bioRxiv2022
Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence of 14-50% and likely association with inflammation, the exact mechanisms underlying postoperative delirium are unclear. This project aimed at characterizing systemic and central nervous system (CNS) inflammatory changes following surgery in both mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the "Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults" (INTUIT; NCT03273335) were used to parallel murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well-established orthopedic surgical model in the FosTRAP reporter mouse, we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing role of YKL-40 in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were also similarly increased after surgery, with a trend toward greater post-operative plasma YKL-40 increase in patients with delirium. In contrast to plasma, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in blood-brain barrier (BBB) after surgery as early as 9 hours in mice, which warrants for more detailed and acute evaluations of BBB integrity following surgery in humans. All together, these results provide a nuanced understanding of the neuroimmune interactions underlying post-operative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.