) group. Aβ(+) participants demonstrated larger declines in executive function than AB− at all three postoperative time points, and a similar trend was seen in other cognitive domains. This study identified preexistent brain β-amyloid as a predictor of short and long-term POCD in cognitively normal subjects.

BioCog: Biomarker Development for Postoperative Cognitive Impairment in the Elderly
Claudia Spies, Charité-University Medicine Berlin

Acute and chronic cognitive disturbances related to surgery are increasingly prevalent in our aging society.1 Both, delirium (acute) and postoperative cognitive dysfunction (POCD); intermediate or long-term) are associated with severe outcome impairments such as reduced discharge to home, less health-related quality of life, and increased mortality.2,3 Currently, there is growing evidence for an essential pathophysiologic role of neuronal network disturbances including cholinergic stress-related pathways: The models generally use the evident finding that surgical interventions lead to local and systemic acute phase inflammatory reactions which are linked to neuro-inflammation that under certain predisposing and precipitating factors might damage neuronal-circuits.4 In our multicenter, EU-FP7 funded (www.biocog.eu), observational trial (BioCog, NCT02265263) investigators aim to develop biomarkers—molecular and neuroimaging-based—for a vulnerable read-out of cognitive impairment, to risk-asses clinical decision-making and to get a more sophisticated insight into the pathophysiology. Therefore, biomarker-panels from 1,200 surgical patients aged ≥65 years recruited in two tertiary medical centers (Berlin and Utrecht) are investigated. The integration of advanced neuroimaging techniques (EEG/fMRI, DTI) providing information on brain structure/function combined with a bio-bank providing information on molecular changes in delirium and POCD and an elaborated clinical assessment will increase the understanding of relevant pathophysiological processes. Every patient passes through an established cognitive assessment before and after surgery, and 3 months later. Patient written informed consent is given to follow-up 5-years. An interim analysis (n=400) of inflammatory and perfusion markers, connectivity of thalamo-cortical networks in postoperative delirium and POCD, and relevant findings on the cholinergic pathway in cognitively impaired patients is scheduled.
 
References:
1. Androsova G, et al., Front Aging Neurosci. 2015;7:112.
2. Nadelson MR, et al., Br J Anaesth 2014:440-51.
3. Radtke F, Spies C, Br J Anaesth. 2013:98-105
4. van Gool WA, et al., Lancet 2010;375:773-5.

Postoperative Delirium and Dementia: Is Inflammation the Connection?
Edward R. Marcantonio, MD, SM, Beth Israel Deaconess Medical Center

Delirium, an acute confusional state, is associated with prolonged hospitalization, nursing home placement, mortality, cognitive and functional decline, incident dementia, and healthcare costs totaling $164 billion/year. Despite growing knowledge of its epidemiology, little is known of delirium pathophysiology, and the link between delirium and dementia remains unexplained. In recent years, elevated inflammatory markers have been associated with delirium. Using a matched case-control cohort of 150 patients selected from 560 enrolled in the Successful Aging after Elective Surgery (SAGES) study, we found that pre- and postoperative levels of C-reactive protein (CRP) and postoperative interleukin (IL)-6 were associated with delirium. Also in SAGES, we found that delirium was associated with an accelerated rate of cognitive decline 2 to 36 months after surgery. These data support an intriguing, relatively new model for delirium pathophysiology in which individuals predisposed to a heightened inflammatory response when exposed to acute stress, such as surgery and anesthesia, are at increased risk for delirium. Under certain conditions, these systemic inflammatory mediators may cross the blood brain barrier, activate brain microglia, and set up a process of neuroinflammation, which if sustained, can cause permanent neuronal injury. This model is intriguing, in that it might provide an explanation for the link between delirium, long-term cognitive decline, and dementia. Moreover, this model suggests that inflammation may be a potential therapeutic target for cognitive decline and dementia, and that delirium might be an appropriate intermediate outcome to test the efficacy of such interventions.

Xenon for Protection from Ongoing Acute Neurologic Injury
Mervyn Maze, MB, ChB, University of California, San Francisco

Xenon's physicochemical properties prevent covalent bonding to other molecules under biologic conditions; despite this chemical inertness, biological interactions can occur through non-covalent Van der Waal's intermolecular forces. Xenon's outer electron shell is full, which prevents covalent binding under biological conditions. However, xenon is highly polarizable, which enables its attraction to surrounding molecules. Franks et al were the first to show that xenon can interact with the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor (Franks et al 1998), a plausible site for its anesthetic properties, by competing for binding at the glycine co-activation site (Dickinson et al 2007) through an interaction with a phenylalanine residue (Armstrong et al 2012). While other targets may also contribute to xenon's anesthetic properties, including other glutamate receptor subtypes (Dinse et al 2005) and molecular species inducing potassium leak currents (Gruss et al 2004), the importance of the NMDA subtype of the glutamate receptor in the excitotoxic phase of acute neurologic injury spurred a series of studies exploring xenon's neuroprotective properties. Pre-clinical studies have assessed the effects of xenon in models of acute neurological injury including neonatal hypoxic ischemic encephalopathy from intrapartum asphyxia, stroke, traumatic brain injury, anesthetic-induced developmental toxicity, and cardiac arrest. A recently reported Phase II clinical trial has established that xenon protects against white matter injury in comatose survivors following an out-of-hospital cardiac arrest. The results of this trial have resulted in the preparation for a Phase III Clinical Trial involving 1370 patients in more than 30 centers.

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