Association of Plasma Neurofilament Light with Postoperative Delirium

Abstract

for the SAGES Study Group Objective: To examine the association of the plasma neuroaxonal injury markers neurofilament light (NfL), total tau, glial fibrillary acid protein, and ubiquitin carboxyl-terminal hydrolase L1 with delirium, delirium severity, and cognitive performance. Methods: Delirium case-no delirium control (n = 108) pairs were matched by age, sex, surgery type, cognition, and vascular comorbidities. Biomarkers were measured in plasma collected preoperatively (PREOP), and 2 days (POD2) and 30 days postoperatively (PO1MO) using Simoa technology (Quanterix, Lexington, MA). The Confusion Assessment Method (CAM) and CAM-S (Severity) were used to measure delirium and delirium severity, respectively. Cognitive function was measured with General Cognitive Performance (GCP) scores. Results: Delirium cases had higher NfL on POD2 and PO1MO (median matched pair difference = 16.2pg/ml and 13.6pg/ml, respectively; p < 0.05). Patients with PREOP and POD2 NfL in the highest quartile (Q4) had increased risk for incident delirium (adjusted odds ratio [OR] = 3.7 [95% confidence interval (CI) = 1.1-12.6] and 4.6 [95% CI = 1.2-18.2], respectively) and experienced more severe delirium, with sum CAM-S scores 7.8 points (95% CI = 1.6-14.0) and 9.3 points higher (95% CI = 3.2-15.5). At PO1MO, delirium cases had continued high NfL (adjusted OR = 9.7, 95% CI = 2.3-41.4), and those with Q4 NfL values showed a −2.3 point decline in GCP score (−2.3 points, 95% CI = −4.7 to −0.9). Interpretation: Patients with the highest PREOP or POD2 NfL levels were more likely to develop delirium. Elevated NfL at PO1MO was associated with delirium and greater cognitive decline. These findings suggest NfL may be useful as a predictive biomarker for delirium risk and long-term cognitive decline, and once confirmed would provide pathophysiological evidence for neuroaxonal injury following delirium.

Neurofilament light: a narrative review on biomarker utility

“… The figure shows a comparative sequential increase in NfL in patients 60 years or older, for a period of 48 hours postoperatively, as described by Evered et al and Fong et al , respectively 12 , 15 . Mean plasma neurofilament light concentration measured at baseline, 6 hours, 24 hours, and 48 hours for patients undergoing hip or knee surgery under general anesthesia (Evered et al 12 ).…”

“…Mean plasma neurofilament light concentration measured at baseline, 6 hours, 24 hours, and 48 hours for patients undergoing hip or knee surgery under general anesthesia (Evered et al 12 ). Baseline and 48-hour NfL concentrations measured in patients undergoing major elective surgery (Fong et al 15 ). Quartile 1 is the lowest median quartile range, defined by NfL concentration of no more than 20.76 pg/mL at baseline and perioperative neurocognitive disorder 28.08 pg/mL at postoperative day 2.…”

Current Challenges in the Recognition and Management of Delirium Superimposed on Dementia

“… 54 In an elective surgery cohort, elevated preoperative serum NfL levels predicted delirium, and an elevated NfL level at one month was associated with greater cognitive decline. 53 Additionally, NfL levels increased in proportion to delirium severity but independently of inflammation. 55 These findings are consistent with diffusion tensor imaging studies, indicating that post-operative delirium is associated with longitudinal microstructural abnormalities one year after surgery.…”

“…Neurofilament light (NfL), which can be measured in both blood and CSF, increases in proportion to the degree of axonal damage. 53 Elevated NfL levels have been noted in several neurodegenerative diseases, including AD, in which CSF NfL levels predict amyloid load, cerebral atrophy, and cognition. 54 In an elective surgery cohort, elevated preoperative serum NfL levels predicted delirium, and an elevated NfL level at one month was associated with greater cognitive decline.…”

“…As there is growing evidence of a dose-dependent relationship between delirium and cognitive dysfunction, both clinically 3 and biochemically (via NfL measurement), 53 , 55 research is needed to investigate the mechanisms by which putative neurotoxicity occurs. In the context of the aforementioned challenges, study methodology must be carefully considered.…”