Cerebrospinal fluid detection of interleukin-1β in phase of remission predicts disease progression in multiple sclerosis

Background: Mitochondrial dysfunction is increasingly recognized as an important feature of multiple sclerosis (MS) pathology and may be relevant for clinical disease progression. However, it is unknown whether mitochondrial DNA (mtDNA) levels in the cerebrospinal fluid (CSF) associate with disease progression and therapeutic response. Objectives: To evaluate whether CSF concentrations of mtDNA in MS patients can serve as a marker of ongoing neuropathology and may be helpful to differentiate between MS disease subtypes. To explore the effect of disease-modifying therapies on mtDNA levels in the CSF. Methods: CSF mtDNA was measured using a digital polymerase chain reaction (PCR) CSF mtDNA in two independent MS cohorts. The cohorts included 92 relapsing-remitting multiple sclerosis (RRMS) patients, 40 progressive multiple sclerosis (PMS) patients (27 secondary progressive and 13 primary progressive), 50 various neurologic disease controls, and 5 healthy controls. Results: Patients with PMS showed a significant increase in CSF mtDNA compared to non-inflammatory neurologic disease controls. Patients with higher T2 lesion volumes and lower normalized brain volumes showed increased concentration of mtDNA. Patients treated with fingolimod had significantly lower mtDNA copy levels at follow-up compared to baseline. Conclusion: Our results showed a non-specific elevation of concentration of mtDNA in PMS patients. mtDNA concentrations respond to fingolimod and may be used to monitor biological effect of this treatment.

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Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study

PLoS ONE ◽

10.1371/journal.pone.0182462 ◽

2017 ◽

Vol 12 (8) ◽

pp. e0182462 ◽

Cited By ~ 10

Author(s):

Sebastian Wurth ◽

Bettina Kuenz ◽

Gabriel Bsteh ◽

Rainer Ehling ◽

Franziska Di Pauli ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

B Cells ◽

Prospective Study ◽

Disease Progression

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Cerebrospinal fluid evidence of increased extra-mitochondrial glucose metabolism implicates mitochondrial dysfunction in multiple sclerosis disease progression

Journal of the Neurological Sciences ◽

10.1016/j.jns.2008.07.032 ◽

2008 ◽

Vol 275 (1-2) ◽

pp. 106-112 ◽

Cited By ~ 53

Author(s):

William T. Regenold ◽

Pornima Phatak ◽

Michael J. Makley ◽

Roger D. Stone ◽

Mitchel A. Kling

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Glucose Metabolism ◽

Mitochondrial Dysfunction ◽

Disease Progression ◽

Multiple Sclerosis Disease

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Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53

Molecular Neurodegeneration ◽

10.1186/1750-1326-9-56 ◽

2014 ◽

Vol 9 (1) ◽

pp. 56 ◽

Cited By ~ 43

Author(s):

Silvia Rossi ◽

Caterina Motta ◽

Valeria Studer ◽

Giulia Macchiarulo ◽

Elisabetta Volpe ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Interleukin 1Β ◽

Protein P53 ◽

Apoptotic Protein ◽

Multiple Sclerosis Disease

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Biochemical Differences in Cerebrospinal Fluid between Secondary Progressive and Relapsing–Remitting Multiple Sclerosis

Cells ◽

10.3390/cells8020084 ◽

2019 ◽

Vol 8 (2) ◽

pp. 84 ◽

Cited By ~ 10

Author(s):

Stephanie Herman ◽

Torbjörn Åkerfeldt ◽

Ola Spjuth ◽

Joachim Burman ◽

Kim Kultima

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

High Resolution Mass Spectrometry ◽

Progressive Multiple Sclerosis ◽

Pyrimidine Metabolism ◽

Secondary Progressive ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

To better understand the pathophysiological differences between secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS), and to identify potential biomarkers of disease progression, we applied high-resolution mass spectrometry (HRMS) to investigate the metabolome of cerebrospinal fluid (CSF). The biochemical differences were determined using partial least squares discriminant analysis (PLS-DA) and connected to biochemical pathways as well as associated to clinical and radiological measures. Tryptophan metabolism was significantly altered, with perturbed levels of kynurenate, 5-hydroxytryptophan, 5-hydroxyindoleacetate, and N-acetylserotonin in SPMS patients compared with RRMS and controls. SPMS patients had altered kynurenine compared with RRMS patients, and altered indole-3-acetate compared with controls. Regarding the pyrimidine metabolism, SPMS patients had altered levels of uridine and deoxyuridine compared with RRMS and controls, and altered thymine and glutamine compared with RRMS patients. Metabolites from the pyrimidine metabolism were significantly associated with disability, disease activity and brain atrophy, making them of particular interest for understanding the disease mechanisms and as markers of disease progression. Overall, these findings are of importance for the characterization of the molecular pathogenesis of SPMS and support the hypothesis that the CSF metabolome may be used to explore changes that occur in the transition between the RRMS and SPMS pathologies.

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Patterns of cerebrospinal fluid pathology correlate with disease progression in multiple sclerosis

Brain ◽

10.1093/brain/124.11.2169 ◽

2001 ◽

Vol 124 (11) ◽

pp. 2169-2176 ◽

Cited By ~ 144

Author(s):

S. Cepok

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression

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Cerebrospinal fluid immunoglobulin light chain ratios predict disease progression in multiple sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-317947 ◽

2018 ◽

Vol 89 (10) ◽

pp. 1044-1049 ◽

Cited By ~ 11

Author(s):

Emma Rathbone ◽

Lindsay Durant ◽

James Kinsella ◽

Antony R Parker ◽

Ghaniah Hassan-Smith ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Lumbar Puncture ◽

Light Chain ◽

Light Chains ◽

Immunoglobulin Kappa ◽

Relapsing Remitting ◽

Diagnostic Lumbar Puncture

ObjectiveTo determine whether the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda light chains at time of multiple sclerosis (MS) diagnosis predicts disease progression and whether this was intrinsic to CSF plasmablasts.MethodsCSF and peripheral blood were obtained from patients undergoing elective diagnostic lumbar puncture and included clinically isolated syndrome (CIS) (n=43), relapsing remitting MS (RRMS; n=50), primary progressive MS (PPMS; n=20) and other neurological disease controls, both inflammatory (ONID; n=23) and non-inflammatory (OND; n=114). CSF samples were assayed for free and immunoglobulin-associated light chains and on B cells and plasmablasts. Clinical follow-up data were collected during a 5-year follow-up period where available.ResultsThere was an increased median CSF κ:λ free light chain (FLC) in all MS groups (CIS: 18.2, 95% CI 6.8 to 30.3; RRMS: 4.4, 95% CI 2.7 to 11.4; PPMS: 12.0, 95% CI 3.6 to 37.1) but not controls (OND: 1.61, 95% CI 1.4 to 1.9; ONID: 1.7, 95% CI 1.3 to 2.2; p<0.001). This ratio predicted Expanded Disability Status Scores (EDSS) progression at 5 years, with a lower median EDSS in the group with high (>10) CSF κ:λ FLC (0.0, 95% CI 0 to 2.5 vs 2.5, 95% CI 0 to 4, high vs low; p=0.049). CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026).ConclusionsThese data demonstrate that CSF immunoglobulin κ:λ ratios, determined at the time of diagnostic lumbar puncture, predict MS disease progression and may therefore be useful prognostic markers for early therapeutic stratification.

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