A Nonhuman Primate Model for Postoperative Delirium and Working Memory Impairment
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PROJECT SUMMARY/ABSTRACT: In this R21 application, we propose to establish a new preclinical model in aged nonhuman primates (NHP), aiming to use it in the long run to investigate the pathophysiology of postoperative delirium (POD), which is known to increase the risk of developing Alzheimer’s disease (AD) and related dementias (ADRD). Notably, NHPs are the uniquely better animal model that can be used to simultaneously determine delirium-like behaviors, invasive neural recording from human-equivalent neocortex, and blood biomarker testing in a functioning animal. Neither humans (infeasible for invasive recording and frequent interventions) nor rodents (limited neocortex, limited human relevance) can provide as useful of a model as NHPs can. Thus, the established NHP model will allow us to perform better delirium studies, including mechanistic insight and targeted interventions, which will better guide future clinical investigations of POD. Extended of our recent NHP studies, we will use a volatile anesthetic sevoflurane and a GABA-mediated intravenous anesthetic propofol to establish the system for POD research in NHPs. Sevoflurane has been reported for its association with POD in patients of various ages. Propofol has not been demonstrated to promote POD in patients. Consistent with the literatures that tauopathy is a hallmark of AD neuropathogenesis, our previous works show that general anesthetics may promote tau phosphorylation in mice and that the patients who developed POD might have higher preoperative and postoperative blood tau and phosphorylated tau (p-tau) levels. Thus, we hypothesize that sevoflurane, but not propofol, promotes delirium-like behaviors and working memory impairment, induces specific cortical neurophysiological changes, and increases plasma p-tau levels in aged monkeys as compared to young adult monkeys. The Specific Aims are: (1) to determine whether sevoflurane promotes delirium-like behaviors (inattention, altered level of consciousness, hallucinations, and locomotor stereotypies), deficits in working memory (in Delayed Matching-to-Sample task), and cortical neural changes in aged monkeys as compared to propofol; and (2) to assess the effect of sevoflurane and propofol on plasma p-tau levels in aged monkeys. We will perform direct intracortical recording in the central (frontoparietal) executive network (dorsolateral prefrontal cortex, posterior parietal cortex), which activities are thought to be associated with delirium and working memory. We will employ a novel nanotechnology to measure blood biomarkers for neuronal injury, plasma tau and p-tau (p-tau217, p-tau181) levels. These measurements will be performed before and after anesthesia up to 3 months. The proposed studies will establish a novel NHP model for the investigation of POD and facilitate validating neurophysiological and blood biomarkers of delirium. Using data from this study we will apply for a R01 to systematically study the pathophysiology of POD in aged NHPs with AD pathology, an advanced model for the most vulnerable population.
