CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

Yan, J; Kothur, K; Mohammad, S; Chung, J; Patel, S; Jones, HF; Keating, BA; Han, VX; Webster, R; Ardern-Holmes, S; Antony, J; Menezes, MP; Tantsis, E; Gill, D; Gupta, S; Kandula, T; Sampaio, H; Farrar, MA; Troedson, C; Andrews, PI; Pillai, SC; Heng, B; Guillemin, GJ; Guller, A; Bandodkar, S; Dale, RC

CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.

Yan, J Kothur, K Mohammad, S Chung, J Patel, S Jones, HF Keating, BA Han, VX Webster, R Ardern-Holmes, S Antony, J Menezes, MP Tantsis, E Gill, D Gupta, S Kandula, T Sampaio, H Farrar, MA Troedson, C Andrews, PI Pillai, SC Heng, B Guillemin, GJ Guller, A Bandodkar, S Dale, RC

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Publisher:: Elsevier
Publication Type:: Journal Article
Citation:: EBioMedicine, 2023, 91, pp. 104589
Issue Date:: 2023-05

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Field	Value	Language
dc.contributor.author	Yan, J
dc.contributor.author	Kothur, K
dc.contributor.author	Mohammad, S
dc.contributor.author	Chung, J
dc.contributor.author	Patel, S
dc.contributor.author	Jones, HF
dc.contributor.author	Keating, BA
dc.contributor.author	Han, VX
dc.contributor.author	Webster, R
dc.contributor.author	Ardern-Holmes, S
dc.contributor.author	Antony, J
dc.contributor.author	Menezes, MP
dc.contributor.author	Tantsis, E
dc.contributor.author	Gill, D
dc.contributor.author	Gupta, S
dc.contributor.author	Kandula, T
dc.contributor.author	Sampaio, H
dc.contributor.author	Farrar, MA
dc.contributor.author	Troedson, C
dc.contributor.author	Andrews, PI
dc.contributor.author	Pillai, SC
dc.contributor.author	Heng, B
dc.contributor.author	Guillemin, GJ
dc.contributor.author	Guller, A
dc.contributor.author	Bandodkar, S
dc.contributor.author	Dale, RC
dc.date.accessioned	2024-10-21T00:47:18Z
dc.date.available	2023-04-12
dc.date.available	2024-10-21T00:47:18Z
dc.date.issued	2023-05
dc.identifier.citation	EBioMedicine, 2023, 91, pp. 104589
dc.identifier.issn	2352-3964
dc.identifier.issn	2352-3964
dc.identifier.uri	http://hdl.handle.net/10453/181471
dc.description.abstract	BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.
dc.language	eng
dc.publisher	Elsevier
dc.relation.ispartof	EBioMedicine
dc.relation.isbasedon	10.1016/j.ebiom.2023.104589
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences, 1117 Public Health and Health Services
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	4202 Epidemiology
dc.subject.mesh	Male
dc.subject.mesh	Humans
dc.subject.mesh	Child
dc.subject.mesh	Infant
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Adolescent
dc.subject.mesh	Tryptophan
dc.subject.mesh	Kynurenine
dc.subject.mesh	Neopterin
dc.subject.mesh	Quinolinic Acid
dc.subject.mesh	Neuroinflammatory Diseases
dc.subject.mesh	Leukocytosis
dc.subject.mesh	Inflammation
dc.subject.mesh	Biomarkers
dc.subject.mesh	Nervous System Diseases
dc.subject.mesh	Male
dc.subject.mesh	Humans
dc.subject.mesh	Child
dc.subject.mesh	Infant
dc.subject.mesh	Child, Preschool
dc.subject.mesh	Adolescent
dc.subject.mesh	Tryptophan
dc.subject.mesh	Kynurenine
dc.subject.mesh	Neopterin
dc.subject.mesh	Quinolinic Acid
dc.subject.mesh	Neuroinflammatory Diseases
dc.subject.mesh	Leukocytosis
dc.subject.mesh	Inflammation
dc.subject.mesh	Biomarkers
dc.subject.mesh	Nervous System Diseases
dc.title	CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammation.
dc.type	Journal Article
utslib.citation.volume	91
utslib.location.activity	Netherlands
utslib.for	1103 Clinical Sciences
utslib.for	1117 Public Health and Health Services
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2024-10-21T00:47:12Z
pubs.publication-status	Published
pubs.volume	91

Abstract:

BACKGROUND: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. METHODS: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1-17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). FINDINGS: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p < 0.0003). As biomarkers, at thresholds with 95% specificity, CSF neopterin had the best sensitivity for defining neuroinflammation (82%, CI 73-89), then quinolinic acid (57%, CI 47-67), KYN/TRP ratio (47%, CI 36-56) and kynurenine (37%, CI 28-48). CSF pleocytosis had sensitivity of 53%, CI 42-64). The area under the receiver operating characteristic curve (ROC AUC) of CSF neopterin (94.4% CI 91.0-97.7%) was superior to that of CSF pleocytosis (84.9% CI 79.5-90.4%) (p = 0.005). CSF kynurenic acid/kynurenine ratio (KYNA/KYN) was statistically decreased in the epilepsy group compared to all control groups (all p ≤ 0.0003), which was evident in most epilepsy subgroups. INTERPRETATION: Here we show that CSF neopterin, kynurenine, quinolinic acid and KYN/TRP are useful diagnostic and monitoring biomarkers of neuroinflammation. These findings provide biological insights into the role of inflammatory metabolism in neurological disorders and provide diagnostic and therapeutic opportunities for improved management of neurological diseases. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, University of Sydney, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP 1176660 and Macquarie University.

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http://hdl.handle.net/10453/181471