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

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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Neurofilament light as a prognostic marker in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458509359725 ◽

2010 ◽

Vol 16 (3) ◽

pp. 287-292 ◽

Cited By ~ 105

Author(s):

Jonatan Salzer ◽

Anders Svenningsson ◽

Peter Sundström

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Prognostic Marker ◽

Neurofilament Light ◽

Light Levels ◽

Relapsing Remitting ◽

Diagnostic Lumbar Puncture ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Relapsing-remitting multiple sclerosis has a variable prognosis and lacks a reliable laboratory prognostic marker. Our aim in this study was to investigate the association between neurofilament light levels in cerebrospinal fluid in early multiple sclerosis and disease severity at long-term follow-up. Neurofilament light levels in cerebrospinal fluid collected at diagnostic lumbar puncture were measured in 99 multiple sclerosis cases. Clinical data were obtained from 95 out of those at follow-up visits made 14 years (range 8—20 years) after disease onset. Significant correlations between neurofilament light levels and the multiple sclerosis severity score were found for all cases ( r = 0.30, p = 0.005), for relapsing-remitting multiple sclerosis cases ( r = 0.47, p < 0.001) and for cases with a recent relapse ( r = 0.60, p < 0.001). In the multivariate logistic regression analysis, neurofilament light levels >386 ng/L (median value of cases with detectable levels) increased the risk for severe multiple sclerosis fivefold (odds ratio 5.2, 95% confidence interval 1.8—15). Kaplan—Meier analysis showed that conversion to secondary-progressive multiple sclerosis was more likely in cases with neurofilament light levels >386 ng/L than in those with neurofilament light levels <60 ng/L ( p = 0.01) or 60—386 ng/L ( p = 0.03). We conclude that elevated levels of neurofilament light in cerebrospinal fluid collected at diagnostic lumbar puncture were associated with unfavourable prognosis. These data suggest that the neurofilament light level could be used as a prognostic marker in early relapsing-remitting multiple sclerosis.

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Cerebrospinal fluid mtDNA concentration is elevated in multiple sclerosis disease and responds to treatment

Multiple Sclerosis Journal ◽

10.1177/1352458517699874 ◽

2017 ◽

Vol 24 (4) ◽

pp. 472-480 ◽

Cited By ~ 10

Author(s):

Cyra E Leurs ◽

Petar Podlesniy ◽

Ramon Trullas ◽

Lisanne Balk ◽

Martijn D Steenwijk ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Progression ◽

Progressive Multiple Sclerosis ◽

Neurologic Disease ◽

Brain Volumes ◽

Multiple Sclerosis Disease ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis ◽

Digital Polymerase Chain Reaction

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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Increased plasma 8,12-iso-iPF2alpha- VI levels in relapsing multiple sclerosis patients are not predictive of disease progression

Multiple Sclerosis Journal ◽

10.1177/1352458511433306 ◽

2012 ◽

Vol 18 (8) ◽

pp. 1092-1098 ◽

Cited By ~ 9

Author(s):

CE Teunissen ◽

M Sombekke ◽

L van Winsen ◽

J Killestein ◽

F Barkhof ◽

...

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Disease Progression ◽

Plasma Levels ◽

Lesion Load ◽

Disability Status ◽

Relapsing Remitting ◽

Multiple Sclerosis Patients ◽

In Cis

Background: Oxidative stress plays an important role in multiple sclerosis (MS). Isoprostanes are biomarkers for oxidative stress and have been related to neurological disease progression. Objective: To study whether plasma isoprostane levels were related to disease progression in MS. Methods: Plasma levels of 8,12-iso-iPF2alpha-VI were determined in 17 patients with clinically isolated syndrome (CIS), 41 relapsing–remitting MS (RRMS) patients and 5 primary progressive MS (PPMS) patients and related to MRI and clinical disease parameters. Results: Isoprostane levels were similar in CIS (60.9, interquartile range (IQR): 47.7–77.7 pg/ml) and RRMS patients (65.3, IQR: 51.9–82.8 pg/ml). The plasma levels were lower in PPMS patients (42.5, IQR: 37.1–49.9) pg/ml, p<0.05) compared to CIS and RRMS patients in this cohort, which was not confirmed in a second cohort. Baseline isoprostane levels were not related to clinical progression defined by conversion form CIS to RRMS or change in Expanded Disability Status Scale (EDSS) or MS Functional Composite (MSFC) scores during six years of follow-up (CIS + RRMS), nor to change in volume of gadolinium enhancing lesions, T2 lesion load or T1 hypointense lesion load during 2.8 years of follow-up (CIS + RRMS). Conclusion: These results do not support a strong role of 8,12-iso-iPF2alpha-VI in the prediction of disease progression in MS.

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Increased cerebrospinal fluid albumin and immunoglobulin A fractions forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517748474 ◽

2017 ◽

Vol 25 (3) ◽

pp. 338-343 ◽

Cited By ~ 3

Author(s):

Julia Kroth ◽

Dumitru Ciolac ◽

Vinzenz Fleischer ◽

Nabin Koirala ◽

Julia Krämer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Functional Disability ◽

Immunoglobulin A ◽

Cortical Atrophy ◽

Disease Evolution ◽

Relapsing Remitting ◽

Magnetic Resonance Imaging Mri ◽

Relapsing Remitting Multiple Sclerosis

Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disability at follow-up. Conclusion: CSF markers of blood–brain barrier integrity and specific immune response forecast emerging gray matter pathology and disease progression in MS.

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Hexosylceramides as intrathecal markers of worsening disability in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458514561908 ◽

2014 ◽

Vol 21 (10) ◽

pp. 1271-1279 ◽

Cited By ~ 21

Author(s):

Antonio Checa ◽

Mohsen Khademi ◽

Daniel G Sar ◽

Jesper Z Haeggström ◽

Jon O Lundberg ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Neurological Diseases ◽

Control Groups ◽

Promising Candidate ◽

Fatty Acid Chain ◽

Disability Status ◽

Relapsing Remitting ◽

Liquid Chromatography Tandem Mass

Background: Sphingolipids are important components of neurons and the myelin sheath whose levels are altered in multiple sclerosis (MS). Objectives: We aimed to determine if cerebrospinal fluid (CSF) sphingolipids can be used as markers of MS disease progression. Methods: Using liquid chromatography tandem mass spectrometry, we analysed sphingolipids in CSF from 134 individuals. The MS group included 65 patients divided into 41 relapsing–remitting MS (RRMS) and 24 progressive MS (ProgMS). In addition, a group of 13 early MS/clinically isolated syndrome (EarlyMS) and two control groups consisting of 38 individuals with other neurological diseases (OND) and 18 OND with signs of inflammation (iOND) were analysed. A follow-up study included 17 additional RRMS patients sampled at two time points 4.7±1.7 years apart. Results: Levels of sphingomyelin (SM)- and hexosylceramide (HexCer)-derived sphingolipids increased in the CSF of patients with MS independently of the fatty acid chain length in RRMS ( p<0.05). Levels of palmitic acid (16:0)-containing HexCer (HexCer16:0) increased significantly in ProgMS compared with the OND ( p<0.001), iOND ( p<0.05) and EarlyMS ( p<0.01) groups and correlated with Expanded Disability Status Scale in RRMS in both studies ( p=0.048; p=0.027). Conclusion: HexCer16:0 is a promising candidate marker of disease progression in MS, especially in RRMS.

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Serum contactin-1 as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/13524585211010097 ◽

2021 ◽

pp. 135245852110100

Author(s):

Zoë YGJ van Lierop ◽

Luuk Wieske ◽

Marleen JA Koel-Simmelink ◽

Madhurima Chatterjee ◽

Iris Dekker ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Progression ◽

Odds Ratio ◽

Prognostic Biomarker ◽

Disability Progression ◽

Lower Baseline ◽

Relapsing Remitting ◽

Natalizumab Treatment

Background: Natalizumab treatment provides a model for non-inflammation-induced disease progression in multiple sclerosis (MS). Objective: To study serum contactin-1 (sCNTN1) as a novel biomarker for disease progression in natalizumab-treated relapsing-remitting MS (RRMS) patients. Methods: Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were included. sCNTN1 was analyzed at baseline (before natalizumab initiation), 3, 12, 24 months (M) and last follow-up (median 5.2 years) and compared to 222 healthy controls (HC) and 15 primary progressive MS patients (PPMS). Results were compared between patients with progressive, stable, or improved disability according to EDSS-plus criteria. Results: Median sCNTN1 levels (ng/mL,) in RRMS (baseline: 10.7, 3M: 9.7, 12M: 10.4, 24M: 10.8; last follow-up: 9.7) were significantly lower compared to HC (12.5; p ⩽ 0.001). It was observed that 48% of patients showed progression during follow-up, 11% improved, and 40% remained stable. sCNTN1 levels were significantly lower in progressors both at baseline and at 12M compared to non-progressors. A 1 ng/mL decrease in baseline sCNTN1 was consistent with an odds ratio of 1.23 (95% confidence interval 1.04–1.45) ( p = 0.017) for progression during follow-up. Conclusion: Lower baseline sCNTN1 concentrations were associated with long-term disability progression during natalizumab treatment, making it a possible blood-based prognostic biomarker for RRMS.

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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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Cerebrospinal fluid growth-associated protein 43 in multiple sclerosis

Scientific Reports ◽

10.1038/s41598-019-54032-1 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Åsa Sandelius ◽

Sofia Sandgren ◽

Markus Axelsson ◽

Clas Malmeström ◽

Lenka Novakova ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Enzyme Linked Immunosorbent Assay ◽

Resonance Imaging ◽

Secondary Progressive ◽

Highly Active ◽

Disease Modifying Therapies ◽

Relapsing Remitting ◽

Disease Modifying

AbstractNeurodegeneration in multiple sclerosis (MS) correlates with disease progression and reparative processes may be triggered. Growth-associated protein 43 (GAP-43) exhibits induced expression during axonal growth and reduced expression during MS progression. We aimed to evaluate if GAP-43 can serve as a biomarker of regeneration in relapsing-remitting MS (RRMS) and whether disease-modifying therapies (DMTs) influence GAP-43 concentration in cerebrospinal fluid (CSF). GAP-43 was measured using an enzyme-linked immunosorbent assay in 105 MS patients (73 RRMS, 12 primary progressive MS, 20 secondary progressive MS) and 23 healthy controls (HCs). In 35 of the patients, lumbar puncture, clinical assessment, and magnetic resonance imaging was performed before initiation of therapeutic intervention, and at follow-up. CSF GAP-43 concentration was significantly lower in progressive MS compared with HCs (p = 0.004) and RRMS (p = < 0.001) and correlated negatively with disability (p = 0.026). However, DMTs did not alter CSF GAP-43. Interestingly, in RRMS CSF GAP-43 levels were higher in patients with signs of active inflammatory disease than in patients in remission (p = 0.042). According to CSF GAP-43 concentrations, regeneration seems reduced in progressive MS, increased during disease activity in RRMS but is unaffected by treatment of highly active DMTs.

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Adiponectin in Cerebrospinal Fluid from Patients Affected by Multiple Sclerosis Is Correlated with the Progression and Severity of Disease

Molecular Neurobiology ◽

10.1007/s12035-021-02287-z ◽

2021 ◽

Author(s):

Elisabetta Signoriello ◽

Marta Mallardo ◽

Ersilia Nigro ◽

Rita Polito ◽

Sara Casertano ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Severe Phenotype ◽

Severity Of Disease ◽

Total Adiponectin ◽

Relapsing Remitting ◽

Worse Prognosis ◽

Age And Sex

AbstractAdiponectin exerts relevant actions in immunity and is modulated in several disorders, such as multiple sclerosis (MS). In this study, we characterized adiponectin expression and profiles in cerebrospinal fluid (CSF) from MS patients to investigate its potential relationship with the severity and progression of the disease. Total adiponectin in CSF was measured by ELISA in 66 unrelated CSF MS patients and compared with 24 age- and sex-matched controls. Adiponectin oligomer profiles were analysed by Western blotting and FPLC chromatography. Total CSF adiponectin was significantly increased in MS patients compared with controls (9.91 ng/mL vs 6.02 ng/mL) (p < 0.001). Interestingly, CSF adiponectin positively correlated with CSF IgG, and CSF/serum albumin directly correlated with CSF/serum adiponectin. Our data demonstrated that CSF adiponectin predicts a worse prognosis: patients with the progressive form of MS had higher levels compared with the relapsing remitting form; patients with higher EDSS at baseline and a higher MS severity score at 4.5-year follow-up had significantly elevated adiponectin levels with respect to patients with a less severe phenotype. Finally, the adiponectin oligomerization profile was altered in CSF from MS patients, with a significant increase in HMW and MMW. The correlation of CSF adiponectin with the severity and prognosis of MS disease confirmed the role of this adipokine in the inflammatory/immune processes of MS and suggested its use as a complementary tool to assess the severity, progression and prognosis of the disease. Further studies on larger MS cohorts are needed to clarify the contribution of adiponectin to the etiopathogenesis of MS.

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Decreased Cerebrospinal Fluid Antioxidative Capacity Is Related to Disease Severity and Progression in Early Multiple Sclerosis

Biomolecules ◽

10.3390/biom11091264 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1264

Author(s):

Margarete M. Voortman ◽

Anna Damulina ◽

Lukas Pirpamer ◽

Daniela Pinter ◽

Alexander Pichler ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Disease Activity ◽

Neuronal Damage ◽

Brain Mri ◽

Time Interval ◽

Antioxidative Capacity ◽

Subclinical Disease ◽

Relapsing Remitting

Background: Oxidative stress-induced neuronal damage in multiple sclerosis (MS) results from an imbalance between toxic free radicals and counteracting antioxidants, i.e., antioxidative capacity (AOC). The relation of AOC to outcome measures in MS still remains inconclusive. We aimed to compare AOC in cerebrospinal fluid (CSF) and serum between early MS and controls and assess its correlation with clinical/radiological measures. Methods: We determined AOC (ability of CSF and serum of patients to inhibit 2,2′-azobis(2-amidinopropane) dihydrochloride-induced oxidation of dihydrorhodamine) in clinically isolated syndrome (CIS)/early relapsing-remitting MS (RRMS) (n = 55/11) and non-inflammatory neurological controls (n = 67). MS patients underwent clinical follow-up (median, 4.5; IQR, 5.2 years) and brain MRI at 3 T (baseline/follow-up n = 47/34; median time interval, 3.5; IQR, 2.1 years) to determine subclinical disease activity. Results: CSF AOC was differently regulated among CIS, RRMS and controls (p = 0.031) and lower in RRMS vs. CIS (p = 0.020). Lower CSF AOC correlated with physical disability (r = −0.365, p = 0.004) and risk for future relapses (exp(β) = 0.929, p = 0.033). No correlations with MRI metrics were found. Conclusion: Decreased CSF AOC was associated with increased disability and clinical disease activity in MS. While our finding cannot prove causation, they should prompt further investigations into the role of AOC in the evolution of MS.

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