The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction.

Abstract

BACKGROUND:Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. OBJECTIVE:MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. METHODS:201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. CONCLUSION:MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

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Citation

Published Version (Please cite this version)

10.3233/jad-191185

Publication Info

VanDusen, Keith W, Sarada Eleswarpu, Eugene W Moretti, Michael J Devinney, Donna M Crabtree, Daniel T Laskowitz, Marty G Woldorff, Kenneth C Roberts, et al. (2020). The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction. Journal of Alzheimer's disease : JAD, 75(4). pp. 1319–1328. 10.3233/jad-191185 Retrieved from https://hdl.handle.net/10161/21265.

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Scholars@Duke

Eleswarpu

Sarada Eleswarpu

Assistant Professor of Anesthesiology
Moretti

Eugene William Moretti

Professor of Anesthesiology

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.

Devinney

Michael Devinney

Assistant Professor of Anesthesiology

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).

Laskowitz

Daniel Todd Laskowitz

Professor of Neurology

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.

Woldorff

Marty G. Woldorff

Professor in Psychiatry and Behavioral Sciences

Dr. Woldorff's main research interest is in the cognitive neuroscience of attention. At each and every moment of our lives, we are bombarded by a welter of sensory information coming at us from a myriad of directions and through our various sensory modalities -- much more than we can fully process. We must continuously select and extract the most important information from this welter of sensory inputs. How the human brain accomplishes this is one of the core challenges of modern cognitive neuroscience. Dr. Woldorff uses a combination of electrophysiological (ERP, MEG) and functional neuroimaging (fMRI) methods to study the time course, functional neuroanatomy, and mechanisms of attentional processes. This multimethodological approach is directed along several main lines of research: (1) The influence of attention on sensory and perceptual processing; (2) Cognitive and attentional control mechanisms; (3) The role of attention in multisensory environments; (4) The interactive relationship between attention and reward; and (5) The role of attention in perceptual awareness.

Browndyke

Jeffrey Nicholas Browndyke

Associate Professor of Psychiatry and Behavioral Sciences

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.

Rockhold

Frank Wesley Rockhold

Professor of Biostatistics & Bioinformatics

Frank is a full time Professor of Biostatistics and Bioinformatics and Faculty Director for Biostatistics at Duke University Medical Center, Affiliate Professor of Biostatistics at Virginia Commonwealth University, and Strategic Consultant at Hunter Rockhold, Inc.  His 40+-year career includes senior research positions at Lilly, Merck, and GlaxoSmithKline, where he retired as Chief Safety Officer and Senior Vice President of Global Clinical Safety and Pharmacovigilance.  He has held faculty appointments at six different universities.    Dr. Rockhold served for 9 years on the board of directors of the non-profit CDISC, most recently as Chairman, and is past president of the Society for Clinical Trials and a past member of the PCORI Clinical Trials Advisory Panel. He is currently Chair of the Board of the Frontier Science and Technology Research Foundation and a technical advisor to EMA.

Dr. Rockhold has diverse research interests and consulting experience in industry and academia including clinical trials design, data monitoring, benefit/risk, safety and pharmacovigilance and has been a leader in the scientific community in promoting data disclosure and transparency in clinical research.    Frank is widely published in major scientific journals across a wide variety of research topics.

Frank holds a BA in Statistics from The University of Connecticut, an ScM in Biostatistics from The Johns Hopkins University, and a PhD in Biostatistics from the Medical College of Virginia at Virginia Commonwealth University. Frank is an Elected Fellow of both the American Statistical Association and the Society for Clinical Trials, a Fellow of the Royal Statistical Society, an Accredited Professional Statistician, PStat®, and a Chartered Statistician, CStat.  

Anakwenze

Oke Adrian Anakwenze

Professor of Orthopaedic Surgery

Complex shoulder and elbow surgeon, researcher and innovator. 

Bolognesi

Michael Paul Bolognesi

Virginia Flowers Baker Distinguished Professor of Orthopaedic Surgery

As chief of the adult reconstruction service, the majority of my research effort has been directed toward clinical outcomes, implant survivorship, functional recovery, the biology of hip and knee arthritis and cost effectiveness.

Easley

Mark Erik Easley

Associate Professor of Orthopaedic Surgery
Berger

Miles Berger

Associate Professor of Anesthesiology

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. 


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