CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396423001548 |
| _version_ | 1797837811708067840 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jingya Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:30:41Z |
| format | Article |
| id | doaj.art-f3f98b36f0cb49b9aa7418bacef1fbf5 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-04-09T15:30:41Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-f3f98b36f0cb49b9aa7418bacef1fbf52023-04-28T08:55:42ZengElsevierEBioMedicine2352-39642023-05-0191104589CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in contextJingya Yan0Kavitha Kothur1Shekeeb Mohammad2Jason Chung3Shrujna Patel4Hannah F. Jones5Brooke A. Keating6Velda X. Han7Richard Webster8Simone Ardern-Holmes9Jayne Antony10Manoj P. Menezes11Esther Tantsis12Deepak Gill13Sachin Gupta14Tejaswi Kandula15Hugo Sampaio16Michelle A. Farrar17Christopher Troedson18P Ian Andrews19Sekhar C. Pillai20Benjamin Heng21Gilles J. Guillemin22Anna Guller23Sushil Bandodkar24Russell C. Dale25Kids 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, AustraliaKids 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, AustraliaKids 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, AustraliaDepartment 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, AustraliaKids 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, AustraliaStarship Hospital, Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New ZealandKids 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, AustraliaKhoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, SingaporeTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, AustraliaTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, AustraliaTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, AustraliaClinical 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, AustraliaKids 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, AustraliaKids 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, AustraliaTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, The University of Sydney, Westmead, NSW, AustraliaDepartment of Neurology, Sydney Children's Hospital Network, Sydney, NSW, AustraliaDepartment of Neurology, Sydney Children's Hospital Network, Sydney, NSW, AustraliaDepartment 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, AustraliaClinical 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, AustraliaDepartment of Neurology, Sydney Children's Hospital Network, Sydney, NSW, AustraliaDepartment of Neurology, Sydney Children's Hospital Network, Sydney, NSW, AustraliaNeuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, AustraliaNeuroinflammation Group, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, NSW, AustraliaComputational NeuroSurgery Lab, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, AustraliaDepartment 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, AustraliaKids 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.http://www.sciencedirect.com/science/article/pii/S2352396423001548Cerebrospinal fluid metabolomicsNeopterinKynurenine pathwayEncephalitisEpilepsyNeurodevelopmental disorders |
| spellingShingle | 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 CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context EBioMedicine Cerebrospinal fluid metabolomics Neopterin Kynurenine pathway Encephalitis Epilepsy Neurodevelopmental disorders |
| title | CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context |
| title_full | CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context |
| title_fullStr | CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context |
| title_full_unstemmed | CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context |
| title_short | CSF neopterin, quinolinic acid and kynurenine/tryptophan ratio are biomarkers of active neuroinflammationResearch in context |
| title_sort | csf neopterin quinolinic acid and kynurenine tryptophan ratio are biomarkers of active neuroinflammationresearch in context |
| topic | Cerebrospinal fluid metabolomics Neopterin Kynurenine pathway Encephalitis Epilepsy Neurodevelopmental disorders |
| url | http://www.sciencedirect.com/science/article/pii/S2352396423001548 |
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