CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context
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
Affiliations
Jingya Yan
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
Kavitha Kothur
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
Shekeeb Mohammad
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
Jason Chung
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
Shrujna Patel
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
Hannah F. Jones
Starship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand
Brooke A. Keating
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
Velda X. Han
Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore
Richard Webster
TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia
Simone Ardern-Holmes
TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia
Jayne Antony
TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia
Manoj P. Menezes
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
Esther Tantsis
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
Deepak Gill
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
Sachin Gupta
TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, Australia
Tejaswi Kandula
Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia
Hugo Sampaio
Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia
Michelle A. Farrar
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
Christopher Troedson
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
P Ian Andrews
Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia
Sekhar C. Pillai
Department of Neurology, Sydney Children's Hospital Network, Sydney, NSW, Australia
Benjamin Heng
Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia
Gilles J. Guillemin
Neuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, Australia
Anna Guller
Computational NeuroSurgery Lab, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia
Sushil Bandodkar
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
Russell C. Dale
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; Corresponding author. Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, NSW, Australia.
Summary: 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.
