European Ancestry Predominates in Neuromyelitis Optica and Multiple Sclerosis Patients from Brazil

Background: Neuromyelitis optica (NMO) is considered relatively more common in non-Whites, whereas multiple sclerosis (MS) presents a high prevalence rate, particularly in Whites from Western countries populations. However, no study has used ancestry informative markers (AIMs) to estimate the genetic ancestry contribution to NMO patients. Methods: Twelve AIMs were selected based on the large allele frequency differences among European, African, and Amerindian populations, in order to investigate the genetic contribution of each ancestral group in 236 patients with MS and NMO, diagnosed using the McDonald and Wingerchuck criteria, respectively. All 128 MS patients were recruited at the Faculty of Medicine of Ribeirão Preto (MS-RP), Southeastern Brazil, as well as 108 healthy bone marrow donors considered as healthy controls. A total of 108 NMO patients were recruited from five Neurology centers from different Brazilian regions, including Ribeirão Preto (NMO-RP). Principal Findings: European ancestry contribution was higher in MS-RP than in NMO-RP (78.5% vs. 68.7%) patients. In contrast, African ancestry estimates were higher in NMO-RP than in MS-RP (20.5% vs. 12.5%) patients. Moreover, principal component analyses showed that groups of NMO patients from different Brazilian regions were clustered close to the European ancestral population. Conclusions: Our findings demonstrate that European genetic contribution predominates in NMO and MS patients from Brazil. © 2013 Brum et al.

Frequency of reported European ancestry among multiple sclerosis patients from four cities in the southern and southeastern regions of Brazil

Recent reports on the prevalence of multiple sclerosis (MS) have described discrepancies between the rates in cities in the northeastern and southeastern regions of Brazil, representing a north-south gradient. European immigrants settled in southeastern and southern Brazil at the beginning of the twentieth century. In this study, we report the frequency of European ancestors among Brazilian MS patients in four cities in the southern and southeastern regions of Brazil. Methods: A total of 652 consecutive patients with confirmed MS diagnoses seen at four centers in Belo Horizonte, Ribeirão Preto, Londrina and Santos were asked about the origin of their ancestors, going back three generations. Results: 287 (44%) reported Italian ancestry, 211 (32%) reported that all ancestors were born in Brazil, 49 (7.5%) had Portuguese ancestry and 70 (10%) had Spanish ancestry. The patients in Belo Horizonte and Londrina reported higher proportions of Italian ancestry than the proportions estimated for the populations of their respective States. Conclusion: Brazil has a north-south gradient of 0.91/100,000 per degree of latitude, which is higher than the gradient for Latin America. Since the largest immigrant group that settled in southern and southeastern Brazil was from Italy, it is possible that Italian immigration was one of the factors that have contributed toward increasing the prevalence of MS in these regions. © 2013 Elsevier B.V. All rights reserved.

Season of birth as a risk factor for multiple sclerosis in Brazil

Risk factors for development of multiple sclerosis (MS) are still a matter of debate. Latitude gradient, vitamin D deficiency and season of birth are among the most investigated environmental factors associated with the disease. Several international studies suggest that birth in spring is a substantial risk factor for MS. We investigated the season of birth as a potential risk for MS in different geographical regions of Brazil. We conducted a cross-sectional retrospective study with 2257 clinically definite MS patients enrolled in 13 Brazilian MS clinics in the south, southeast, and northeast regions of Brazil. Demographic and clinical data relating to date of birth and clinical features of the disease were collected and analysed, and subsequently compared with birth date among the general Brazilian population. The distribution of date of birth of MS patients showed an increase in spring and a decrease in autumn, with no difference being observed in the other seasons. In conclusion, season of birth is a probable risk factor for MS in most parts of Brazil. These findings may be related to the role that vitamin D plays in MS pathogenesis. © 2013 Elsevier B.V. All rights reserved.

Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis: Consensus of the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology

A esclerose múltipla (EM) é uma doença inflamatória, autoimune, desmielinizante e degenerativa do sistema nervoso central. Estudos epidemiológicos têm identificado associações de hipovitaminose D com doenças autoimunes. O principal objetivo desta revisão é responder se há evidências que indiquem o uso terapêutico de vitamina D em monoterapia para pacientes com EM. Por meio dos sites PUBMED, EMBASE, LILACS e Scielo foram realizadas buscas usando os descritores “vitamin D”, e “multiple sclerosis” até 12/09/2013. Estudos clínicos randomizados, controlados e duplo-cegos foram selecionados para avaliar a resposta terapêutica da vitamina D na EM. Não foram encontradas evidências científicas que justifiquem o uso da vitamina D em monoterapia no tratamento da EM, na prática clínica.

Translation, cross-cultural adaptation and validation of the Portuguese version of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis

Translation, cross-cultural adaptation and validation of the DYMUS questionnaire for the assessment of dysphagia in multiple sclerosis. The original English version of the DYMUS was translated using the forward-backward technique, cross-culturally adaptated, pilot-tested in 40 patients, and then applied to 100 multiple sclerosis patients to assess the reliability and construct validity. Construct validity was assessed by Mann–Whitney test and Spearman’s correlation coefficient (rs). The internal consistency of the questionnaire was evaluated using Cronbach’s alpha coefficient and inter-item correlation. DYMUS-BR internal consistency was high (Cronbach’s alpha= 0.72); Cronbach’s alpha was 0.65 for the ‘dysphagia for solids’ subscale and 0.67 for the ‘dysphagia for liquids’ subscale and positive inter-item correlations was found between all items, except for weight loss question. Significant association (p<0.001) and correlation (rs = 0,357; p = 0.01) was found between DYMUS-BR and dysphagia self-assessment. The DYMUS-BR questionnaire maintained the characteristics of that originally described, demonstrating to be a reliable, valid, easy and consistent tool to be used by health professionals for preliminary selection of Brazilian MS patients who need more specific instrumental analyses of swallowing.

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C- T-1562 and (CA)(n) polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4 +/- 0.18 versus 0.93 +/- 0.18 A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96 +/- 0.25 versus 1.21 +/- 0.09 A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT + TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL Drug therapy resistance, disease severity. MMP-9 plasma activity and polymorphisms are associated with MS. (C) 2012 Elsevier B.V. All rights reserved.

Quantification of Retinal Neural Loss in Patients with Neuromyelitis Optica and Multiple Sclerosis with or without Optic Neuritis Using Fourier-Domain Optical Coherence Tomography

PURPOSE. We compared retinal nerve fiber layer (RNFL) and macular thickness measurements in patients with multiple sclerosis (MS) and neuromyelitis optica (NMO) with or without a history of optic neuritis, and in controls using Fourier-domain (FD) optical coherence tomography (OCT). METHODS. Patients with MS (n = 60), NMO (n = 33), longitudinal extensive transverse myelitis (LETM, n = 28) and healthy controls (n = 41) underwent ophthalmic examination, including automated perimetry, and FD-OCT RNFL and macular thickness measurements. Five groups of eyes were compared: MS with or without previous optic neuritis, NMO, LETM, and controls. Correlation between OCT and visual field (VF) findings was investigated. RESULTS. With regard to most parameters, RNFL and macular thickness measurements were significantly smaller in eyes of each group of patients compared to controls. MS eyes with optic neuritis did not differ significantly from MS eyes without optic neuritis, but measurements were smaller in NMO eyes than in all other groups. RNFL (but not macular thickness) measurements were significantly smaller in LETM eyes than in controls. While OCT abnormalities were correlated significantly with VF loss in NMO/LETM and MS, the correlation was much stronger in the former. CONCLUSIONS. Although FD-OCT RNFL and macular thickness measurements can reveal subclinical or optic neuritis-related abnormalities in NMO-spectrum and MS patients, abnormalities are predominant in the macula of MS patients and in RFNL measurements in NMO patients. The correlation between OCT and VF abnormalities was stronger in NMO than in MS, suggesting the two conditions differ regarding structural and functional damage. (ClinicalTrials.gov number, NCT01024985.) Invest Ophthalmol Vis Sci. 2012;53:3959-3966) DOI:10.1167/iovs.11-9324

miR-15a and 16-1 Are Downregulated in CD4(+) T Cells of Multiple Sclerosis Relapsing Patients

The pathology of relapsing-remitting multiple sclerosis (RR-MS) is largely attributed to activated autoreactive effector T lymphocytes. The influence of microRNAs on the immune response has been shown to occur in different pathways of lymphocyte differentiation and function. Here, the expression of the miRNAs miR-15a/161 in PBMC, CD4(+), and CD8(+) from RR-MS patients has been investigated. BCL2, a known miR-15a/16-1 target, has also been analyzed. The results have shown that miR-15a/16-1 is downregulated in CD4(+) T cells, whereas BCL2 is highly expressed in RR-MS patients only. Our data suggest that miR-15a/16-1 can also modulate the BCL2 gene expression in CD4(+) T cells from RR-MS patients, thereby affecting apoptosis processes.

Comparison of Visual Acuity and Automated Perimetry Findings in Patients With Neuromyelitis Optica or Multiple Sclerosis After Single or Multiple Attacks of Optic Neuritis

Objective: To review the clinical characteristics of patients with neuromyelitis optica (NMO) and to compare their visual outcome with those of patients with optic neuritis (ON) and multiple sclerosis (MS). Methods: Thirty-three patients with NMO underwent neuro-ophthalmic evaluation, including automated perimetry along with 30 patients with MS. Visual function in both groups was compared overall and specifically for eyes after a single episode of ON. Results: Visual function and average visual field (VF) mean deviation were significantly worse in eyes of patients with NMO. After a single episode of ON, the VF was normal in only 2 of 36 eyes of patients with NMO compared to 17 of 35 eyes with MS (P < 0.001). The statistical analysis indicated that after a single episode of ON, the odds ratio for having NMO was 6.0 (confidence interval [CI]: 1.6-21.9) when VF mean deviation was worse than -20.0 dB while the odds ratio for having MS was 16.0 (CI: 3.6-68.7) when better than -3.0 dB. Conclusion: Visual outcome was significantly worse in NMO than in MS. After a single episode of ON, suspicion of NMO should be raised in the presence of severe residual VF deficit with automated perimetry and lowered in the case of complete VF recovery.

Serum levels of brain-derived neurotrophicfactor correlate with the number of T2 MRI lesions in multiple sclerosis

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.

Genomic analysis of ERVWE2 locus in patients with multiple sclerosis: absence of genetic association but potential role of human endogenous retrovirus type W elements in molecular mimicry with myelin antigen

Human endogenous retroviruses (HERVs) arise from ancient infections of the host germline cells by exogenous retroviruses, constituting 8% of the human genome. Elevated level of envelope transcripts from HERVs-W has been detected in CSF, plasma and brain tissues from patients with Multiple Sclerosis (MS), most of them from Xq22.3, 15q21.3, and 6q21 chromosomes. However, since the locus Xq22.3 (ERVWE2) lack the 5' LTR promoter and the putative protein should be truncated due to a stop codon, we investigated the ERVWE2 genomic loci from 84 individuals, including MS patients with active HERV-W expression detected in PBMC. In addition, an automated search for promoter sequences in 20 kb nearby region of ERVWE2 reference sequence was performed. Several putative binding sites for cellular cofactors and enhancers were found, suggesting that transcription may occur via alternative promoters. However, ERVWE2 DNA sequencing of MS and healthy individuals revealed that all of them harbor a stop codon at site 39, undermining the expression of a full-length protein. Finally, since plaque formation in central nervous system (CNS) of MS patients is attributed to immunological mechanisms triggered by autoimmune attack against myelin, we also investigated the level of similarity between envelope protein and myelin oligodendrocyte glycoprotein (MOG). Comparison of the MOG to the envelope identified five retroviral regions similar to the Ig-like domain of MOG. Interestingly, one of them includes T and B cell epitopes, capable to induce T effector functions and circulating Abs in rats. In sum, although no DNA substitutions that would link ERVWE2 to the MS pathogeny was found, the similarity between the envelope protein to MOG extends the idea that ERVEW2 may be involved on the immunopathogenesis of MS, maybe facilitating the MOG recognizing by the immune system. Although awaiting experimental evidences, the data presented here may expand the scope of the endogenous retroviruses involvement on MS pathogenesis