Postoperative delirium is associated with increased plasma neurofilament light

Abstract

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, a neuronal 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 (ΔR2 = 0.129, P = 0.015)] and white matter changes including fractional anisotropy of white matter (ΔR2 = 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) log10 (pg/ml), P < 0.001], suggesting putative neuronal injury. Next, we tested 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) log10 (pg/ml), P < 0.001]. This relationship showed dose-dependence, such that neurofilament light rose proportionately to delirium severity (ΔR2 = 0.199, P < 0.001). Given that inflammation is considered 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-inflammatory cytokine IL-8 exhibited a strong correlation with delirium severity (ΔR2 = 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 (ΔR2 = 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.

Keywords: cognition; delirium; inflammation; neuronal injury; surgery.

Figure 1

Associations of NfL with imaging markers of neurodegeneration. (A) T-map showing the anatomical location of changes in fractional anisotropy (FA) that correlate with NfL. (B) Raw data for correlation of fractional anisotropy and NfL. Fractional anisotropy values were averaged over all significant voxels. (C) Association of hippocampal volume and NfL. WM = white matter.

Figure 2

The postoperative change in NfL. (A) Time course of NfL change from baseline levels over first 4 days after surgery. (B) Change in NFL from baseline to postoperative Day 1 (POD1).

Figure 3

Relationship of NFL and IL-8 to delirium. (A and E) Difference in NfL/IL-8 from baseline to postoperative Day 1 (POD1) by delirium outcome. (B and F) Time course of NfL/IL-8 change from baseline levels over first 4 days after surgery by delirium outcome. (C) DRS scores over time divided by delirium status. (D and G) Correlation between change in NfL/IL-8 from baseline to POD1 and peak DRS scores. (H) Correlation between the change in values from baseline to POD1 for NFL and IL-8 following surgery.