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

Jingya Yan; Kavitha Kothur; Shekeeb Mohammad; Jason Chung; Shrujna Patel; Hannah F Jones; Brooke A Keating; Velda X Han; Richard Webster; Simone Ardern-Holmes; Jayne Antony; Manoj P Menezes; Esther Tantsis; Deepak Gill; Sachin Gupta; Tejaswi Kandula; Hugo Sampaio; Michelle A Farrar; Christopher Troedson; P Ian Andrews; Sekhar C Pillai; Benjamin Heng; Gilles J Guillemin; Anna Guller; Sushil Bandodkar; Russell C Dale

doi:10.1016/j.ebiom.2023.104589

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

EBioMedicine. 2023 May:91:104589. doi: 10.1016/j.ebiom.2023.104589. Epub 2023 Apr 27.

Authors

Jingya Yan¹, Kavitha Kothur², Shekeeb Mohammad³, Jason Chung⁴, Shrujna Patel⁵, Hannah F Jones⁶, Brooke A Keating⁵, Velda X Han⁷, Richard Webster⁸, Simone Ardern-Holmes⁸, Jayne Antony⁸, Manoj P Menezes⁹, Esther Tantsis², Deepak Gill², Sachin Gupta⁸, Tejaswi Kandula¹⁰, Hugo Sampaio¹⁰, Michelle A Farrar¹¹, Christopher Troedson⁹, P Ian Andrews¹⁰, Sekhar C Pillai¹⁰, Benjamin Heng¹², Gilles J Guillemin¹², Anna Guller¹³, Sushil Bandodkar⁴, Russell C Dale¹⁴

Affiliations

¹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
² Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia.
³ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia.
⁴ Department of Biochemistry, The Children's Hospital at Westmead, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁵ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
⁶ Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
⁷ Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
⁸ TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia.
⁹ Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia.
¹⁰ Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia.
¹¹ Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia; Discipline of Paediatrics and Child Health, School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, NSW, Australia.
¹² Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia.
¹³ Computational NeuroSurgery Lab, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.
¹⁴ Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Clinical School, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia. Electronic address: russell.dale@health.nsw.gov.au.

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.

Keywords: Cerebrospinal fluid metabolomics; Encephalitis; Epilepsy; Kynurenine pathway; Neopterin; Neurodevelopmental disorders.

MeSH terms

Adolescent
Biomarkers / metabolism
Child
Child, Preschool
Humans
Infant
Inflammation / diagnosis
Inflammation / metabolism
Kynurenine
Leukocytosis
Male
Neopterin / metabolism
Nervous System Diseases*
Neuroinflammatory Diseases
Quinolinic Acid / cerebrospinal fluid
Tryptophan* / metabolism

Substances

Tryptophan
Kynurenine
Neopterin
Quinolinic Acid
Biomarkers