Enhancement of balance, and mobility in individuals with multiple sclerosis using visual cue guided multidirectional step training - A pilot study.

BACKGROUND: Individuals with multiple sclerosis (MS) often experience limitations in mobility due to impairment of gait and balance. Rehabilitation approaches to improve balance and mobility in individuals with MS are limited. We have developed a novel visual cue guided multi-direction step (MDS) training method to improve balance and mobility in individuals with MS. OBJECTIVE: To examine the effect of MDS training on balance, gait, and mobility in individuals with MS. METHODS: Five individuals with relapsing- remitting MS participated in the 4-week training involving stepping in eight directions in response to a visual cue. Balance, gait, and mobility were assessed before and after training. RESULTS: Training related improvements were seen in the limits of stability (p< .05), spatial and temporal gait parameters (p<.05), and performance of the Tinetti Mobility Assessment (p=.001), 10-Meter Walk test (p<.001), and Four-Square Step test (p<.002). CONCLUSION: Balance, gait, and mobility in individuals with MS could be improved after 4 weeks of visual cue guided multi-direction stepping training. Outcomes from this feasibility study could help to refocus conventional rehabilitation strategies aimed at aiding individuals with MS to achieve maximal independence in mobility.

Deep DNA metagenomic sequencing reveals oral microbiome divergence between monozygotic twins discordant for multiple sclerosis severity.

In contrast to gut, the oral microbiome of MS patients has not been characterized. Deep sequencing of saliva DNA from a pair of monozygotic twins (MSF1 with relapsing remitting MS; MSF2 with clinically isolated syndrome) identified 2036 bacterial species. Relative abundances of 3 phyla were higher, and 3 lower in MSF1 versus MSF2. Species diversity was greater in MSF2, and 20 abundant species differed at least 2-fold. Pathway analysis identified 116 functional hierarchies differing 50% or more. Although limited to one pair of twins, our data suggests that oral microbiome analysis may be useful for diagnosis or monitoring therapeutic efficacy.

Sulfatides in extracellular vesicles isolated from plasma of multiple sclerosis patients.

Extracellular vesicles (EVs) are membrane nanovesicles of diverse sizes secreted by different cell types and are involved in intercellular communication. EVs shuttle proteins, nucleic acids, and lipids that reflect their cellular origin and could mediate their biological function in recipient cells. EVs circulate in biological fluids and are considered as potential biomarkers that could be used to analyze and characterize disease development, course and response to treatment. EVs exhibit specific distribution of glycolipids and membrane organization, but little is known about the biological significance of this distribution or how it could contribute to pathological conditions such as multiple sclerosis (MS). We provide the first description of sulfatide composition in plasma-derived EVs by ultra-high-performance liquid chromatography tandem mass spectrometry. We found that EVs of different sizes showed C16:0 sulfatide but no detectable levels of C18:0, C24:0, or C24:1 sulfatide species. Small EVs isolated at 100,000 × g-enriched in exosomes-from plasma of patients with MS showed a significant increase of C16:0 sulfatide compared with healthy controls. Nanoparticle tracking analysis showed that the particle size distribution in MS plasma was significantly different compared with healthy controls. Characterization of small EVs isolated from MS plasma showed similar protein content and similar levels of exosomal markers (Alix, Rab-5B) and vesicular marker MHC class I (major histocompatibility complex class I) compared with healthy controls. Our findings indicate that C16:0 sulfatide associated with small EVs is a candidate biomarker for MS that could potentially reflect pathological changes associated with this disease and/or the effects of its treatment. © 2016 Wiley Periodicals, Inc.

A single-nucleotide polymorphism in serine-threonine kinase 11, the gene encoding liver kinase B1, is a risk factor for multiple sclerosis.

We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress.

A pilot test of pioglitazone as an add-on in patients with relapsing remitting multiple sclerosis.

The peroxisome proliferator-activated receptor gamma agonist pioglitazone is FDA-approved for treatment of type-2 diabetes due to insulin sensitizing effects. However pioglitazone has anti-inflammatory and neuroprotective effects, reduces glial and T-cell activation, and reduces signs in an animal model of multiple sclerosis (MS). We tested the effects of daily treatment with pioglitazone in a small cohort of relapsing remitting MS patients. RRMS patients taking IFNbeta-1alpha and having an EDSS score <6.5 were randomized to treatment with pioglitazone (30 mg daily, p.o.) or placebo and monitored clinically and by MRI for 1 year. Primary outcomes were safety and tolerability, secondary outcomes included changes in neurological outcome, lesion burden, and gray matter volume. After 1 year 11 patients in the pioglitazone arm and 10 in the placebo arm completed the trial. Pioglitazone was well tolerated with a similar incidence of non-serious adverse events in placebo and treatment groups. After 1 year there were no significant differences in clinical symptoms as assessed by EDSS; however MRI showed a significant reduction in gray matter atrophy, and a trend for reduced lesion burden in the treatment group. These results show that pioglitazone was well tolerated in RRMS patients with indications of beneficial effects, warranting further trials to establish clinical efficacy.