Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis

IF 8.8 2区医学 Q1 IMMUNOLOGY

Brain, Behavior, and Immunity Pub Date : 2025-03-01 DOI:10.1016/j.bbi.2025.02.005

Jacob Ahlberg Weidenfors , Vytautas Griška , Xueqi Li , Aistė Pranckevičienė , Jolita Pakalnienė , Ann Atlas , Elisabeth Franzén-Röhl , Fredrik Piehl , Lars Lindquist , Auksė Mickienė , Göran Engberg , Lilly Schwieler , Sophie Erhardt

{"title":"Dysregulation of the kynurenine pathway is related to persistent cognitive impairment in tick-borne encephalitis","authors":"Jacob Ahlberg Weidenfors , Vytautas Griška , Xueqi Li , Aistė Pranckevičienė , Jolita Pakalnienė , Ann Atlas , Elisabeth Franzén-Röhl , Fredrik Piehl , Lars Lindquist , Auksė Mickienė , Göran Engberg , Lilly Schwieler , Sophie Erhardt","doi":"10.1016/j.bbi.2025.02.005","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Tick-borne encephalitis (TBE) patients frequently suffer cognitive and neuropsychiatric sequelae, which may be severe and long-lasting. The underlying mechanisms remain poorly understood, but likely involve dysregulation of immunological and neuroinflammatory processes. Here, we investigated the activity of the kynurenine pathway (KP), an immunologically induced set of enzymes generating neuroactive metabolites <em>via</em> degradation of the amino acid tryptophan and their correlation with the cognitive performance in TBE patients.</div></div><div><h3>Methods</h3><div>KP metabolite concentrations were measured in serum and cerebrospinal fluid (CSF) samples from patients taken during hospitalization for acute TBE (n = 87) and a control group (n = 12) by UPLC/MS-MS. At two follow-up occasions, 6 and 18 months after hospital discharge, additional serum samples were obtained from TBE patients and their cognitive performance was evaluated by the Matrics Consensus Cognitive Battery.</div></div><div><h3>Results</h3><div>Relative to controls, TBE patients exhibited a robust induction of the KP in both the central nervous system and peripheral blood during the acute phase of the disease, with drastic elevations of the neuroactive QUIN and KYNA in CSF. KP activity remained significantly elevated in serum of TBE patients at the 6- and 18-month follow-ups. Several inverse associations between cognitive performance and measurements of KP activity recorded in both CSF and serum were found by rank correlation analysis. Further, <em>via</em> ROC analysis, serum rKT was found to be an accurate predictor of impaired overall cognition (<35 T-score) 6 months after acute TBE (AUC 0.79, CI 0.64–0.93, p < 0.01 for rKT measured during acute TBE; AUC 0.68, CI 0.50–0.86, p < 0.05 for rKT measured at 6 months).</div></div><div><h3>Interpretation</h3><div>We have found evidence of both acute and chronic dysregulation of KP activity in TBE patients, which correlated with degree of cognitive impairment at long-term follow-up. Our findings suggest that KP metabolites may serve as biomarkers for TBE-related cognitive sequelae, and more broadly, that the KP may offer avenues for development of novel treatments.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"125 ","pages":"Pages 452-465"},"PeriodicalIF":8.8000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain, Behavior, and Immunity","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0889159125000431","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background

Tick-borne encephalitis (TBE) patients frequently suffer cognitive and neuropsychiatric sequelae, which may be severe and long-lasting. The underlying mechanisms remain poorly understood, but likely involve dysregulation of immunological and neuroinflammatory processes. Here, we investigated the activity of the kynurenine pathway (KP), an immunologically induced set of enzymes generating neuroactive metabolites via degradation of the amino acid tryptophan and their correlation with the cognitive performance in TBE patients.

Methods

KP metabolite concentrations were measured in serum and cerebrospinal fluid (CSF) samples from patients taken during hospitalization for acute TBE (n = 87) and a control group (n = 12) by UPLC/MS-MS. At two follow-up occasions, 6 and 18 months after hospital discharge, additional serum samples were obtained from TBE patients and their cognitive performance was evaluated by the Matrics Consensus Cognitive Battery.

Results

Relative to controls, TBE patients exhibited a robust induction of the KP in both the central nervous system and peripheral blood during the acute phase of the disease, with drastic elevations of the neuroactive QUIN and KYNA in CSF. KP activity remained significantly elevated in serum of TBE patients at the 6- and 18-month follow-ups. Several inverse associations between cognitive performance and measurements of KP activity recorded in both CSF and serum were found by rank correlation analysis. Further, via ROC analysis, serum rKT was found to be an accurate predictor of impaired overall cognition (<35 T-score) 6 months after acute TBE (AUC 0.79, CI 0.64–0.93, p < 0.01 for rKT measured during acute TBE; AUC 0.68, CI 0.50–0.86, p < 0.05 for rKT measured at 6 months).

Interpretation

We have found evidence of both acute and chronic dysregulation of KP activity in TBE patients, which correlated with degree of cognitive impairment at long-term follow-up. Our findings suggest that KP metabolites may serve as biomarkers for TBE-related cognitive sequelae, and more broadly, that the KP may offer avenues for development of novel treatments.

查看原文本刊更多论文

犬尿氨酸通路的失调与蜱传脑炎的持续性认知障碍有关。

背景：蜱传脑炎（TBE）患者经常出现严重和持久的认知和神经精神后遗症。潜在的机制尚不清楚，但可能涉及免疫和神经炎症过程的失调。在这里，我们研究了犬尿氨酸途径（KP）的活性及其与TBE患者认知表现的相关性。KP是一组免疫诱导的酶，通过氨基酸色氨酸的降解产生神经活性代谢物。方法：采用UPLC/MS-MS法测定急性TBE住院患者（n = 87）和对照组（n = 12）血清和脑脊液中KP代谢物浓度。在出院后6个月和18个 月的两次随访中，从TBE患者中获得额外的血清样本，并通过matrix Consensus cognitive Battery评估他们的认知表现。结果：与对照组相比，在疾病的急性期，TBE患者在中枢神经系统和外周血中都表现出强烈的KP诱导，脑脊液中神经活性的QUIN和KYNA急剧升高。在6个月和18个月的随访中，TBE患者血清中的KP活性仍显着升高。通过秩相关分析发现认知能力与脑脊液和血清中KP活性测量值之间存在负相关。此外，通过ROC分析，我们发现血清rKT是整体认知功能受损的准确预测指标(解释：我们发现TBE患者急性和慢性KP活性失调的证据，这与长期随访的认知功能障碍程度相关。我们的研究结果表明，KP代谢物可能作为tbe相关认知后遗症的生物标志物，更广泛地说，KP可能为开发新的治疗方法提供途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Brain, Behavior, and Immunity 医学-免疫学

CiteScore

29.60

自引率

2.00%

发文量

290

审稿时长

28 days

期刊介绍： Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.