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

Agenda

* Presentation times are subject to change.

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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