Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation

Kuhn, Maike; Sühs, Kurt‐Wolfram; Akmatov, Manas K.; Klawonn, Frank; Wang, Junxi; Skripuletz, Thomas; Kaever, Volkhard; Stangel, Martin; Peßler, Frank

doi:10.1186/s12974-017-1041-0

Cited by 24 publications

(44 citation statements)

References 49 publications

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“…Following our previous results of increased CSF concentrations of free phospholipids in viral CNS infections compared to disease controls without CNS infection [7,8], we tested the hypothesis that selected CSF phospholipid species are preferentially abundant also in bacterial meningitis. For this purpose, we analyzed a targeted metabolomic data set comprising 221 CSF samples spanning bacterial, viral, and non-infectious inflammatory and noninflammatory diagnoses and identified elevated PC ae C44:6 concentration as an accurate biomarker to differentiate bacterial meningitis from viral CNS infections and autoimmune neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“…2413-2014). Recruitment of patients, processing of CSF and sociodemographic and standard laboratory diagnostic data of the diagnostic groups are also described in [4,7,8]. Briefly, CSF was obtained during clinically indicated lumbar puncture and processed within 2 h. The following standard diagnostic CSF parameters were analyzed directly after lumbar puncture: leukocyte count (counted manually with a Fuchs-Rosenthal counting chamber), protein concentration (Bradford dye-binding assay), lactate concentration (photometric assay), Q-albumin ratio (albumin concentration in CSF/albumin concentration in serum), IgG-index (IgG concentration in CSF/ IgG concentration in serum divided by Q-albumin ratio; age-adjusted reference limit = 4 + (age/15).…”

Section: Study Population and Biosamplesmentioning

confidence: 99%

“…This kit allows the quantification of 188 analytes, comprising 42 amino acids and amino acid metabolites, 91 glycerophospholipids, 15 sphingolipids, 40 acylcarnitines, and the sum of hexoses. Details of the measurement procedure are described in [7]. Other aspects of the resulting data set, which do not include PC ae C44:6, have been published separately [4,7,8].…”

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

“…Other aspects of the resulting data set, which do not include PC ae C44:6, have been published separately [4,7,8]. References [7,8] feature comprehensive analyses of the data set, but PC ae C44:6 was excluded from those analyses due to the high frequency of concentrations below limit of detection (LOD) in the samples other than bacterial meningitis. The LOD of PC ae C44:6 was determined to be 9 nM, and all values < LOD were replaced with the pseudo-value of LOD/2 ≈ 5 nM.…”

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

“…Emerging evidence suggests that measuring concentrations of small molecules in CSF can help to identify CSF biomarkers for various aspects of central nervous system (CNS) infections such as differentiating between infectious and autoimmune etiologies [4], assessing CNS complications of chronic infections [5,6], or detecting CNS extension of infections with a presumed primary site outside of the CNS [7]. We have recently shown that major changes in CSF metabolite populations occur in viral CNS infections [4,7,8] and that certain membrane phospholipids, when measured in cell-free CSF, constitute highly accurate CSF biomarkers for meningoencephalitis during varicella zoster virus (VZV) reactivation [7] and for a diagnosis of enterovirus meningitis even in patients with normal CSF cell counts [8]. However, these analyses also showed that in virally infected, autoimmune, or non-inflamed samples many metabolites including phospholipids were present in only low concentrations, raising the hypothesis that some of them may be selectively more abundant in CSF from bacterial meningitis and may therefore constitute biomarkers for this challenging/ life-threatening infectious disease.…”

Section: Introductionmentioning

confidence: 99%

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Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

et al. 2020

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Background: The timely diagnosis of bacterial meningitis is of utmost importance due to the need to institute antibiotic treatment as early as possible. Moreover, the differentiation from other causes of meningitis/encephalitis is critical because of differences in management such as the need for antiviral or immunosuppressive treatments. Considering our previously reported association between free membrane phospholipids in cerebrospinal fluid (CSF) and CNS involvement in neuroinfections we evaluated phosphatidylcholine PC ae C44:6, an integral constituent of cell membranes, as diagnostic biomarker for bacterial meningitis. Methods:We used tandem mass spectrometry to measure concentrations of PC ae C44:6 in cell-free CSF samples (n = 221) from patients with acute bacterial meningitis, neuroborreliosis, viral meningitis/encephalitis (herpes simplex virus, varicella zoster virus, enteroviruses), autoimmune neuroinflammation (anti-NMDA-receptor autoimmune encephalitis, multiple sclerosis), facial nerve and segmental herpes zoster (shingles), and noninflammatory CNS disorders (Bell's palsy, Tourette syndrome, normal pressure hydrocephalus).Results: PC ae C44:6 concentrations were significantly higher in bacterial meningitis than in all other diagnostic groups, and were higher in patients with a classic bacterial meningitis pathogen (e.g. Streptococcus pneumoniae, Neisseria meningitidis, Staphylococcus aureus) than in those with less virulent or opportunistic pathogens as causative agents (P = 0.026). PC ae C44:6 concentrations were only moderately associated with CSF cell count (Spearman's ρ = 0.45; P = 0.009), indicating that they do not merely reflect neuroinflammation. In receiver operating characteristic curve analysis, PC ae C44:6 equaled CSF cell count in the ability to distinguish bacterial meningitis from viral meningitis/encephalitis and autoimmune CNS disorders (AUC 0.93 both), but had higher sensitivity (91% vs. 41%) and negative predictive value (98% vs. 89%). A diagnostic algorithm comprising cell count, lactate and PC ae C44:6 had a sensitivity of 97% (specificity 87%) and negative predictive value of 99% (positive predictive value 61%) and correctly diagnosed three of four bacterial meningitis samples that were misclassified by cell count and lactate due to low values not suggestive of bacterial meningitis. © The Author(s) 2020. 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'

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Section: Discussionmentioning

confidence: 99%

Section: Study Population and Biosamplesmentioning

confidence: 99%

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

Section: Measurement Of Pc Ae C44:6 Concentrations In Csf By Mass Spementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

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Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease

et al. 2021

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The high morbidity and mortality of neuroinflammatory diseases drives significant interest in understanding the underlying mechanisms involved in the innate and adaptive immune response of the central nervous system (CNS). Diagnostic biomarkers are important to define treatable neuroinflammation. Metabolomics is a rapidly evolving research area offering novel insights into metabolic pathways, and elucidation of reliable metabolites as biomarkers for diseases. This review focuses on the emerging literature regarding the detection of neuroinflammation using cerebrospinal fluid (CSF) metabolomics in human cohort studies. Studies of classic neuroinflammatory disorders such as encephalitis, CNS infection and multiple sclerosis confirm the utility of CSF metabolomics. Additionally, studies in neurodegeneration and neuropsychiatry support the emerging potential of CSF metabolomics to detect neuroinflammation in common CNS diseases such as Alzheimer's disease and depression. We demonstrate metabolites in the tryptophan–kynurenine pathway, nitric oxide pathway, neopterin and major lipid species show moderately consistent ability to differentiate patients with neuroinflammation from controls. Integration of CSF metabolomics into clinical practice is warranted to improve recognition and treatment of neuroinflammation.

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Cerebrospinal fluid proteomics in meningitis patients with reactivated varicella zoster virus

Liu,

Wang,

Zhang

et al. 2023

Immunity Inflam & Disease

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ObjectiveThis study investigated the proteomic characteristics of cerebrospinal fluid (CSF) in patients with varicella zoster virus (VZV) meningitis to understanding the pathogenesis of central nervous system (CNS) infection by reactivated VZV.MethodWe used data‐independent acquisition model to analyze the CSF proteomic differences of 28 patients with VZV meningitis and 11 herpes zoster (HZ) patients. According to the clinical manifestations at discharge, 28 VZV meningitis patients were divided into favorable outcome group and unfavorable outcome (UO) group and their differences in CSF proteome were also analyzed.ResultsCompared with the HZ group, the proteins (CXCL10, ELANE, IL‐1RN, MPO, PRTN3, etc.) related to inflammation and immune cell activation were significantly upregulated in the VZV meningitis group (p < .01). The protein related to the nerve function and energy metabolism (CKMT1B, SLITRK3, Synaptotagmin‐3, KIF5B, etc.) were significantly downregulated (p < .05). The levels of a pro‐inflammatory factor, IL‐18, in CSF were significantly higher in patients in the UO group as compared to patients with favorable prognosis (p < .05).ConclusionInflammatory immune response is an important pathophysiological mechanism of CNS infection by VZV, and the CSF IL‐18 levels might be a potential prognostic indicator of the outcomes of VZV meningitis.

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Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation

Cited by 24 publications

References 49 publications

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

Phosphatidylcholine PC ae C44:6 in cerebrospinal fluid is a sensitive biomarker for bacterial meningitis

Cerebrospinal fluid metabolomics: detection of neuroinflammation in human central nervous system disease

Cerebrospinal fluid proteomics in meningitis patients with reactivated varicella zoster virus

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