Cargando…

Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation

BACKGROUND: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervo...

Descripción completa

Detalles Bibliográficos
Autores principales: Al-Mekhlafi, Amani, Waqas, Fakhar H., Krueger, Maike, Klawonn, Frank, Akmatov, Manas K., Müller-Vahl, Kirsten, Trebst, Corinna, Skripuletz, Thomas, Stangel, Martin, Sühs, Kurt-Wolfram, Pessler, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621113/
https://www.ncbi.nlm.nih.gov/pubmed/37919735
http://dx.doi.org/10.1186/s12967-023-04637-y
_version_ 1785130344997978112
author Al-Mekhlafi, Amani
Waqas, Fakhar H.
Krueger, Maike
Klawonn, Frank
Akmatov, Manas K.
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Stangel, Martin
Sühs, Kurt-Wolfram
Pessler, Frank
author_facet Al-Mekhlafi, Amani
Waqas, Fakhar H.
Krueger, Maike
Klawonn, Frank
Akmatov, Manas K.
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Stangel, Martin
Sühs, Kurt-Wolfram
Pessler, Frank
author_sort Al-Mekhlafi, Amani
collection PubMed
description BACKGROUND: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions. METHODS: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell’s palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison. RESULTS: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89–0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89–0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation. CONCLUSIONS: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04637-y.
format Online
Article
Text
id pubmed-10621113
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-106211132023-11-03 Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation Al-Mekhlafi, Amani Waqas, Fakhar H. Krueger, Maike Klawonn, Frank Akmatov, Manas K. Müller-Vahl, Kirsten Trebst, Corinna Skripuletz, Thomas Stangel, Martin Sühs, Kurt-Wolfram Pessler, Frank J Transl Med Research BACKGROUND: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions. METHODS: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell’s palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison. RESULTS: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89–0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89–0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation. CONCLUSIONS: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04637-y. BioMed Central 2023-11-02 /pmc/articles/PMC10621113/ /pubmed/37919735 http://dx.doi.org/10.1186/s12967-023-04637-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Al-Mekhlafi, Amani
Waqas, Fakhar H.
Krueger, Maike
Klawonn, Frank
Akmatov, Manas K.
Müller-Vahl, Kirsten
Trebst, Corinna
Skripuletz, Thomas
Stangel, Martin
Sühs, Kurt-Wolfram
Pessler, Frank
Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title_full Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title_fullStr Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title_full_unstemmed Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title_short Elevated phospholipids and acylcarnitines C4 and C5 in cerebrospinal fluid distinguish viral CNS infections from autoimmune neuroinflammation
title_sort elevated phospholipids and acylcarnitines c4 and c5 in cerebrospinal fluid distinguish viral cns infections from autoimmune neuroinflammation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621113/
https://www.ncbi.nlm.nih.gov/pubmed/37919735
http://dx.doi.org/10.1186/s12967-023-04637-y
work_keys_str_mv AT almekhlafiamani elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT waqasfakharh elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT kruegermaike elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT klawonnfrank elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT akmatovmanask elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT mullervahlkirsten elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT trebstcorinna elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT skripuletzthomas elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT stangelmartin elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT suhskurtwolfram elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation
AT pesslerfrank elevatedphospholipidsandacylcarnitinesc4andc5incerebrospinalfluiddistinguishviralcnsinfectionsfromautoimmuneneuroinflammation