Marie Kupjetz, Martin Langeskov-Christensen, Morten Riemenschneider, Stefan Inerle, Uwe Ligges, Tobias Gaemelke, Nadine Patt, Jens Bansi, Roman Rudolf Gonzenbach, Marcel Reuter, Friederike Rosenberger, Tim Meyer, Adrian McCann, Per Magne Ueland, Simon Fristed Eskildsen, Mikkel Karl Emil Nygaard, Niklas Joisten, Lars Hvid, Ulrik Dalgas, Philipp Zimmer
{"title":"多发性硬化症患者显示不同的犬尿氨酸途径代谢物模式：一项跨国横断面研究。","authors":"Marie Kupjetz, Martin Langeskov-Christensen, Morten Riemenschneider, Stefan Inerle, Uwe Ligges, Tobias Gaemelke, Nadine Patt, Jens Bansi, Roman Rudolf Gonzenbach, Marcel Reuter, Friederike Rosenberger, Tim Meyer, Adrian McCann, Per Magne Ueland, Simon Fristed Eskildsen, Mikkel Karl Emil Nygaard, Niklas Joisten, Lars Hvid, Ulrik Dalgas, Philipp Zimmer","doi":"10.1212/NXI.0000000000200461","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and objectives: </strong>Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures.</p><p><strong>Methods: </strong>In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression.</p><p><strong>Results: </strong>The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (<i>NeuroTox</i>) and a neuroprotective pattern (<i>NeuroPro</i>). Greater <i>NeuroTox</i> was associated with a higher EDSS score, older age, and higher body fat percentage. Greater <i>NeuroPro</i> was associated with a lower EDSS score and higher cardiorespiratory fitness.</p><p><strong>Discussion: </strong>Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, <i>NeuroTox</i> and <i>NeuroPro</i>, in MS. Greater <i>NeuroTox</i> and lower <i>NeuroPro</i> were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS.</p><p><strong>Trial registration information: </strong>NCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.</p>","PeriodicalId":19472,"journal":{"name":"Neurology® Neuroimmunology & Neuroinflammation","volume":"12 6","pages":"e200461"},"PeriodicalIF":7.5000,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448327/pdf/","citationCount":"0","resultStr":"{\"title\":\"Persons With Multiple Sclerosis Reveal Distinct Kynurenine Pathway Metabolite Patterns: A Multinational Cross-Sectional Study.\",\"authors\":\"Marie Kupjetz, Martin Langeskov-Christensen, Morten Riemenschneider, Stefan Inerle, Uwe Ligges, Tobias Gaemelke, Nadine Patt, Jens Bansi, Roman Rudolf Gonzenbach, Marcel Reuter, Friederike Rosenberger, Tim Meyer, Adrian McCann, Per Magne Ueland, Simon Fristed Eskildsen, Mikkel Karl Emil Nygaard, Niklas Joisten, Lars Hvid, Ulrik Dalgas, Philipp Zimmer\",\"doi\":\"10.1212/NXI.0000000000200461\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and objectives: </strong>Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures.</p><p><strong>Methods: </strong>In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression.</p><p><strong>Results: </strong>The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (<i>NeuroTox</i>) and a neuroprotective pattern (<i>NeuroPro</i>). Greater <i>NeuroTox</i> was associated with a higher EDSS score, older age, and higher body fat percentage. Greater <i>NeuroPro</i> was associated with a lower EDSS score and higher cardiorespiratory fitness.</p><p><strong>Discussion: </strong>Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, <i>NeuroTox</i> and <i>NeuroPro</i>, in MS. Greater <i>NeuroTox</i> and lower <i>NeuroPro</i> were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS.</p><p><strong>Trial registration information: </strong>NCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.</p>\",\"PeriodicalId\":19472,\"journal\":{\"name\":\"Neurology® Neuroimmunology & Neuroinflammation\",\"volume\":\"12 6\",\"pages\":\"e200461\"},\"PeriodicalIF\":7.5000,\"publicationDate\":\"2025-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448327/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurology® Neuroimmunology & Neuroinflammation\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1212/NXI.0000000000200461\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/9/18 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurology® Neuroimmunology & Neuroinflammation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1212/NXI.0000000000200461","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/9/18 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Persons With Multiple Sclerosis Reveal Distinct Kynurenine Pathway Metabolite Patterns: A Multinational Cross-Sectional Study.
Background and objectives: Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures.
Methods: In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression.
Results: The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (NeuroTox) and a neuroprotective pattern (NeuroPro). Greater NeuroTox was associated with a higher EDSS score, older age, and higher body fat percentage. Greater NeuroPro was associated with a lower EDSS score and higher cardiorespiratory fitness.
Discussion: Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, NeuroTox and NeuroPro, in MS. Greater NeuroTox and lower NeuroPro were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS.
期刊介绍：
Neurology Neuroimmunology & Neuroinflammation is an official journal of the American Academy of Neurology. Neurology: Neuroimmunology & Neuroinflammation will be the premier peer-reviewed journal in neuroimmunology and neuroinflammation. This journal publishes rigorously peer-reviewed open-access reports of original research and in-depth reviews of topics in neuroimmunology & neuroinflammation, affecting the full range of neurologic diseases including (but not limited to) Alzheimer's disease, Parkinson's disease, ALS, tauopathy, and stroke; multiple sclerosis and NMO; inflammatory peripheral nerve and muscle disease, Guillain-Barré and myasthenia gravis; nervous system infection; paraneoplastic syndromes, noninfectious encephalitides and other antibody-mediated disorders; and psychiatric and neurodevelopmental disorders. Clinical trials, instructive case reports, and small case series will also be featured.
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