Plasma Neurofilament Light Chain is Markedly Elevated in General Hospital Inpatients with Delirium
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Objective
To determine whether plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are elevated in hospitalised patients with delirium relative to patients with dementia and primary psychiatric disorders (PPD).
Methods and analysis
This was a cross-sectional observational study conducted at the Royal Melbourne Hospital, Melbourne, Australia, between April and October 2024, with comparator samples from a research biobank. In Phase 1 (Delirium Discovery Cohort), we measured plasma NfL and GFAP using the Single molecule array (Simoa) platform in hospitalised patients with delirium and compared them with dementia and PPD groups. Biomarker concentrations were the primary outcome and were compared using general linear models adjusted for age, sex, and estimated glomerular filtration rate, with bootstrapped confidence intervals. Discriminative performance was assessed as a secondary outcome using receiver operating characteristic (ROC) curve analysis,. In Phase 2, we applied this threshold to independent dementia and PPD groups.
Results
In Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia (β = 0.78; 95% CI [0.37, 1.20] and β = 0.39 [0.07, 0.73] respectively) or PPD groups (β = 1.17; [0.69, 1.66] and β = 0.83 [0.51, 1.24] respectively). ROC curve analysis for differentiating delirium from dementia and PPD groups yielded an optimal NfL threshold of 24.1 pg/mL (AUC = 0.89, 96% sensitivity, 70% specificity). In comparison, GFAP showed lower accuracy (AUC = 0.85), and combining NfL with GFAP (AUC = 0.90) did not significantly improve performance. In Phase 2 (n = 154), the NfL threshold of > 24 pg/ml maintained strong performance (AUC = 0.95, 96% sensitivity, and 77% specificity).
Conclusions
Plasma NfL shows promise as a biomarker for delirium in hospitalised patients, distinguishing it with high sensitivity from patients with dementia and PPD. Larger multicentre studies are needed to refine cut-offs, evaluate temporal dynamics, and determine integration into acute hospital delirium pathways.
What is already known on this topic
Delirium is highly prevalent in general hospitals but remains frequently underdiagnosed. Currently, no validated blood-based biomarker exists to reliably assist in clinical identification.
What this study adds
Plasma neurofilament light chain (NfL) is substantially elevated in general hospital inpatients with delirium compared to those with dementia or primary psychiatric disorders. This includes patients with delirium superimposed on dementia, yielding a discriminative profile well-suited for ruling out the diagnosis.
How this study might affect research, practice or policy
These findings support the prospective evaluation of plasma NfL as an objective adjunct to clinical bedside assessments. This biomarker could significantly aid in evaluating patients with acute confusion, particularly when hypoactive presentations make clinical diagnosis challenging.
