Plasma Neurofilament Light Chain is Markedly Elevated in General Hospital Inpatients with Delirium
- 1Neuropsychiatry Centre, Royal Melbourne Hospital, Melbourne, Australia
Abstract
ObjectiveTo 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 analysisThis 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.
ResultsIn Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia ({beta} = 0.78; 95% CI [0.37, 1.20] and {beta} = 0.39 [0.07, 0.73] respectively) or PPD groups ({beta} = 1.17; [0.69, 1.66] and {beta} = 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).
ConclusionsPlasma 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 topicDelirium 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 addsPlasma 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 policyThese 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.
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BibTeX
@misc{kang2026plasma,
title = {{Plasma Neurofilament Light Chain is Markedly Elevated in General Hospital Inpatients with Delirium}},
author = {M. J. Kang and D. Eratne and T. Borchard and K. Patel and C. B. Malpas and C. Dang and M. Storer and O. G. Bhalala and J. J. Yu and A. F. Santillo and M. Forbes and H. Zetterberg and S. Farrand and S. M. Loi and P. B. Mitchell and M. Hopwood and J. Smith and C. Chiang and D. Velakoulis},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.26365854},
url = {https://www.medrxiv.org/content/10.64898/2026.10.18.26365854v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Plasma Neurofilament Light Chain is Markedly Elevated in General Hospital Inpatients with Delirium
AU - M. J. Kang
AU - D. Eratne
AU - T. Borchard
AU - K. Patel
AU - C. B. Malpas
AU - C. Dang
AU - M. Storer
AU - O. G. Bhalala
AU - J. J. Yu
AU - A. F. Santillo
AU - M. Forbes
AU - H. Zetterberg
AU - S. Farrand
AU - S. M. Loi
AU - P. B. Mitchell
AU - M. Hopwood
AU - J. Smith
AU - C. Chiang
AU - D. Velakoulis
PY - 2026
DA - 2026/10/18
PB - medRxiv
DO - 10.64898/2026.10.18.26365854
UR - https://www.medrxiv.org/content/10.64898/2026.10.18.26365854v1
AB - ObjectiveTo 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 analysisThis 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. ResultsIn Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia ({beta} = 0.78; 95% CI [0.37, 1.20] and {beta} = 0.39 [0.07, 0.73] respectively) or PPD groups ({beta} = 1.17; [0.69, 1.66] and {beta} = 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). ConclusionsPlasma 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 topicDelirium 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 addsPlasma 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 policyThese 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.
ER -