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).

Whittle

John Whittle

Assistant Professor of Anesthesiology

I am a UK trained Anesthesiologist with special interests in Critical Care and Perioperative Medicine.  I aim to combine my clinical practice with my research interests to reduce the risks associated with Major Surgery for all patients, but especially those at highest risk of complications.

My research interests are in preoperative optimization, including exercise and nutritional prehabilitation, as well as investigating how subclinical autonomic dysfunction impacts on key outcomes including cardiac performance and the immune/inflammatory response to surgery.

I am a founder and director of Trainees with an Interest in Perioperative Medicine and am on the Faculty for the UCL Masters in Perioperative Medicine Degree.


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