Examining CSF and Blood Biomarkers to Gain Insight into Postoperative Delirium and Neurocognitive Dysfunction

PROJECT SUMMARY/ABSTRACT Delirium occurs in 10-40% of surgical hospitalizations and has been associated with post-discharge declines in cognition and function, including Alzheimer’s Disease (AD). After hospital discharge, the incidence of neurocognitive dysfunction is estimated to be up to 10-25% in the year after surgery. However, pathways leading to postoperative delirium and neurocognitive dysfunction are not understood. Biomarkers obtained during and after surgery may provide important insights, similar to how biomarkers are used in AD research. In AD research, the use of biomarkers has transformed the conceptualization of AD from a syndrome to a pathologic entity. The AT(N) framework has provided researchers with a clear approach for staging, diagnosis, and monitoring disease, with several cerebrospinal fluid (CSF) biomarkers, such as β-amyloid, tau, and phosphorylated tau isoforms, having utility in this framework. The goal of this proposal is to pursue a parallel strategy of examining CSF and blood biomarkers to understand pathways leading to postoperative delirium and neurocognitive dysfunction. One hypothesized pathway is blood brain barrier (BBB) injury, followed by neuroinflammation, and neuron/astrocyte injury or astrocytosis, all layered over heterogeneity in baseline patient vulnerability. Both animal and human studies support aspects of this hypothesis. However, few human studies have collected serial measurements of CSF, which is important for brain-specificity. Relevant domains (and associated markers) that support conceptual models of postoperative neurocognitive dysfunction include baseline risk (AD- related biomarkers; e.g. β-amyloid and phosphorylated tau isoforms), BBB injury (CSF/blood albumin, platelet derived growth factor receptorβ), neuroinflammation (cytokines/chemokines, microglial activation), neuronal injury (neurofilament light, tau), and astrocyte injury/astrocytosis (glial fibrillary acidic protein). The potential of using biomarkers to understand postoperative brain dysfunction is profound, but there are important limitations, including (a) most studies have not collected CSF (b) studies reporting associations of biomarkers and delirium or neurocognitive dysfunction have been suggestive but inconsistent, and (c) most studies have few postoperative samples (particularly for CSF), a small number of biomarkers, and limited cognitive follow-up. To address these gaps, we propose a 3-center study of 180 patients undergoing open or endovascular aortic surgery, who have a CSF drain placed as standard of care. We will obtain serial CSF and blood samples for 2- 3 days. We will then determine whether CSF biomarkers of baseline risk, BBB injury, inflammation, neuronal injury, and astrocyte injury/astrocytosis are associated with delirium (Aim 1) and neurocognitive dysfunction (Aim 2). We will also examine the associations of blood biomarkers with delirium and neurocognitive dysfunction and the correlations of serial blood and CSF biomarkers (Aim 3). This study will provide a unique resource of serial CSF and blood samples to explore how BBB injury, inflammation, and brain injury contribute to delirium and neurocognitive dysfunction. The results will also provide insight into the utility of blood-based biomarkers.