Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit

Abstract

BackgroundDelirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference.MethodsBlood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients.ResultsOf the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02).ConclusionsSerum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.

Neurofilament Proteins as Biomarkers to Monitor Neurological Diseases and the Efficacy of Therapies

“…Serum NfL levels in delirium in hip fracture patients were 1.7-fold higher than in controls (94 vs. 54 pg/ml) ( Halaas et al, 2018 ) and plasma NfL was associated with delirium severity ( Fong et al, 2020 ) independent of changes in inflammation ( Casey et al, 2019 ). In addition to elevated NfL, higher serum pNfH levels also correlated with more severe postoperative delirium ( Inoue et al, 2017 ; Mietani et al, 2019 ). These results suggests NfPs can be sensitive markers of neuronal injury associated with delirium.…”

Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges

“…Non-specific markers of systemic inflammation, such as CRP, IL-6, IL-1B, or TNF-a, in the blood or CSF are frequently associated with delirium but poorly predict POCD [ 63 – 66 ]. Conversely, biomarkers of neuronal damage, such as S100ß, NSE [ 67 ], or phosphorylated neurofilament heavy subunit, are more consistently associated with POD and POCD [ 68 ]. In 2012, one study explored ICU survivors in a pilot study combining diffusion tensor imaging MRI, acute delirium monitoring, and cognitive outcomes in 47 patients evaluated after 3 and 12 months of follow-up.…”

Neurofilaments: The C-Reactive Protein of Neurology

“…Currently, the diagnosis of delirium is clinically based and depends on the absence or presence of certain features. As delirium appears to be associated with permanent encephalopathy with neuronal damage and/or dysfunction, several studies have investigated NFs as potential new biomarkers of neuroaxonal damage in delirium patients [156][157][158][159][160][161]. In a recent prospective, pilot observational study, Ehler and colleagues [161] demonstrated, using ELISA, that plasma NF-L levels increased in sepsis patients over time and remained stable in patients without sepsis.…”