Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway

Luo, Yi; Möhn, Nora; Skripuletz, Thomas; Şenel, Makbule; Tumani, Hayrettin; Peßler, Frank; Stangel, Martin

doi:10.1002/acn3.51383

Cited by 5 publications

(4 citation statements)

References 22 publications

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“…Using LC-MS/MS analysis of the same cohort, we have previously reported that CSF kynurenine and the tryptophan/kynurenine ratio constitute biomarkers for the differentiation between viral CNS infections and autoimmune neuroin ammation (14), which was subsequently corroborated using a simple immunoassay for these analytes (29). Kynurenine was studied in ( 14) because it had been detected > LOD preferentially in infected samples, but it was excluded from the present analysis because it was detected > LOD in < 80% of the samples.…”

Section: Discussionmentioning

confidence: 87%

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

Al-Mekhlafi,

Waqas,

Krueger

et al. 2023

Preprint

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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 effect 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. As opposed to autoimmune neuroinflammation, viral CNS infections likely interfere with mitochondrial energy generation in target cells, thus identifying short-chain acylcarnitines as potential diagnostic biomarkers for the differentiation between the two conditions.

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Section: Discussionmentioning

confidence: 87%

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

Al-Mekhlafi,

Waqas,

Krueger

et al. 2023

Preprint

Self Cite

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show abstract

“…Using LC–MS/MS analysis of the same cohort, we have previously reported that CSF kynurenine and the tryptophan/kynurenine ratio constitute biomarkers for the differentiation between viral CNS infections and autoimmune neuroinflammation [ 18 ], which was subsequently corroborated using a simple immunoassay for these analytes [ 33 ]. Kynurenine was studied in [ 18 ] because it had been detected > LOD preferentially in infected samples and therefore held promise as a biomarker for infectious CNS processes, but it was excluded from the present analysis because it was detected > LOD in < 80% of the samples.…”

Section: Discussionmentioning

confidence: 99%

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

Al-Mekhlafi,

Waqas,

Krueger

et al. 2023

J Transl Med

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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.

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“…Enzyme-linked immunosorbent assay (ELISA) is a qualitative and quantitative detection method, using antigen–antibody binding specificity ( 37 ). One study measured CSF concentrations of tryptophan (Trp) and kynurenine (Kyn) using ELISA in 76 patients and found that Kyn concentrations and Kyn/Trp ratio were highly increased in viral CNS infections, while patients with autoimmune neuroinflammatory and non-inflammatory diseases showed low concentrations ( 38 ). Day et al ( 39 ) performed ELISA to detect enterovirus-specific IgM in serum samples from 557 patients clinically diagnosed with meningitis or encephalitis and found that the detection rate was much higher than the virus isolation rate.…”

Section: Etiological Examinationmentioning

confidence: 99%

Progress in etiological diagnosis of viral meningitis

Xu,

Chen,

Guo

et al. 2023

Front. Neurol.

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In recent years, with the rapid development of molecular biology techniques such as polymerase chain reaction and molecular biochip, the etiological diagnosis of viral encephalitis has a very big step forward. At present, the etiological examination of viral meningitis mainly includes virus isolation, serological detection and molecular biological nucleic acid detection. This article reviews the progress in etiological diagnosis of viral meningitis.

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Differentiation of viral and autoimmune central nervous system inflammation by kynurenine pathway

Cited by 5 publications

References 22 publications

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

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

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

Progress in etiological diagnosis of viral meningitis

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