The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine.

BACKGROUND: Interactions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. METHODS: The case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. RESULTS: Patients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. CONCLUSION: The MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.

Neutrophil to lymphocyte ratio and systemic immune-inflammatory index as markers of response to autologous hematopoietic stem cell transplantation in persons with multiple sclerosis.

INTRODUCTION: Biomarkers that help to evaluate the immune system and could be useful in multiple sclerosis (MS) are the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammatory index (SII). The objective of this work is to evaluate the significance of the SII index, PLR, and NLR before and after transplantation in individuals with MS who underwent autologous hematopoietic stem cell transplant (aHSCT) at a single institution. METHODS: Patients with MS who received an aHSCT between 2017 and 2022 were included in the study. NLR, PLR, and SII index were calculated prior to the transplant and 100 days after, and evaluation of the expanded disability status scale (EDSS) was done before the transplant and 12 months after. The cohort was divided into two groups: aHSCT responders (R) and nonresponders (NR). RESULTS: Fifty-eight individuals were examined: 37 patients in the responders group R group and 21 in NR group. There was no statistically significant difference in the SII, NLR, and PLR prior to the transplant, however at 100 days post-HSCT, NLR in the R group was 1.8 versus 3.1 in the NR group (p = 0.003), PLR was 194 versus 295, respectively (p = 0.024), meanwhile SII index was 489.5 versus 729.3 (p < 0.001). CONCLUSION: High NLR and SII index values after the aHSCT were associated with a worsening in the EDSS score. However, since this is the first ever study that compared NLR and SII index with the aHSCT response in persons with MS, further studies must be performed to corroborate this information.

Advanced Oxidative Protein Products Role in Multiple Sclerosis: a Systematic Review and Meta-analysis.

Multiple sclerosis (MS) is an autoimmune-mediated disease that damages the central nervous system. MS pathophysiological features are not entirely understood, but the increase of reactive oxygen species (ROS) possibly causes myelin and oligodendrocyte degeneration. ROS-increased production generates new compounds through oxidative modifications, including advanced oxidative protein products (AOPPs). The AOPPs are oxidative stress biomarkers and inflammatory mediators commonly formed by hypochlorous acid oxidative action on albumin. Considering that AOPPs accumulation produces ROS and induces neuronal apoptosis, these may represent a new target for drug development to MS treatment and a possible biomarker to monitor the severity of the disease. Thus, this review aims to investigate if there is an alteration in the AOPPs levels in MS and its possible involvement in patient disability. The second objective is to analyze whether drugs or compounds used in MS treatment could modify the AOPPs levels. The protocol was registered in PROSPERO (CRD42020203268). The databases' search yielded 327 articles. We excluded 259 duplicated articles and evaluated 68 articles by the title and abstract. We full-text analyzed 17 articles and included 13 articles. The AOPPs levels were increased in not-treated MS patients. Furthermore, the increase in disability status was associated with AOPPs accumulation in not-treated MS patients. Additionally, the AOPPs levels were reduced in MS patients after treatment. Therefore, AOPPs seem to play a role in MS pathophysiology and may become a new target for drug development and help MS diagnosis or treatment follow-up.

A preliminary study of the concentration of metallic elements in the blood of patients with multiple sclerosis as measured by ICP-MS.

It is estimated that multiple sclerosis (MS) affects 35,000 Brazilians and 2.5 million individuals worldwide. Many studies have suggested a possible role of metallic elements in the etiology of MS, but their concentration in the blood of MS patients is nonetheless little investigated in Brazil. In this work, these elements were studied through Inductively Coupled Plasma Mass Spectrometry (ICP-MS), whose analysis provides a tool to quantify the concentrations of metal elements in the blood samples of individuals with neurodegenerative disorders. This study aimed to compare the concentration of metallic elements in blood samples from patients with MS and healthy individuals. Blood was collected from 30 patients with multiple sclerosis and compared with the control group. Blood samples were digested in closed vessels using a microwave and ICP-MS was used to determine the concentrations of 12 metallic elements (Ba, Be, Ca, Co, Cr, Cu, Fe, Mg, Mo, Ni, Pb and Zn). In MS patients, we observed a reduction in the concentrations of beryllium, copper, chromium, cobalt, nickel, magnesium and iron. The mean concentration of lead in blood was significantly elevated in the MS group. However, no difference was observed in the concentrations of Mo, Ba, Ca and Zn in blood samples from MS patients and the control group. According to our data, there is a possible role for the concentrations of 8 of the 12 evaluated metallic elements in multiple sclerosis. Abnormalities in transition metals levels in biological matrices have been reported in several neurological diseases.

Serum levels of matrix metalloproteinase-2, -9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity.

In recent years, extreme attention has been focused on the role of human herpesvirus-6 (HHV-6) in multiple sclerosis (MS) pathogenesis. However, the pathogenesis of MS associated with HHV-6 infection remains unknown. In this study, we measured the serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection. Five hundred sixty (including 300 females and 260 males) MS patients along with 560 healthy subjects were analyzed for HHV-6 seropositivity using enzyme-linked immunosorbent assay (ELISA). Subsequently, we measured the serum levels of MMP-2, MMP-9, and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection by ELISA. About 90.7% of MS patients (508/560) were seropositive for HHV-6, while 82.3% (461/560) of healthy subjects were seropositive for this virus (p = 0.001). Moreover, there was a significant increase in the levels of MMP-2, MMP-9, and lower vitamin D in the serum samples of MS patients when compared with healthy subjects. Additionally, we demonstrated that the MMP-9 levels in seropositive MS patients were significantly higher than seronegative MS patients (p =  0.001). Finally, our results demonstrated that the mean of expanded disability status scale (EDSS) in seropositive MS patients was significantly higher in comparison to seronegative MS patients (p < 0.05). In conclusion, we suggest that the HHV-6 infection may play a role in MS pathogenesis.

Serum levels of matrix metalloproteinase-2, -9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity

ABSTRACT In recent years, extreme attention has been focused on the role of human herpesvirus-6 (HHV-6) in multiple sclerosis (MS) pathogenesis. However, the pathogenesis of MS associated with HHV-6 infection remains unknown. In this study, we measured the serum levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection. Five hundred sixty (including 300 females and 260 males) MS patients along with 560 healthy subjects were analyzed for HHV-6 seropositivity using enzyme-linked immunosorbent assay (ELISA). Subsequently, we measured the serum levels of MMP-2, MMP-9, and vitamin D levels in MS patients with HHV-6 infection and MS patients without HHV-6 infection by ELISA. About 90.7% of MS patients (508/560) were seropositive for HHV-6, while 82.3% (461/560) of healthy subjects were seropositive for this virus (p = 0.001). Moreover, there was a significant increase in the levels of MMP-2, MMP-9, and lower vitamin D in the serum samples of MS patients when compared with healthy subjects. Additionally, we demonstrated that the MMP-9 levels in seropositive MS patients were significantly higher than seronegative MS patients (p = 0.001). Finally, our results demonstrated that the mean of expanded disability status scale (EDSS) in seropositive MS patients was significantly higher in comparison to seronegative MS patients (p < 0.05). In conclusion, we suggest that the HHV-6 infection may play a role in MS pathogenesis.

Antioxidant and Anti-inflammatory Diagnostic Biomarkers in Multiple Sclerosis: A Machine Learning Study.

An imbalance of inflammatory/anti-inflammatory and oxidant/antioxidant molecules has been implicated in the demyelination and axonal damage in multiple sclerosis (MS). The current study aimed to evaluate the plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, sTNFR2, adiponectin, hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites, total plasma antioxidant capacity using the total radical-trapping antioxidant parameter (TRAP), sulfhydryl (SH) groups, as well as serum levels of zinc in 174 MS patients and 182 controls. The results show that MS is characterized by lowered levels of zinc, adiponectin, TRAP, and SH groups and increased levels of AOPP. MS was best predicted by a combination of lowered levels of zinc, adiponectin, TRAP, and SH groups yielding an area under the receiver operating characteristic (AUC/ROC) curve of 0.986 (±0.005). The combination of these four antioxidants with sTNFR2 showed an AUC/ROC of 0.997 and TRAP, adiponectin, and zinc are the most important biomarkers for MS diagnosis followed at a distance by sTNFR2. Support vector machine with tenfold validation performed on the four antioxidants showed a training accuracy of 92.9% and a validation accuracy of 90.6%. The results indicate that lowered levels of those four antioxidants are associated with MS and that these antioxidants are more important biomarkers of MS than TNF-α signaling and nitro-oxidative biomarkers. Adiponectin, TRAP, SH groups, zinc, and sTNFR2 play a role in the pathophysiology of MS, and a combination of these biomarkers is useful for predicting MS with high sensitivity, specificity, and accuracy. Drugs that increase the antioxidant capacity may offer novel therapeutic opportunities for MS.

Brain and spinal MRI features distinguishing MS from different AQP4 antibody serostatus NMOSD at disease onset in a cohort of Latin American patients.

OBJECTIVE: We aimed to evaluate magnetic resonance imaging (MRI) previously used criteria (Matthews's criteria, MC) for differentiating multiple sclerosis (MS) from neuromyelitis optica spectrum disorders (NMOSD) in Caucasian and non-Caucasian populations (Argentina, Brazil and Venezuela) with positive (P-NMOSD), negative (N-NMOSD), and unknown (U-NMOSD) aquaporin-4 antibody serostatus at disease onset and to assess the added diagnostic value of spinal cord MRI in these populations. METHODS: We reviewed medical records, and MRIs were assessed by two blinded evaluators and were scored using MC. Short-segment transverse myelitis (STM) was added as a new criterion. MC sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined. RESULTS: We included 282 patients (MS = 188 and NMOSD = 94). MC applied to the entire cohort showed 97.8% sensitivity, 82.9% specificity, 92.0% PPV, and 95.1% NPV for differentiating MS from NMOSD. A subanalysis applied only to non-Caucasian (MS = 89 and NMOSD = 47) showed 100% sensitivity, 80.8% specificity, 90.8% PPV, and 100% NPV. Similar sensitivity, specificity, PPV, and NPV of MC for MS versus P-NMOSD (n = 55), N-NMOSD (n = 28), and U-NMOSD (n = 21) were observed. CONCLUSION: MC distinguished MS from NMOSD of all serostatus in a Latin American cohort that included non-Caucasian populations. Addition of STM to MC did not raise the accuracy significantly.

A highly specific and sensitive nanoimmunosensor for the diagnosis of neuromyelitis optica spectrum disorders.

A precise diagnosis for neuromyelitis optica spectrum disorders (NMOSD) is crucial to improve patients' prognostic, which requires highly specific and sensitive tests. The cell-based assay with a sensitivity of 76% and specificity of 100% is the most recommended test to detect anti-aquaporin-4 antibodies (AQP4-Ab). Here, we tested four AQP4 external loop peptides (AQP461-70, AQP4131-140, AQP4141-150, and AQP4201-210) with an atomic force microscopy nanoimmunosensor to develop a diagnostic assay. We obtained the highest reactivity with AQP461-70-nanoimunosensor. This assay was effective in detecting AQP4-Ab in sera of NMOSD patients with 100% specificity (95% CI 63.06-100), determined by the cut-off adhesion force value of 241.3 pN. NMOSD patients were successfully discriminated from a set of healthy volunteers, patients with multiple sclerosis, and AQP4-Ab-negative patients. AQP461-70 sensitivity was 81.25% (95% CI 56.50-99.43), slightly higher than with the CBA method. The results with the AQP461-70-nanoimmunosensor indicate that the differences between NMOSD seropositive and seronegative phenotypes are related to disease-specific epitopes. The absence of AQP4-Ab in sera of NMOSD AQP4-Ab-negative patients may be interpreted by assuming the existence of another potential AQP4 peptide sequence or non-AQP4 antigens as the antibody target.

Multiple sclerosis has a distinct lipid signature in plasma and cerebrospinal fluid.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) has changed over the last decade, but remains a composite of clinical assessment and magnetic resonance imaging to prove dissemination of lesions in time and space. The intrathecal synthesis of immunoglobulin may be a nonspecific marker and there are no plasma biomarkers that are useful in the diagnosis of MS, presenting additional challenges to their early detection. METHODS: We performed a preliminary untargeted qualitative lipidomics mass spectrometry analysis, comparing cerebrospinal fluid (CSF) and plasma samples from patients with MS, other inflammatory neurological diseases and idiopathic intracranial hypertension. RESULTS: Lipid identification revealed that fatty acids and sphingolipids were the most abundant classes of lipids in the CSF and that glycerolipids and fatty acids were the main class of lipids in the plasma of patients with MS. The area under the curve was 0.995 (0.912-1) and 0.78 (0.583-0.917), respectively. The permutation test indicated that this ion combination was useful for distinguishing MS from other inflammatory diseases (p < 0.001 and 0.055, respectively). CONCLUSION: This study concluded that the CSF and plasma from patients with MS bear a unique lipid signature that can be useful as a diagnostic biomarker.

Multiple sclerosis has a distinct lipid signature in plasma and cerebrospinal fluid / Esclerose múltipla tem uma assinatura lipídica distinta no plasma e no líquido cefalorraquiano

ABSTRACT The diagnosis of multiple sclerosis (MS) has changed over the last decade, but remains a composite of clinical assessment and magnetic resonance imaging to prove dissemination of lesions in time and space. The intrathecal synthesis of immunoglobulin may be a nonspecific marker and there are no plasma biomarkers that are useful in the diagnosis of MS, presenting additional challenges to their early detection. Methods We performed a preliminary untargeted qualitative lipidomics mass spectrometry analysis, comparing cerebrospinal fluid (CSF) and plasma samples from patients with MS, other inflammatory neurological diseases and idiopathic intracranial hypertension. Results Lipid identification revealed that fatty acids and sphingolipids were the most abundant classes of lipids in the CSF and that glycerolipids and fatty acids were the main class of lipids in the plasma of patients with MS. The area under the curve was 0.995 (0.912-1) and 0.78 (0.583-0.917), respectively. The permutation test indicated that this ion combination was useful for distinguishing MS from other inflammatory diseases (p < 0.001 and 0.055, respectively). Conclusion This study concluded that the CSF and plasma from patients with MS bear a unique lipid signature that can be useful as a diagnostic biomarker.

RESUMO Embora o diagnóstico da EM tenha se modificado na última década, ainda tem como requisito básico a demonstração da disseminação no tempo e no espaço, através do quadro clínico e do exame de ressonância magnética. A síntese intratecal de imunoglobulina pode ser um marcador inespecífico e não há biomarcadores plasmáticos que sejam úteis no diagnóstico da EM, impondo desafios à sua detecção precoce. Métodos Realizamos uma análise lipidômica preliminar por espectrometria de massas, não direcionada, qualitativa, comparando amostras de LCR e plasma de pacientes com EM, outras doenças neurológicas inflamatórias e hipertensão intracraniana idiopática (HII). Resultados A identificação lipídica revelou que os ácidos graxos e esfingolipídios foram as classes mais abundantes de lipídios no LCR e que glicerolipídios e ácidos graxos foram a principal classe de lipídios no plasma de pacientes com EM. A AUC foi de 0,995 (0,912-1) e 0,78 (0,583-0,917), respectivamente. O teste de permutação indicou que essa combinação de íons foi útil para distinguir a EM de outras doenças inflamatórias (p < 0,001 e 0,055, respectivamente). Conclusão Este estudo sugere que o líquido cefalorraquidiano (LCR) e o plasma de pacientes com EM possuem uma assinatura lipídica única, pode ser útil como um biomarcador diagnóstico.

The rs3761548 FOXP3 variant is associated with multiple sclerosis and transforming growth factor ß1 levels in female patients.

OBJECTIVE: The aim of this study was to evaluate the association between rs3761548 FOXP3 (-3279 C > A) variant and multiple sclerosis (MS), disability, disability progression, as well as transforming growth factor (TGF)-ß1 and interleukin (IL)-10 plasma levels in MS patients. METHODS AND SUBJECTS: The study included 170 MS patients and 182 controls. Disability was evaluated using Expanded Disability Status Scale (EDSS) and categorized as mild (EDSS ≤ 3) and moderate/high (EDSS > 3). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS). The rs3761548 variant was determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma levels of TGF-ß1 and IL-10 were determined using immunofluorimetric assay. RESULTS: CA and AA genotypes were associated with MS [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.66-3.53, p = 0.012; OR 8.19, 95% CI 3.04-22.07, p < 0.001, respectively). With the dominant model, the CA + AA genotypes were associated with MS (OR 2.57, 95% CI 1.50-4.37, p < 0.001). In the recessive model, the AA genotype was also associated with MS (OR 5.38, 95% CI 2.12-13.64, p < 0.001). After adjustment by age, ethnicity, BMI and smoking, all these results remained significant, as well as female patients carrying the CA + AA genotypes showed higher TGF-ß1 than those carrying the CC genotype (OR 1.35, 95% CI 1.001-1.054, p = 0.043). No association was observed between the genotypes and disability, disability progression and IL-10 levels. CONCLUSION: These results suggest that the A allele of FOXP3 -3279 C > A variant may exert a role in the T regulatory cell function, which could be one of the factors involved in the susceptibility for MS in females.

Disability in multiple sclerosis is associated with age and inflammatory, metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures.

The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS.

Neurofilament light chain in the assessment of patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune, inflammatory, and degenerative disease of the central nervous system. Axonal degeneration is triggered by inflammation and is the pathological substrate of progressive disability in patients with MS. Therapeutic interventions can reduce inflammatory activity, thus delaying neurodegeneration and the progression of disability. Disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and accuracy, so new biomarkers are necessary. Several markers have been studied and to date the most promising is neurofilament light (NfL), a component of the axonal cytoskeleton, which is released into cerebrospinal fluid (CSF) following axonal damage. In the present study, we review the current knowledge about CSF NfL determination in MS, clinically isolated syndrome, and radiologically isolated syndrome, and critically discuss how CSF NfL measurement may contribute to therapeutic decision-making in these patients.

Neurofilament light chain in the assessment of patients with multiple sclerosis / Neurofilamento de cadeia leve na avaliação de pacientes com esclerose múltipla

ABSTRACT Multiple sclerosis (MS) is an autoimmune, inflammatory, and degenerative disease of the central nervous system. Axonal degeneration is triggered by inflammation and is the pathological substrate of progressive disability in patients with MS. Therapeutic interventions can reduce inflammatory activity, thus delaying neurodegeneration and the progression of disability. Disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and accuracy, so new biomarkers are necessary. Several markers have been studied and to date the most promising is neurofilament light (NfL), a component of the axonal cytoskeleton, which is released into cerebrospinal fluid (CSF) following axonal damage. In the present study, we review the current knowledge about CSF NfL determination in MS, clinically isolated syndrome, and radiologically isolated syndrome, and critically discuss how CSF NfL measurement may contribute to therapeutic decision-making in these patients.

RESUMO A esclerose múltipla (EM) é uma doença autoimune, inflamatória e degenerativa do sistema nervoso central. A degeneração axonal é deflagrada pelo processo inflamatório e é o substrato patológico da incapacidade na EM. As intervenções terapêuticas reduzem a inflamação retardando a neurodegeneração e a progressão da incapacidade. A neurodegeneração é avaliada pelo quadro clínico e pela ressonância magnética. Estas mensurações não suficientemente acuradas, havendo necessidade de novos biomarcadores. Diversos biomarcadores têm sido estudados e, até o presente, o mais promissor é o neurofilamento de cadeia leve (NfL). O mesmo é um componente do citoesqueleto que é liberado no líquido cefalorraquidiano após injúria axonal. No presente estudo nós revisamos o conhecimento atual acerca do NfL na EM, síndrome clinica isolada e síndrome radiológica isolada, discutindo criticamente como a determinação deste biomarcador pode contribuir na tomada de decisões clínicas.

Familial multiple sclerosis in a Brazilian sample: Is HLA-DR15 involved in susceptibility to the disease?

BACKGROUND: The HLA-DR15 extended haplotype HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 comprises the strongest genetic risk factor for multiple sclerosis (MS). The aim of this work was to investigate whether HLA-DR15 alleles were significantly associated with the susceptibility to MS familial forms (MSf) in an admixed Brazilian population. METHODS: Association analyses between DR15 and the clinical and demographic variables were made. RESULTS: We have genotyped 25 familial cases. The DR15 was detected in 11/25 (44%) of them and in none of controls (P < .00001). DR15 was significantly associated to a foreign ancestor background (P = .029) and later age of onset (P = .018).

Variants in NLRP3 and NLRC4 inflammasome associate with susceptibility and severity of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a neurodegenerative disease of central nervous system (CNS) with autoimmune and inflammatory characteristics, and a still uncertain pathogenesis. Early events as well as evolution of MS are heterogeneous (three main clinical forms) and multifactorial. Genome-wide association studies indicate that MS pathogenesis shares features with both autoimmune and inflammatory diseases. Innate immunity has been recently proved to be an important factor in MS. Genetic variants in inflammasome components have been associated with both autoimmune and neurodegenerative diseases, letting us hypothesize that inflammasome, and related cytokines IL-1ß and IL-18, could represent important contributors in MS pathogenesis, and eventually explain, at least in part, the heterogeneity observed in MS patients. AIM: To evaluate the contribution of inflammasome in MS, in term of (a) genetic effect on development, severity and/or prognosis, and (b) complex activation in peripheral blood as a measure of systemic inflammation. METHODS: Functional genetic variants in inflammasome components were analyzed in a cohort of MS patients, by the use of allele-specific assays and qPCR. Multivariate analysis was performed based on clinical form (recurrent remittent/RR, primary progressive/PP or secondary progressive/SP), severity index (EDSS) and progression index (PI), response to IFN-ß treatment. Peripheral blood monocytes (PBM) of patients were examined for inflammasome activation and expression profile. RESULTS AND DISCUSSION: Variants associated with low serum levels of IL-18 were significantly less frequent in MS patients than in controls, suggesting a protective role of diminished IL-18-mediate inflammation in MS development. On the other hands, gain-of-function variants in NLRP3 (Q705K) and IL1B (-511 C >T) associated with severity and progression of MS, suggesting that a constitutive activation of NLRP3 inflammasome could represent a risk factor for MS clinical presentation. Accordingly, -511C >T SNP resulted more frequent in progressive forms than in RR MS, reinforcing the idea that increased inflammasome activation characterized bad prognosis of MS. Altogether these findings corroborate previous data about the harmful role of NLRP3 inflammasome in experimental autoimmune encephalitis (EAE). Moreover, we reported for the first time the beneficial effect of NLRC4 rs479333 G >C variant in MS progression and in the response to IFN-ß treatment. This intronic polymorphism have been previously associated to decreased NLRC4 transcription and low IL-18 serum level, indicated once more that less activation of inflammasome and IL-18 production are beneficial for MS patients. PBM analysis showed that MS cells express higher level of inflammasome genes than HD ones, and are more prone to respond to a classical NLRP3 stimulus than HD.

Serological profile of John Cunningham virus (JCV) in patients with multiple sclerosis.

Treatment options for multiple sclerosis (MS) have changed over the last few years, bringing about a new category of drugs with more efficient profiles. However, these drugs have come with a whole new profile of potential adverse events that neurologists have to learn well and quickly. One of the most feared complications of these MS treatments is progressive multifocal leukoencephalopathy caused by the reactivation of the John Cunningham virus (JCV). OBJECTIVE: To identify the serologic profile of JCV in patients with MS. METHODS: Data on serum antibodies for JCV were obtained using the enzyme-linked immunosorbent assay provided by the STRATIFY-JCV program. RESULTS: A total of 1,501 blood tests were obtained from 1,102 patients with MS. There were 633 patients (57.1%) who were positive for antibodies for JCV and 469 patients who were negative (42.9%). Twenty-three patients became positive after initially having negative JCV antibody status. The rate of seroconversion was 18.5% over 22 months. CONCLUSION: The JCV serologic profile and seroconversion in Brazilian patients were similar to those described in other countries.

Serological profile of John Cunningham virus (JCV) in patients with multiple sclerosis / Perfil sorológico do vírus John Cunningham (JCV) em pacientes com esclerose múltipla

ABSTRACT Treatment options for multiple sclerosis (MS) have changed over the last few years, bringing about a new category of drugs with more efficient profiles. However, these drugs have come with a whole new profile of potential adverse events that neurologists have to learn well and quickly. One of the most feared complications of these MS treatments is progressive multifocal leukoencephalopathy caused by the reactivation of the John Cunningham virus (JCV). Objective: To identify the serologic profile of JCV in patients with MS. Methods: Data on serum antibodies for JCV were obtained using the enzyme-linked immunosorbent assay provided by the STRATIFY-JCV program. Results: A total of 1,501 blood tests were obtained from 1,102 patients with MS. There were 633 patients (57.1%) who were positive for antibodies for JCV and 469 patients who were negative (42.9%). Twenty-three patients became positive after initially having negative JCV antibody status. The rate of seroconversion was 18.5% over 22 months. Conclusion: The JCV serologic profile and seroconversion in Brazilian patients were similar to those described in other countries.

RESUMO As opções terapêuticas para esclerose múltipla (EM) modificaram-se ao longo dos últimos anos, trazendo uma nova categoria de drogas com melhor perfil de eficácia. No entanto, estas drogas vieram com um novo perfil de potenciais eventos adversos que exigem que o neurologista os reconheça bem e rapidamente. Uma das complicações mais temidas destes tratamentos para a EM é a leucoencefalopatia multifocal progressiva (LEMP), causada pela reativação do vírus John Cunningham (JCV). Objetivo: Identificar o perfil sorológico de JCV em pacientes com EM. Métodos: Dados sorológicos de JCV foram obtidos através do ensaio por enzimas imuno-adsorvidas (ELISA) fornecido pelo programa STRATIFY-JCV. Resultados: Um total de 1.501 testes sanguíneos foram obtidos de 1.102 pacientes com EM. O grupo teve 633 pacientes (57,1%) soropositivos para anticorpos anti-JCV e 469 pacientes negativos (42,9%). Vinte e três pacientes se tornaram posivitos após resultados iniciais negativos para anticorpos anti-JCV. A taxa de soroconversão foi 18,5% em 22 meses. Conclusão: O perfil sorológico do JCV e a soroconversão nos pacientes brasileiros foi semelhante àquela descrita em outros países.

BDNF and Tau as biomarkers of severity in multiple sclerosis.

AIM: Determine if serum levels of tau and BDNF can be used as severity biomarkers in multiple sclerosis (MS). PATIENTS & METHODS: Subjects with MS, older than 18 and younger than 55 years old were included; 74 patients with a diagnosis of relapsing-remitting MS, 11 with secondary-progressive MS, and 88 controls were included. Total tau and BDNF were measured by Western blot. RESULTS: Increased tau and decreased BDNF in MS patients compared with controls was found. Total-tau has a peak in relapsing-remitting MS, the second decile of the multiple sclerosis severity score, and in the lowest expanded disability status scale and is no different than controls for secondary-progressive MS patients and the most severe cases of MS. CONCLUSION: BDNF is a good biomarker for diagnosis of MS but not for severity or progression. Tau appears to have a more active role in the progression of MS.