Routine Gadolinium Use for MRI Follow-up of Multiple Sclerosis: Point—The Role of Leptomeningeal Enhancement

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

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The Ala/Ala genotype of PPARY Pro12 Ala polymorphism is associated with late onset of multiple sclerosis

Archives of Biological Sciences ◽

10.2298/abs1302447l ◽

2013 ◽

Vol 65 (2) ◽

pp. 447-453

Author(s):

N. Lukic ◽

A. Stankovic ◽

E. Dincic ◽

M. Bundalo ◽

Z. Krsmanovic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Late Onset ◽

Age At Onset ◽

Peroxisome Proliferator ◽

Pro12ala Polymorphism ◽

Peroxisome Proliferator Activated Receptor ◽

Post Hoc ◽

Genotype And Allele Frequencies

The function of peroxisome proliferator-activated receptor ? (PPAR?) in immune regulation, as well as in antiinflammatory and anti-proliferative actions towards T lymphocytes, has been reported. A potential role of PPARs in multiple sclerosis (MS) was suggested. The aim of this study was to investigate if there is an association of PPAR?-2 Pro12Ala polymorphism with MS in 361 patients from Serbia. The genotype and allele frequencies of Pro12Ala polymorphism were not significantly different between controls and patients, or between females and males. In contrast to controls, we detected a rare Ala/Ala genotype in patients with MS. We found that there is a significant association of Ala/Ala genotype with older age at onset (ANOVA, p=0.07; LSD post-hoc, Ala/Ala vs. Pro/Ala, p=0.03, Ala/Ala vs. Pro/Pro p=0.02). It would be useful to validate our results in other populations, as well as to perform follow-up of the disease progression in regard to PPAR? genotypes.

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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.

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Continued dysregulation of the B cell lineage promotes multiple sclerosis activity despite disease modifying therapies

F1000Research ◽

10.12688/f1000research.74506.1 ◽

2021 ◽

Vol 10 ◽

pp. 1305

Author(s):

Ana C. Londoño ◽

Carlos A. Mora

Keyword(s):

Multiple Sclerosis ◽

B Cells ◽

B Cell ◽

Cell Lineage ◽

Clear Understanding ◽

Cellular Activity ◽

Regulatory B Cells ◽

Disease Modifying Therapies

A clear understanding of the origin and role of the different subtypes of the B cell lineage involved in the activity or remission of multiple sclerosis (MS) is important for the treatment and follow-up of patients living with this disease. B cells, however, are dynamic and can play an anti-inflammatory or pro-inflammatory role, depending on their milieu. Depletion of B cells has been effective in controlling the progression of MS, but it can have adverse side effects. A better understanding of the role of the B cell subtypes, through the use of surface biomarkers of cellular activity with special attention to the function of memory and regulatory B cells (Bregs), will be necessary in order to offer specific treatments without inducing undesirable effects.

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Long-term follow-up of isolated optic neuritis: the risk of developing multiple sclerosis, its outcome, and the prognostic role of paraclinical tests

Journal of Neurology ◽

10.1007/s004150050453 ◽

1999 ◽

Vol 246 (9) ◽

pp. 770-775 ◽

Cited By ~ 62

Author(s):

A. Ghezzi ◽

V. Martinelli ◽

V. Torri ◽

M. Zaffaroni ◽

M. Rodegher ◽

...

Keyword(s):

Multiple Sclerosis ◽

Optic Neuritis ◽

Prognostic Role ◽

Long Term Follow Up

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Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS

Neuroepidemiology ◽

10.1159/000508229 ◽

2020 ◽

Vol 54 (6) ◽

pp. 433-445

Author(s):

Lazaros Belbasis ◽

Vanesa Bellou ◽

Ioanna Tzoulaki ◽

Evangelos Evangelou

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Early Life ◽

Significant Risk ◽

Perinatal Period ◽

Age At Menarche ◽

Early Life Factors ◽

Average Body

Background: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce. Methods: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS. Results: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90–0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24–1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79–0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach. Conclusions: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.

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Inflammatory Diseases Among Norwegian LRRK2 Mutation Carriers. A 15-Years Follow-Up of a Cohort

Frontiers in Neuroscience ◽

10.3389/fnins.2021.634666 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jan O. Aasly

Keyword(s):

Rheumatoid Arthritis ◽

Multiple Sclerosis ◽

Autosomal Dominant ◽

Inflammatory Diseases ◽

Carrier Status ◽

Founder Effects ◽

Mutation Carriers ◽

The World

The first families with LRRK2 related Parkinson’s disease (PD) were presented around 15 years ago and numerous papers have described the characteristics of the LRRK2 phenotype. The prevalence of autosomal dominant PD varies around the world mainly depending on local founder effects. The highest prevalence of LRRK2 G2019S PD in Norway is located to the central part of the country and most families could be traced back to common ancestors. The typical Norwegian LRRK2 phenotype is not different from classical PD and similar to that seen in most other LRRK2 families. The discovery of LRRK2 PD has allowed us to follow-up multi-incident families and to study their phenotype longitudinally. In the Norwegian LRRK2 families there has been a significantly higher incidence of inflammatory diseases like multiple sclerosis and rheumatoid arthritis that seen in other PD populations. Recent studies in LRRK2 mechanisms have indicated that this protein may be crucial in initiating disease processes. In this short survey of 100 Norwegian mutation carriers followed through more than 15 years are presented. The prevalence of inflammatory diseases among these cases is highlighted. The role of LRRK2 in the conversion process from carrier status to PD phenotype is still unknown and disease generating mechanisms important for initiating LRRK2 PD are still to be identified.

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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.

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CD46 in a Spanish cohort of multiple sclerosis patients: genetics, mRNA expression and response to interferon-beta treatment

Multiple Sclerosis Journal ◽

10.1177/1352458510393263 ◽

2010 ◽

Vol 17 (5) ◽

pp. 513-520 ◽

Cited By ~ 12

Author(s):

Roberto Alvarez-Lafuente ◽

Fiona Blanco-Kelly ◽

Marta Garcia-Montojo ◽

Alfonso Martínez ◽

Virginia De Las Heras ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mrna Expression ◽

Interferon Beta ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Multiple Sclerosis Patients ◽

Spanish Cohort ◽

Independent Cohort

Background: In a prior study of our group we found an up-regulation of CD46 expression in a cohort of Spanish multiple sclerosis (MS) patients. Objective: To evaluate the potential role of CD46 in the response to interferon-beta treatment in MS patients through the analysis of five tagging single nucleotide polymorphisms (SNPs) and measurement of mRNA. Methods: A total of 406 MS patients and 513 control patients were analysed for five SNPs at the CD46 locus. Furthermore, 163 MS patients and 163 matched control patients were analysed by RT-PCR for the CD46 mRNA expression in three blood samples (basal, and at 6 and 12 months of interferon-beta treatment) collected in the course of a 1-year follow-up. Results: Two genotypes of rs2724385 polymorphism (AT and TT) could be markers of response to interferon-beta therapy in MS patients ( p = 0.007 and p = 0.006, respectively). Furthermore, the frequency of interferon-beta responders was 44.4% (32/72) in MS patients with an increased CD46 mRNA expression, vs. 65.9% (60/91) in patients with a decreased CD46 mRNA expression ( p = 0.006). Conclusion: The present study shows that CD46 could be associated with the response to interferon-beta therapy; however, the genetic results should be replicated in an independent cohort and further studies are needed to confirm the role of CD46.

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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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