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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
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.
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.
EBioMedicine. 2023 May;91:104589. doi: 10.1016/j.ebiom.2023.104589. Epub 2023 Apr 27.
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.
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).
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.
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.
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.
由于临床表现和病因的异质性，临床医生仍然难以确定急性和慢性脑炎症的存在。然而，鉴于神经炎症具有可逆转和潜在的破坏性，定义其存在并监测治疗效果非常重要。我们研究了脑脊液代谢物在诊断原发性神经炎症性疾病（如脑炎）中的作用，并探讨了炎症在癫痫中的潜在致病作用。
对 341 名儿科患者（男性 169 名，中位年龄 5.8 岁，范围 0.1-17.1）的脑脊液进行了检查。患者分为原发性炎症性疾病组（n=90）和癫痫组（n=80），并与三个对照组进行比较，包括神经遗传和结构组（n=76）、神经发育障碍、精神科和功能性神经障碍组（n=63）和头痛组（n=32）。
与所有对照组相比，炎症组的脑脊液中新喋呤、犬尿氨酸、喹啉酸和犬尿氨酸/色氨酸比值（KYN/TRP）均有统计学显著升高（均 p<0.0003）。作为生物标志物，在具有 95%特异性的阈值下，脑脊液新喋呤对定义神经炎症的敏感性最好（82%，CI 73-89%），其次是喹啉酸（57%，CI 47-67%）、KYN/TRP 比值（47%，CI 36-56%）和犬尿氨酸（37%，CI 28-48%）。脑脊液白细胞增多的敏感性为 53%，CI 42-64%）。脑脊液新喋呤的受试者工作特征曲线下面积（ROC AUC）（94.4%CI 91.0-97.7%）优于脑脊液白细胞增多（84.9%CI 79.5-90.4%）（p=0.005）。与所有对照组相比，癫痫组脑脊液中犬尿氨酸酸/犬尿氨酸比值（KYNA/KYN）显著降低（均 p≤0.0003），在大多数癫痫亚组中均如此。
在这里，我们表明脑脊液中新喋呤、犬尿氨酸、喹啉酸和 KYN/TRP 是神经炎症有用的诊断和监测生物标志物。这些发现为炎症代谢在神经疾病中的作用提供了生物学见解，并为改善神经疾病的管理提供了诊断和治疗机会。
该研究的资金由达勒姆 NHMRC 研究员资助（APP1193648）、悉尼大学、佩特雷基金会、脑瘫联盟和韦斯特米德儿童医院的生物化学系提供。Guillemin 教授的研究得到了 NHMRC 研究员资助（APP 1176660）和麦考瑞大学的资助。
