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

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.

Download Full-text

Leukocyte telomere length in patients with multiple sclerosis and its association with clinical phenotypes

10.1101/2020.11.17.20232975 ◽

2020 ◽

Author(s):

Michael Hecker ◽

Brit Fitzner ◽

Kathrin Jäger ◽

Jan Bühring ◽

Margit Schwartz ◽

...

Keyword(s):

Multiple Sclerosis ◽

Biological Aging ◽

Leukocyte Telomere Length ◽

Telomere Shortening ◽

Secondary Progressive ◽

Relapsing Remitting ◽

Age And Sex

AbstractAging is a significant factor influencing the course of multiple sclerosis (MS). Accelerated telomere attrition is an indicator of premature biological aging and a potential contributor to various chronic diseases, including neurological disorders. However, there is currently a lack of studies focusing on telomere lengths in patients with MS.We measured the average leukocyte telomere length (LTL) in biobanked DNA samples of 40 relapsing-remitting MS patients (RRMS), 20 primary progressive MS patients (PPMS) and 60 healthy controls using a multiplex quantitative polymerase chain reaction method. Changes in LTL over a period of >10 years were evaluated in a subset of 10 patients. Association analyses of baseline LTL with the long-term clinical profiles of the patients were performed using inferential statistical tests and regression models adjusted for age and sex.The cross-sectional analysis revealed that the RRMS group was characterized by a significantly shorter relative LTL, on average, as compared to the PPMS group and controls. Shorter telomeres at baseline were also associated with a higher conversion rate from RRMS to secondary progressive MS (SPMS) in the 10-year follow-up. The LTL decrease over time was similar in RRMS patients and PPMS patients in the longitudinal analysis.Our data suggest a possible contributory role of accelerated telomere shortening in the pathobiology of MS. The interplay between disease-related immune system alterations, immunosenescence and telomere dynamics deserves further investigation. New insights into the mechanisms of disease might be obtained, e.g., by exploring the distribution of telomere lengths in specific blood cell populations.Research in contextEvidence before this studyThere is a growing research interest in the relationship between age and the pathophysiology and clinical presentation of multiple sclerosis (MS). Telomere shortening is a hallmark of biological aging. However, the role of telomeres in this chronic immune-mediated neurodegenerative disease has not yet been widely studied. Two research groups provided evidence that the telomeres of immune cells in the peripheral blood are shorter in patients with MS than in healthy subjects.Added value of this studyWe found that leukocytes from patients with relapsing-remitting MS (RRMS) are characterized by relatively short telomere lengths (TL). On average, we observed 18% shorter TL in the RRMS patient cohort (n=40) than in the age- and sex-matched healthy control cohort (n=60). We further analyzed the association of TL and long-term clinical outcomes. RRMS patients with shorter TL had a higher rate of converting to secondary progressive MS over a 10-year follow-up period.Implications of all the available evidenceAs we and others have shown, TL are generally shorter in MS patients and associated with disease progression, independent of age. These findings suggest a link between biological aging and the heterogeneous clinical course of MS patients. It currently remains unclear whether shortened telomeres in MS are a cause or a consequence of the pathophysiological processes. Further studies with larger patient cohorts and different cell populations will be needed to expand our knowledge of age-related disease mechanisms and the use of TL as a biomarker in MS.

Download Full-text

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.

Download Full-text

The Neutrophil-to-Lymphocyte Ratio is Related to Disease Activity in Relapsing Remitting Multiple Sclerosis

Cells ◽

10.3390/cells8101114 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1114 ◽

Cited By ~ 6

Author(s):

D’Amico ◽

Zanghì ◽

Romano ◽

Sciandra ◽

Palumbo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Disease Activity ◽

Large Scale ◽

Total Sample ◽

Neutrophil To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis

: Background: The role of the neutrophil-to-lymphocyte ratio (NLR) of peripheral blood has been investigated in relation to several autoimmune diseases. Limited studies have addressed the significance of the NLR in terms of being a marker of disease activity in multiple sclerosis (MS). Methods: This is a retrospective study in relapsing–remitting MS patients (RRMS) admitted to the tertiary MS center of Catania, Italy during the period of 1 January to 31 December 2018. The aim of the present study was to investigate the significance of the NLR in reflecting the disease activity in a cohort of early diagnosed RRMS patients. Results: Among a total sample of 132 patients diagnosed with RRMS, 84 were enrolled in the present study. In the association analysis, a relation between the NLR value and disease activity at onset was found (V-Cramer 0.271, p = 0.013). In the logistic regression model, the variable NLR (p = 0.03 ExpB 3.5, CI 95% 1.089–11.4) was related to disease activity at onset. Conclusion: An elevated NLR is associated with disease activity at onset in RRMS patients. More large-scale studies with a longer follow-up are needed.

Download Full-text

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.

Download Full-text

Correlation between DJ-1 levels in the cerebrospinal fluid and the progression of disabilities in multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458508093616 ◽

2008 ◽

Vol 14 (8) ◽

pp. 1056-1060 ◽

Cited By ~ 28

Author(s):

M Hirotani ◽

C Maita ◽

M Niino ◽

SM Iguchi-Ariga ◽

S Hamada ◽

...

Keyword(s):

Oxidative Stress ◽

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Healthy Subjects ◽

Significant Positive Correlation ◽

Healthy Controls ◽

Significant Difference ◽

Relapsing Remitting ◽

Multiple Sclerosis Patients

Objectives DJ-1 plays a key role in the anti-oxidative stress function. Increasing evidence supports the role of oxidative stress in the pathogenesis of multiple sclerosis (MS). The aim of this study was to investigate whether the DJ-1 levels were increased in patients with MS and to examine its association with the progression of MS. Methods Quantitative immunoblot assays were performed to evaluate the DJ-1 level in serum and cerebrospinal fluid (CSF) collected from relapsing–remitting patients with MS ( n = 29), disease controls subjects ( n = 14), and healthy subjects ( n = 44). Results No significant difference was observed in the serum DJ-1 level among the patients with MS, disease controls, and healthy controls. However, the CSF DJ-1 levels were significantly higher in the patients with MS than in the disease control subjects ( P < 0.0001). A significant positive correlation was also found between the CSF DJ-1 levels and the Multiple Sclerosis Severity Score ( P < 0.005, r = 0.501). Conclusions These results show that the CSF DJ-1 levels are significantly increased in the CSF of patients with MS and that the CSF DJ-1 levels may be associated with the disease progression of MS. Therefore, DJ-1 possibly plays an important role in the pathogenesis of MS.

Download Full-text

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.

Download Full-text

Cerebrospinal fluid brain specific proteins in relation to nitric oxide metabolites during relapse of multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458507082061 ◽

2008 ◽

Vol 14 (1) ◽

pp. 59-66 ◽

Cited By ~ 36

Author(s):

K. Rejdak ◽

A. Petzold ◽

Z. Stelmasiak ◽

G. Giovannoni

Keyword(s):

Nitric Oxide ◽

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Nitrosative Stress ◽

Study Groups ◽

Relapsing Remitting ◽

Specific Proteins ◽

Nitric Oxide Metabolites ◽

Nitrate And Nitrite

This study investigated the cerebrospinal fluid (CSF) levels of ferritin, S100B as biomarkers for glial activation and NfHSM135 — a biomarker of axonal damage — in relation to nitric oxide (NO) metabolites: nitrate and nitrite (NOx) during acute multiple sclerosis (MS) relapse. Thirty-four relapsing—remitting MS (RR-MS) patients during acute relapse and 12 controls were enrolled. Patients were assessed on Expanded Disability Status Scale (EDSS) and underwent lumbar puncture within two weeks following relapse. Twenty patients were available for further follow-up and were assessed on EDSS 6—8 weeks since the relapse onset. The CSF NOx ( P < 0.0001), NfHSM135 ( P = 0.01) and S100B ( P = 0.009) but not ferritin ( P > 0.05) were significantly raised in MS group. There was a significant correlation between CSF ferritin and S100B in RR-MS group ( P = 0.004). CSF NOx did not correlate with S100B and ferritin in study groups. RR-MS patients with detectable NfHSM135 levels had higher NOx compared with subjects having undetectable NfHSM135 ( P = 0.03). In the follow-up study, raised baseline levels of NOx ( P = 0.016) or NfHSM135 ( P = 0.04) inversely correlated with the clinical recovery grade expressed as relative EDSS change between baseline and follow-up. In conclusion, NO metabolites were increased and because of their correlation with a biomarker of axonal degeneration (neurofilaments) and a measure for clinical disability (EDSS), relapse-related nitrosative stress is likely to be relevant to the development of sustained disability in an individual patient. Multiple Sclerosis 2008; 14: 59—66. http://msj.sagepub.com

Download Full-text

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.

Download Full-text

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.

Download Full-text

Interferon β therapy increases serum ferritin levels in patients with relapsing-remitting multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458508089687 ◽

2008 ◽

Vol 14 (6) ◽

pp. 857-859 ◽

Cited By ~ 5

Author(s):

A Sena ◽

R Pedrosa ◽

V Ferret-Sena ◽

MJ Cascais ◽

R Roque ◽

...

Keyword(s):

Multiple Sclerosis ◽

Serum Ferritin ◽

Matched Control ◽

Progressive Multiple Sclerosis ◽

Interferon Β ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis ◽

Immunomodulatory Therapies ◽

Age And Sex

Serum ferritin levels have been found to be increased in patients with active progressive multiple sclerosis (MS). However, its levels are reported to be unchanged in stable and in active relapsing-remitting (RR) form of the disease. No research to date has assessed the influence of interferon β (IFN-β) on ferritin concentrations. In this study, serum ferritin levels were measured in 43 individuals with RR-MS and 38 age- and sex-matched control volunteers. There were no significant differences between controls and patients under stable and untreated conditions. In patients at 12 months after the beginning of IFN-β therapy, ferritin levels were higher in women and in men, in comparison with baseline (71.4 ± 58.6 vs 43.4 ± 29.9 ng/mL, P = 0.0006 and 216.0 ± 124.3 vs 127.8 ± 74.9 ng/mL, P = 0.0022, respectively). These results suggest that larger prospective studies are required to evaluate the role of serum ferritin in MS and its potential usefulness in monitoring responses to immunomodulatory therapies.

Download Full-text