Altered Plasma Metabolic Profiles in Chinese Patients With Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease that leads to the demyelination of nerve axons. An increasing number of studies suggest that patients with MS exhibit altered metabolic profiles, which might contribute to the course of MS. However, the alteration of metabolic profiles in Chinese patients with MS and their potential roles in regulating the immune system remain elusive. In this study, we performed a global untargeted metabolomics approach in plasma samples from 22 MS-affected Chinese patients and 21 healthy subjects. A total of 42 differentially abundant metabolites (DAMs) belonging to amino acids, lipids, and carbohydrates were identified in the plasma of MS patients and compared with those in healthy controls. We observed an evident reduction in the levels of amino acids, such as L-tyrosine, L-isoleucine, and L-tryptophan, whereas there was a great increase in the levels of L-glutamic acid and L-valine in MS-affected patients. The levels of lipid and carbohydrate metabolites, such as sphingosine 1-phosphate and myo-inositol, were also reduced in patients with MS. In addition, the concentrations of proinflammatory cytokines, such as IL-17 and TNF-α, were significantly increased, whereas those of several anti-inflammatory cytokines and chemokines, such as IL-1ra, IL-7, and MIP-1α, were distinctly reduced in the plasma of MS patients compared with those in healthy subjects. Interestingly, some DAMs, such as L-tryptophan and sphingosine 1-phosphate, showed an evident negative correlation with changes in the level of TNF-α and IL-17, while tightly positively correlating with altered concentrations of anti-inflammatory cytokines and chemokines, such as MIP-1α and RANTES. Our results revealed that altered metabolomic profiles might contribute to the pathogenesis and course of MS disease by modulating immuno-inflammatory responses in the peripheral system, which is essential for eliciting autoimmune responses in the central nervous system, thus resulting in the progression of MS. This study provides potential clues for developing therapeutic strategies for MS in the near future.

Characteristics of multiple sclerosis in aboriginals living in British Columbia, Canada.

OBJECTIVES: The objectives of this study were to identify and describe the demographic and clinical characteristics of multiple sclerosis (MS) in aboriginals in British Columbia (BC), Canada and compare these findings with non-aboriginal MS patients. METHODS: This retrospective chart and database review accessed patient information from the linked BC-wide MS clinical and genetics databases. Data gathered included: demographics (age, sex and ethnicity); clinical characteristics (MS onset date, disease course and disability scores (Expanded Disability Status Scale [EDSS]). Aboriginals were identified via the database linkage augmented by physician and nurse recall. Two non-aboriginal comparator groups with definite MS were selected. Group one included all definite MS patients in the BC MS database, and group two comprised MS patients matched by sex, age at onset and initial disease course. Patient characteristics were compared using the Student's t-test, chi-squared test, and Kaplan-Meier survival analysis was used to examine disease progression (time to sustained and confirmed EDSS 6) RESULTS: We identified 26 aboriginals with MS, of which 19/26 (73%) were female, 23/26 (89%) had relapsing-onset MS and a mean onset age of 31.1 years. There were no significant differences between the MS aboriginals and the non-matched (n = 5708) comparator group with respect to age, sex or disease course (p > 0.1), However, aboriginals progressed more rapidly to EDSS 6 from disease onset (p < 0.001) when compared with the matched and unmatched comparator groups. CONCLUSION: We identified a small, but important cohort of aboriginals with MS; being the largest identified to date. There was evidence of more rapid MS progression in aboriginals compared with non-aboriginals.

Differences in the progression of primary progressive multiple sclerosis in Brazilians of African descent versus white Brazilian patients.

Recent studies have suggested faster clinical progression and greater disability in multiple sclerosis patients of African descent. This study analysed the effect of ethnicity on progression and disability. Sixty-five patients with primary progressive multiple sclerosis were selected and classified as being of African descent or white. Time from onset of the disease until reaching Expanded Disability Status Scale grades 3, 6, and 8 was assessed, as well as irreversible disability (Expanded Disability Status Scale grade maintained for >or=6 months). In the African descent group, the median time to reach Expanded Disability Status Scale 3 was 1 year shorter (1 year vs 2 years, p= 0.02), and to reach Expanded Disability Status Scale 6 was 2 years shorter (3 years vs 5 years, p= 0.01) than in the group of white patients. According to the Kaplan-Meier survival curves, patients of African descent reached every disability stage faster than white patients (p= 0.03, p = 0.04, and p = 0.03, respectively, for Expanded Disability Status Scale grades 3, 6, and 8). As in United States and European patients of African descent, the more severe and faster progression of multiple sclerosis seen in Brazilian primary progressive multiple sclerosis patients of African descent suggests a possibly greater effect of ethnicity rather than environment on the progression of multiple sclerosis.

Relationship between Barkhof criteria and the clinical features of multiple sclerosis in northern Japan.

We previously reported that the prevalence of multiple sclerosis (MS) in the Tokachi Province of Hokkaido increased from 8.6 to 13.1 per 100,000 individuals between 2001 and 2006. Here, we study the frequency of MS patients who fulfill the Barkhof criteria and identified their common features. All 47 subjects in our previous study, who fulfilled Poser's criteria, were included in this study. Of these, 33 satisfied the Barkhof criteria. In 2006, 9.2 per 100,000 MS patients fulfilled the Barkhof criteria; the percentage of patients who fulfilled these criteria was significantly higher among patients born after 1960 than among those born before 1960 (84.3% and 40.0%, respectively). The proportion of patients with conventional MS (C-MS) who fulfilled the Barkhof criteria was higher than that of patients with opticospinal MS (OS-MS) who fulfilled these criteria (93.9% and 71.4%, respectively). Longitudinally extensive spinal cord lesions (LESCLs) were not associated with the brain lesions defined in the Barkhof criteria (Barkhof brain lesions). In Tokachi Province, the increased percentage of MS patients who fulfill the Barkhof criteria was associated with increased C-MS incidence and an increase in the proportion of C-MS patients with Barkhof brain lesions among people born after 1960.

Does the DRB1*1501 allele confer more severe and faster progression in primary progressive multiple sclerosis patients? HLA in primary progressive multiple sclerosis.

The effect of HLA alleles on the outcome of multiple sclerosis (MS) has been widely investigated; however, results are conflicting and no consistent correlation has been established. This study evaluated the association between the HLA DR2 haplotype in patients with primary progressive MS (PPMS) and the effect of alleles on progression. An association was found between PPMS and the DR2 and DRB1*1501 and DQB1*0602 alleles. Severe morbidity was found in DRB1*1501-positive PPMS patients. This exploratory study raises new hypotheses for future research and emphasizes the need to investigate possible candidate genes other than HLA that may contribute towards heterogeneity in the course of the disease.

Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese.

BACKGROUND: Antibodies to aquaporin-4 (AQP4) are found in a fraction of Japanese opticospinal multiple sclerosis (OSMS) patients. However, it remains unknown whether anti-AQP4 antibody-positive and negative OSMS patients possess an identical disease. OBJECTIVE: The objective of the current study was to clarify immunological differences between the two groups of patients. METHODS: We studied the serum antibody titers against AQP4 in 191 patients with idiopathic central nervous system demyelinating diseases and clarified their relationships with immunological parameters. RESULTS: Anti-AQP4 antibody positivity rate was higher in patients with OSMS (21/58, 36.2%), idiopathic recurrent myelitis (4/17, 23.5%), and recurrent optic neuritis (7/26, 26.9%), than in conventional MS (CMS) patients (6/90, 6.7%) and patients with other diseases (0/87). Anti-AQP4 antibody titer was significantly higher in patients with SS-A/B antibodies than in those without them. Anti-AQP4 antibody-negative OSMS patients showed significantly higher CD4(+)IFN-gamma(+)IL-4(-)T cell percentages and intracellular IFN-gamma/IL-4 ratios than anti-AQP4 antibody-positive patients, anti-AQP4 antibody-negative CMS patients, and healthy controls, and CD4(+)IFN-gamma(+)IL-4(-)T cell percentages were negatively correlated with anti-AQP4 antibody titers. CONCLUSION: Anti-AQP4 antibody-positive patients are immunologically distinct from anti-AQP4 antibody-negative OSMS patients owing to a Th2 shift in the former group in comparison to a Th1 shift in the latter.

Association between synapsin III gene promoter SNPs and multiple sclerosis in Basque patients.

BACKGROUND: Synapsins are a family of neuron-specific phosphoproteins, one of whose subunits is encoded by the SYN3 gene. This gene is located close to one of the multiple sclerosis susceptibility regions (in 22q13.1). Two single-nucleotide polymorphisms (SNPs) (rs133945 and rs133946) in the promoter region of this gene have been proposed as factors protecting against MS. This relationship is not clear because another report failed to found such association. OBJECTIVES: In an attempt to clarify this association, the frequency of these SNPs was analyzed in a population of 221 Spanish MS patients with a cluster of 72 Basque patients and in 373 controls with a cluster of 138 controls of a Basque origin. METHODS: The SNis analysis was performed by 9 PCR. RESULTS: According to our findings, these SNPs are differently distributed in the two populations. This significant bias should therefore be taken into account in association studies. Our data suggest that the C/C genotype in rs133946 and the G/G genotype in rs133945 could be protecting factors against MS in the Basque population.

Clinical features of patients with multiple sclerosis from a survey in Shanghai, China.

OBJECTIVE: To describe clinical features of patients with multiple sclerosis (MS) in Shanghai, China. METHODS: Prevalent patients with MS were identified and investigated by a network of physicians in 11 districts of Shanghai during the period from 1 September 2004 to 31 August 2005. Admission registries of each hospital in the study area were checked systematically for patients with a diagnosis of MS, neuromyelitis optica or other demyelinating disorders. All patients with collected information were evaluated by four senior neurologists according to the McDonald criteria. RESULTS: There were 249 (146 female and 103 male) patients with a confirmed MS diagnosis, at a female-to-male ratio of 1.4. The mean age at onset of MS was 37.4 years for the 249 patients with MS and, on the prevalence day, 42.7 years. The most frequent location of clinical MS lesions in the central nervous system was the spinal cord (61%), followed by the cerebrum (55%) and optic nerves (41%). Nearly all (96%) of the patients with MS had been examined by magnetic resonance imaging, and 226 (94%) patients of those examined were suggestive of MS. No family history of MS was found in any of the patients. Most (86%) of the patients had no or mild disability on the prevalence day (31 December 2004). Almost all (96%) patients with MS had been treated with corticosteroids. CONCLUSION: Clinical features of patients with MS are described based on the information from the largest case series reported among Chinese. Comparisons and discussions are made with findings from the other populations.

Western and Asian features of multiple sclerosis in Mexican Mestizos.

OBJECTIVES: The objective of this study was to compare the clinical expression of MS in Mexican Mestizos with that of patients of European or Asian descent; as well as to compare the annual frequency of new cases with that observed in the previous decades. PATIENTS AND METHODS: All patients with diagnosis of definite MS seen at the National Institute of Neurology and Neurosurgery of Mexico from January 1993 to December 2003 were studied (n=312). Sociodemographic and clinical characteristics were compared with reports of patients from either Western or Asian origin; the long-term disability score was analyzed according to gender, age of onset of MS and the initial symptom. RESULTS: The clinical expression of MS in Mexican Mestizos shares some characteristics with both, Asian and Western forms of MS indicating that the genetic composition of Mexican Mestizos participates in the clinical expression of the disease. Also, at the prevalence date, the mean age of patients and the duration of the disease were lower in our patients than in MS patients from endemic countries suggesting a true increasing incidence in recent times, rather than only improved case ascertainment. CONCLUSIONS: Clinical expression of MS in Mexican Mestizos shows the coexistence of some features common in European and in Asian cases.

Influence of JC virus coding region genotype on risk of multiple sclerosis and progressive multifocal leukoencephalopathy.

Two features of the biology of JC virus make it a particularly suitable candidate for an agent in MS-like disease: its neurotropic capability targeting glial cells as evidenced in progressive multifocal leukoencephalopathy lesions, and its capacity for latency and persistence as illustrated by its behaviour in the kidney. JC virus is chronically or intermittently excreted in the urine by some 40% of the population. The existence of JC virus in multiple coding-region genotypes provides a unique approach to the study of JC virus-induced neurological disease. We have previously shown that a genotype originating in Asia but also present in Europe and the US, called Type 2B, is more frequently found in PML brain than expected based on its prevalence in urine samples from a control population. In contrast, we find that the excretion of JCV in MS patients is similar in both genotype and frequency to that of control individuals, and appears to be regulated by factors unrelated to those that control CNS disease activity.