Postoperative delirium is associated with increased plasma neurofilament light

While delirium is associated with cognitive decline and dementia, there is limited evidence to support causality for this relationship. Clarification of how delirium may cause cognitive decline, perhaps through evidence of contemporaneous neuronal injury, would enhance plausibility for a causal relationship. Dose-dependence of neuronal injury with delirium severity would further enhance the biological plausibility for this relationship. We tested whether delirium is associated with neuronal injury in 114 surgical patients recruited to a prospective biomarker cohort study. Patients underwent perioperative testing for changes in neurofilament light, aneuronal injury biomarker, as well as a panel of 10 cytokines, with contemporaneous assessment of delirium severity and incidence.A subset of patients underwent preoperative MRI. Initially we confirmed prior reports that neurofilament light levels correlated with markers of neurodegeneration [hippocampal volume (Delta R-2 = 0.129, P = 0.015)] and white matter changes including fractional anisotropy of white matter (Delta R-2 = 0.417, P < 0.001) with similar effects on mean, axial and radial diffusivity)in our cohort and that surgery was associated with increasing neurofilament light from preoperative levels [mean difference(95% confidence interval, CI) = 0.240 (0.178, 0.301) log(10) (pg/ml), P < 0.001], suggesting putative neuronal injury. Next, wetested the relationship with delirium. Neurofilament light rose more sharply in participants with delirium compared to non-sufferers[mean difference (95% CI) = 0.251 (0.136, 0.367) log(10) (pg/ml), P < 0.001]. This relationship showed dose-dependence,such that neurofilament light rose proportionately to delirium severity (Delta R-2 = 0.199, P < 0.001). Given that inflammation isconsidered an important driver of postoperative delirium, next we tested whether neurofilament light, as a potential marker of neurotoxicity, may contribute to the pathogenesis of delirium independent of inflammation. From a panel of 10 cytokines, the pro-inflammatorycytokine IL-8 exhibited a strong correlation with delirium severity (Delta R-2 = 0.208, P < 0.001). Therefore, we tested whether the change in neurofilament light contributed to delirium severity independent of IL-8. Neurofilament light was independently associated with delirium severity after adjusting for the change in inflammation (Delta R-2 = 0.040, P = 0.038). These data suggest delirium is associated with exaggerated increases in neurofilament light and that this putative neurotoxicity may contribute to the pathogenesis of delirium itself, independent of changes in inflammation.