Relapsing-remitting Multiple Sclerosis Subjects Research Articles

Symbol Digit Modalities Test in progressive multiple sclerosis.

The Symbol Digit Modalities Test (SDMT) is a highly sensitive neuropsychological tool used for the assessment of information processing speed (IPS) in various neurological disorders. In this review, we have focused on the current knowledge regarding the use of SDMT selectively in the evaluation of progressive multiple sclerosis (PMS) patients. A literature review was performed regarding the application of SDMT in PMS, with a focus on the primary progressive and secondary progressive subtypes. Relationships of diverse disease-associated factors with SDMT have been described, including disease course, imaging findings, molecular biomarkers, treatment and others. SDMT is a very useful and easily applicable instrument in the diagnostic armamentarium of neurologists and neuropsychologists. It is especially valuable in the evaluation of PMS patients, in whom the prevalence of IPS deficits is higher than in relapsing-remitting multiple sclerosis subjects or in healthy individuals. An emphasis should be laid on larger study groups and differentiating between individual PMS subtypes and their separate analysis in the context of cognitive assessment.

MR Susceptibility Separation for Quantifying Lesion Paramagnetic and Diamagnetic Evolution in Relapsing-Remitting Multiple Sclerosis.

Multiple sclerosis (MS) lesion evolution may involve changes in diamagnetic myelin and paramagnetic iron. Conventional quantitative susceptibility mapping (QSM) can provide net susceptibility distribution, but not the discrete paramagnetic and diamagnetic components. To apply susceptibility separation (χ separation) to follow lesion evolution in MS with comparison to R2 */R2 ' /QSM. Longitudinal, prospective. Twenty relapsing-remitting MS subjects (mean age: 42.5 ± 9.4 years, 13 females; mean years of symptoms: 4.3 ± 1.4 years). Three-dimensional multiple echo gradient echo (QSM and R2 * mapping), two-dimensional dual echo fast spin echo (R2 mapping), T2 -weighted fluid attenuated inversion recovery, and T1-weighted magnetization prepared gradient echo sequences at 3 T. Data were analyzed from two scans separated by a mean interval of 14.4 ± 2.0 months. White matter lesions on fluid-attenuated inversion recovery were defined by an automatic pipeline, then manually refined (by ZZ/AHW, 3/25 years' experience in MRI), and verified by a radiologist (MN, 25 years' experience in MS). Susceptibility separation yielded the paramagnetic and diamagnetic susceptibility content of each voxel. Lesions were classified into four groups based on the variation of QSM/R2 * or separated into positive/negative components from χ separation. Two-sample paired t tests for assessment of longitudinal differences. Spearman correlation coefficients to assess associations between χ separation and R2 */R2 ' /QSM. Significant level: P < 0.005. A total of 183 lesions were quantified. Categorizing lesions into groups based on χ separation demonstrated significant annual changes in QSM//R2 */R2 ' . When lesions were grouped based on changes in QSM and R2 *, both changing in unison yielded a significant dominant paramagnetic variation and both opposing yielded a dominant diamagnetic variation. Significant Spearman correlation coefficients were found between susceptibility-sensitive MRI indices and χ separation. Susceptibility separation changes in MS lesions may distinguish and quantify paramagnetic and diamagnetic evolution, potentially providing additional insight compared to R2 * and QSM alone. 2 TECHNICAL EFFICACY: Stage 2.

Assessment of executive functions: Planning, interference and mental flexibility in subjects with relapsing-remitting and secondary progressive multiple sclerosis

Multiple sclerosis is a neurodegenerative disease due to progressive demyelination of the nerve fibers that make up the white matter of the central nervous system. According to the latest World Health Organization (WHO) estimates, this disease is clearly increasing, affecting on average, a young and active population. This has implications at the socioprofessional level. All studies converge to underline the cognitive decline, including executive functions, in this population. These information processing processes are essential for adapting to new situations for which there are no pre-established operating patterns. In line with previous studies, the present study aims to assess three executive functions, such as planning, interference and mental flexibility, in 30 subjects with multiple sclerosis divided into two groups. One group consists of 15 subjects with Relapsing-Remitting MS (RRMS), and the other group consists of 15 subjects with Secondary Progressive MS (SPMS). They are compared to a group of 15 healthy subjects. The results of the statistical analysis show a clear inferiority in terms of raw score and completion time for the MS and SPMS subjects compared to the RRMS subjects. This can be explained by a significant slowdown in the speed of information processing, according to the scientific literature.

Upper cervical cord atrophy is independent of cervical cord lesion volume in early multiple sclerosis: A two-year longitudinal study

BackgroundUpper cervical cord atrophy and lesions have been shown to be associated with disease and disability progression already in early relapsing-remitting multiple sclerosis (RRMS). However, their longitudinal relationship remains unclear. ObjectiveTo investigate the cross-sectional and longitudinal relation between focal T2 cervical cord lesion volume (CCLV) and regional and global mean upper cervical cord area (UCCA), and their relations with disability. MethodsOver a two-year interval, subjects with RRMS (n = 36) and healthy controls (HC, n = 16) underwent annual clinical and MRI examinations. UCCA and CCLV were obtained from C1 through C4 level. Linear mixed model analysis was performed to investigate the relation between UCCA, CCLV, and disability over time. ResultsUCCA at baseline was significantly lower in RRMS subjects compared to HCs (p = 0.003), but did not decrease faster over time (p ≥ 0.144). UCCA and CCLV were independent of each other at any of the time points or cervical levels, and over time. Lower baseline UCCA, but not CCLV, was related to worsening of both upper and lower extremities function over time. ConclusionUCCA and CCLV are independent from each other, both cross-sectionally and longitudinally, in early MS. Lower UCCA, but not CCLV, was related to increasing disability over time.

Ocrelizumab modifies circulating immune asset in relapsing-remitting multiple sclerosis subjects

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system, mediated by autoreactive lymphocytes. Ocrelizumab, a humanized monoclonal anti-CD20 antibody, has shown pronounced effects in reduction of disease activity. Although the clinical response to Ocrelizumab is related to a specific B cell depletion, other circulating lymphocytes may be affected by this treatment.1. Here, we investigated overtime the possible effects of Ocrelizumab on circulating immune asset in relapsing remitting (RR)-MS subjects.

Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential

Human CD4+CD25hiFOXP3+ regulatory T (Treg) cells are key players in the control of immunological self-tolerance and homeostasis. Here, we report that signals of pseudo-starvation reversed human Treg cell invitro anergy through an integrated transcriptional response, pertaining to proliferation, metabolism, and transmembrane solute carrier transport. At the molecular level, the Treg cell proliferative response was dependent on the induction of the cystine/glutamate antiporter solute carrier (SLC)7A11, whose expression was controlled by the nuclear factor erythroid 2-related factor 2 (NRF2). SLC7A11 induction in Treg cells was impaired in subjects with relapsing-remitting multiple sclerosis (RRMS), an autoimmune disorder associated with reduced Treg cell proliferative capacity. Treatment of RRMS subjects with dimethyl fumarate (DMF) rescued SLC7A11 induction and fully recovered Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmunity and unveil SLC7A11 as major target for the rescue of Treg cell proliferation.

Defective CD19+CD24hiCD38hi transitional B-cell function in patients with relapsing-remitting MS

Background: Multiple sclerosis (MS) is characterized by central nervous system (CNS) infiltration of T and B cells, excess inflammatory cytokine and chemokine production and failure of immune regulation. CD19+CD24hiCD38hi transitional B cells producing interleukin (IL)-10 have been shown to suppress interferon-γ (IFNγ) and tumour necrosis factor-α (TNFα) production by CD4+ T cells and to be dysfunctional in autoimmune arthritis and systemic lupus erythematosus. Objective: We hypothesized that transitional B-cell-dependent immune regulation could be defective in MS and examined their function in healthy subjects and patients with relapsing-remitting multiple sclerosis (RRMS). Methods: A total of 62 healthy donors and 21 RRMS subjects donated peripheral blood for the study. IL-10-producing B cells, IFNγ and TNFα-producing T cells and proliferating T cells were quantified by flow cytometry. Results: In healthy individuals, CD19+CD24hiCD38hi transitional B cells produce more IL-10 than CD19+CD24+CD38+ naive and CD19+CD24hiCD38− memory B cells and are able to suppress CD4+ T-cell proliferation and IFNγ and TNFα-production. In subjects with RRMS, CD19+CD24hiCD38hi transitional B cells produce significantly less IL-10 and to fail to suppress effector T-cell function. Conclusion: CD19+CD24hiCD38hi transitional B cells physiologically represent the most potent regulatory B-cell subset and are functionally defective in patients with RRMS, an abnormality that may contribute to the immune pathological process.

Altered expression of SIRPγ on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells.

Factors regulating self-antigen directed immune-responses in autoimmunity are poorly understood. Signal regulatory protein gamma (SIRPγ) is a human T-cell specific protein with genetic variants associated with type 1 diabetes (T1D). SIRPγ’s function in the immune system remains unclear. We show that T1D and relapsing remitting multiple sclerosis (RRMS) subjects have significantly greater frequency of rs2281808 T genetic variant, that correlates with reduced SIRPγ-expression in T-cells. Importantly, reduced SIRPγ-expression in RRMS and T1D subjects was not restricted to T variant, suggesting SIRPγ-expression is also regulated by disease specific factors in autoimmunity. Interestingly, increased frequencies of SIRPγlow T-cells in RRMS and T1D positively correlated with proinflammatory molecules from T-cells. Finally, we show that SIRPγlow T-cells have enhanced pathogenecity in vivo in a GVHD model. These findings suggest that decreased-SIRPγ expression, either determined by genetic variants or through peripherally acquired processes, may have a mechanistic link to autoimmunity through induction of hyperactive T-cells.

Single-cell RNA-seq analysis of human CSF microglia and myeloid cells in neuroinflammation

ObjectiveTo identify and characterize myeloid cell populations within the CSF of patients with MS and anti-myelin oligodendrocyte glycoprotein (MOG) disorder by high-resolution single-cell gene expression analysis.MethodsSingle-cell RNA sequencing (scRNA-seq) was used to profile individual cells of CSF and blood from 2 subjects with relapsing-remitting MS (RRMS) and one with anti-MOG disorder. Publicly available scRNA-seq data from the blood and CSF of 2 subjects with HIV were also analyzed. An informatics pipeline was used to cluster cell populations by transcriptomic profiling. Based on gene expression by CSF myeloid cells, a flow cytometry panel was devised to examine myeloid cell populations from the CSF of 11 additional subjects, including individuals with RRMS, anti-MOG disorder, and control subjects without inflammatory demyelination.ResultsCommon myeloid populations were identified within the CSF of subjects with RRMS, anti-MOG disorder, and HIV. These included monocytes, conventional and plasmacytoid dendritic cells, and cells with a transcriptomic signature matching microglia. Microglia could be discriminated from other myeloid cell populations in the CSF by flow cytometry.ConclusionsHigh-resolution single-cell gene expression analysis clearly distinguishes distinct myeloid cell types present within the CSF of subjects with neuroinflammation. A population of microglia exists within the human CSF, which is detectable by surface protein expression. The function of these cells during immunity and disease requires further investigation.

7T MRI cerebral leptomeningeal enhancement is common in relapsing-remitting multiple sclerosis and is associated with cortical and thalamic lesions

Background: Meningeal inflammation may contribute to gray matter (GM) involvement in multiple sclerosis (MS) and is proposed to manifest as magnetic resonance imaging (MRI) leptomeningeal enhancement (LME). Objective: To investigate how LME relates to GM lesions in relapsing-remitting multiple sclerosis (RRMS) at 7T. Methods: A total of 30 RRMS subjects (age (mean ± standard deviation (SD)): 44.0 ± 11.3 years, 93% on disease-modifying treatment) and 15 controls underwent gadolinium-enhanced three-dimensional (3D) MP2RAGE (magnetization-prepared 2 rapid gradient-echo) and fluid-attenuated inversion recovery (FLAIR) MRI. LME, cortical lesions (CLs), thalamic lesions (TLs), and white matter (WM) lesions were expert-quantified. Wilcoxon rank-sum, two-sample t-tests, Spearman correlations, and regression models were employed. Results: Two-thirds (20/30) of MS subjects and 1/15 controls (6.7%) had LME. LME+ MS subjects had 2.7 ± 1.5 foci, longer disease duration (14.9 ± 10.4 vs. 8.1 ± 5.7 years, p = 0.028), increased CL number (21.5 ± 12.6 vs. 5.5 ± 5.0, p < 0.001) and volume (0.80 ± 1.13 vs. 0.13 ± 0.13 mL, p = 0.002), and increased TL number (3.95 ± 2.11 vs. 0.70 ± 1.34, p < 0.001) and volume (0.106 ± 0.09 vs. 0.007 ± 0.01 mL, p < 0.001) versus LME– subjects. LME focus number correlated more highly with CL (rs = 0.50, p = 0.01) and TL (rs = 0.81, p < 0.001) than WM lesion (rs = 0.34, p > 0.05) volume. Similar LME–CL number associations were observed in unadjusted and WM lesion–adjusted comparisons (both p < 0.001). Conclusion: Cerebral LME is common in RRMS at 7T and is independently associated with GM injury. We hypothesize that cerebrospinal fluid (CSF)-related inflammation links cortical and thalamic injury.

Reduced Annexin A1 Expression Associates with Disease Severity and Inflammation in Multiple Sclerosis Patients

Chronic neuroinflammation is a key pathological hallmark of multiple sclerosis (MS) that suggests that resolution of inflammation by specialized proresolving molecules is dysregulated in the disease. Annexin A1 (ANXA1) is a protein induced by glucocorticoids that facilitates resolution of inflammation through several mechanisms that include an inhibition of leukocyte recruitment and activation. In this study, we investigated the ability of ANXA1 to influence T cell effector function in relapsing/remitting MS (RRMS), an autoimmune disease sustained by proinflammatory Th1/Th17 cells. Circulating expression levels of ANXA1 in naive-to-treatment RRMS subjects inversely correlated with disease score and progression. At the cellular level, there was an impaired ANXA1 production by CD4+CD25- conventional T and CD4+RORγt+ T (Th17) cells from RRMS subjects that associated with an increased migratory capacity in an in vitro model of blood brain barrier. Mechanistically, ANXA1 impaired monocyte maturation secondarily to STAT3 hyperactivation and potently reduced T cell activation, proliferation, and glycolysis. Together, these findings identify impaired disease resolution pathways in RRMS caused by dysregulated ANXA1 expression that could represent new potential therapeutic targets in RRMS.

Genetic polymorphisms and epigenetic regulation of survivin encoding gene, BIRC5, in multiple sclerosis patients

BackgroundThe persistent the inflammatory condition in multiple sclerosis (MS) may due to the aberrant regulation of the elimination of the pathogenic autoreactive lymphocytes through apoptosis. Survivin, encoded by the BIRC5 gene, has been indicated to be involved in the regulation of apoptosis. This survey intended to investigate the genetic and microRNA mediated regulation of survivin in relapsing-remitting MS (RRMS) disease.ResultsIt was observed that the C allele (OR = 1.38, 95% CI = 1.05–1.348, P = 0.022) and CC genotype (OR = 1.84, 95% CI = 1.06–3.19; P = 0.029) in the rs9904341 polymorphism increased the disease risk. Furthermore, miR-34a was significantly downregulated (Fold change = 0.41, P = 0.001) in the PBMCs from RRMS subjects. Survivin mRNA expression in PBMCs and serum survivin level were increased in RRMS patients in comparison to the controls. Downregulation of miR-34a was negatively correlated with increased survivin level.ConclusionAlthough the genetic polymorphism of BIRC5 gene was associated with the disease risk, miR-34a was suggested to be involved in the regulation of survivin in the RRMS patients.

Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow-up.

Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS). This prospective, longitudinal study (n=154) included 41 healthy controls, 76 relapsing-remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol and the apolipoproteins ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped. Greater percentage increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low-density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL-C (P=0.032) and ApoA-I (P=0.007) were smaller in patients with relapsing-remitting MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status. Increases in HDL-C and ApoA-I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

Changes in cortical motor outputs after a motor relapse of multiple sclerosis.

BackgroundMotor recovery following a multiple sclerosis (MS) relapse depends on mechanisms of tissue repair but also on the capacity of the central nervous system for compensating of permanent damage.ObjectivesWe aimed to investigate changes in corticospinal plasticity and interhemispheric connections after a relapse of MS using transcranial magnetic stimulation (TMS).MethodsTwenty healthy and 13 relapsing–remitting MS subjects with a first motor relapse were included. TMS mapping and ipsilateral silent period (iSP) were performed after relapse and at 6-month follow-up.ResultsStrength and dexterity of the paretic hand were impaired at baseline and improved over time. After relapse, mapamplitude and mapdensity were decreased for the ipsilesional-corticospinal tract (IL-CST) while expanded for the contralesional-CST (CL-CST). At follow-up, map parameters normalized for the CL-CST independently from recovery while the increase of outputs from the IL-CST was associated with straight and dexterity improvement. iSP measurements were impaired in MS irrespective of the phase of the disease. Prolonged iSPduration at baseline was associated with less dexterity recovery.ConclusionsAfter a motor relapse, TMS mapping shows acute changes in corticospinal excitability and rearrangements of motor outputs. iSP is less influenced by the phase of disease but may better predict recovery, possibly reflecting the integrity of interhemispheric motor networks.

Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis

IntroductionIn this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. MethodsWe studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. ResultsThe mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 ± 1.0 vs 1.7 ± 1.0, p < 0.05) and at T2 (1.4 ± 1.3 vs 2.9 ± 1.8, p < 0.001). Volume loss of thalamus (−0.5% ± 0.2% vs. −1.1% ± 0.4%; p < 0.001), globus pallidus (−4.4% ± 3.1% vs. −8.2% ± 4.5%; p < 0.001), hippocampus (−0.7% ± 0.3% vs. −1.5% ± 0.5%; p < 0.001) and cerebellum (−0.5% ± 0.3% vs. −0.9% ± 0.4%; p < 0.001) was also lower in the GA group. A more pronounced cortical thinning was observed in cingulate (p = 0.04), cuneus and frontomarginal gyrus (p = 0.01 for both comparisons) of the untreated patients. ConclusionOur findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage.

Functional Connectivity Alterations Reveal Complex Mechanisms Based on Clinical and Radiological Status in Mild Relapsing Remitting Multiple Sclerosis.

Resting state functional MRI (rs-fMRI) has provided important insights into functional reorganization in subjects with Multiple Sclerosis (MS) at different stage of disease. In this cross-sectional study we first assessed, by means of rs-fMRI, the impact of overall T2 lesion load (T2LL) and MS severity score (MSSS) on resting state networks (RSNs) in 62 relapsing remitting MS (RRMS) patients with mild disability (MSSS < 3). Independent Component Analysis (ICA) followed by dual regression analysis confirmed functional connectivity (FC) alterations of many RSNs in RRMS subjects compared to healthy controls. The anterior default mode network (DMNa) and the superior precuneus network (PNsup) showed the largest areas of decreased FC, while the sensory motor networks area M1 (SMNm1) and the medial visual network (MVN) showed the largest areas of increased FC. In order to better understand the nature of these alterations as well as the mechanisms of functional alterations in MS we proposed a method, based on linear regression, that takes into account FC changes and their correlation with T2LL and MSSS. Depending on the sign of the correlation between FC and T2LL, and furthermore the sign of the correlation with MSSS, we suggested the following possible underlying mechanisms to interpret altered FC: (1) FC reduction driven by MS lesions, (2) “true” functional compensatory mechanism, (3a) functional compensation attempt, (3b) “false” functional compensation, (4a) neurodegeneration, (4b) pre-symptomatic condition (damage precedes MS clinical manifestation). Our data shows areas satisfying 4 of these 6 conditions (i.e., 1,2,3b,4b), supporting the suggestion that increased FC has a complex nature that may exceed the simplistic assumption of an underlying compensatory mechanism attempting to limit the brain damage caused by MS progression. Exploring differences between RRMS subjects with short disease duration (MSshort) and RRMS with similar disability but longer disease duration (MSlong), we found that MSshort and MSlong were characterized by clearly distinct pattern of FC, involving predominantly sensory and cognitive networks respectively. Overall, these results suggest that the analysis of FC alterations in multiple large-scale networks in relation to radiological (T2LL) and clinical (MSSS, disease duration) status may provide new insights into the pathophysiology of relapse onset MS evolution.

Multimodal assessment of normal-appearing corpus callosum is a useful marker of disability in relapsing-remitting multiple sclerosis: an MRI cluster analysis study.

Corpus callosum (CC) is frequently involved in relapsing-remitting multiple sclerosis (RRMS). Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) allow to study CC macrostructural and microstructural tissue integrity. Here, we applied a data-driven approach to MRI and DTI data of normal-appearing CC in RRMS subjects, and subsequently evaluated if differences in tissue integrity corresponded to different levels of physical disability and cognitive impairment. 74 RRMS patients and 20 healthy controls (HC) underwent 3T MRI and DTI. Thickness and fractional anisotropy (FA) along midsagittal CC were extracted, and values from RRMS patients were fed to a hierarchical clustering algorithm. We then used ANOVA to test for differences in clinical and cognitive variables across the imaging-based clusters and HC. We found three distinct MRI-based subgroups of RRMS patients with increasing severity of CC damage. The first subgroup showed callosal integrity similar to HC (Cluster 1); Cluster 2 had milder callosal damage; a third subgroup showed the most severe callosal damage (Cluster 3). Cluster 3 included patients with longer disease duration and worst scores in Expanded Disability Status Scale. Cognitive domains of verbal memory, executive functions and processing speed were impaired in Cluster 3 and Cluster 2 compared to Cluster 1 and HC. Within the same homogeneous cohort of patients, we could identify three neuroimaging RRMS clusters characterized by different involvement of normal-appearing CC. Interestingly, these corresponded to three distinct levels of clinical and cognitive disability.

Dysequilibrium of the PTH-FGF23-vitamin D axis in relapsing remitting multiple sclerosis; a longitudinal study

BackgroundParathyroid glands of people with relapsing remitting multiple sclerosis (RRMS) fail to respond to low serum 25-hydroxyvitamin D (25OHD) and low serum calcium, which are stimuli for parathyroid hormone (PTH) secretion. This led us to hypothesise: that there is suppression of PTH in RRMS due to higher than normal serum concentrations of fibroblast growth factor 23 (FGF23). We therefore sought evidence for dysregulation of the PTH-FGF23-vitamin D axis in RRMS.MethodsLongitudinal study (winter to summer) with fasting venepunctures. For RRMS subjects who recruited a healthy control (HC) friend, pairs analyses were performed. For each pair, the within-pair difference of the variable of interest was calculated (RRMS minus HC). Then, the median of the differences from all pairs was compared against a median of zero (Wilcoxon) and the 95% confidence interval of that median difference (CI) was calculated (Sign Test).ResultsRRMS had lower winter PTH than HC, P = 0.005, (CI -2.4 to 0.5 pmol/L, n = 28 pairs), and lower summer PTH, P = 0.04, (CI -1.8 to 0.5, n = 21 pairs). Lower PTH associates physiologically with lower intact FGF23 (iFGF23), yet RRMS had higher iFGF23 than HC in winter, P = 0.04, (CI -3 to 15 pg/mL, n = 28 pairs) and iFGF23 levels comparable to HC in summer, P = 0.14, (CI -5 to 13, n = 21 pairs). As PTH stimulates and FGF23 reduces, renal 1-alpha hydroxylase enzyme activity, which synthesises serum 1,25-dihyroxyvitamin D (1,25(OH)2D) from serum 25OHD, we examined the ratio of serum 1,25(OH)2D to serum 25OHD. In winter, this ratio was lower in RRMS versus HC, P = 0.013, (CI -1.2 to - 0.3, n = 28 pairs).ConclusionsThis study revealed a dysequilibrium of the PTH-FGF23-vitamin D axis in RRMS, with lower plasma PTH, higher plasma iFGF23 and a lower serum 1,25(OH)2D to 25OHD ratio in RRMS compared with HC subjects. This dysequilibrium is consistent with the study hypothesis that in RRMS there is suppression of the parathyroid glands by inappropriately high plasma concentrations of iFGF23. Studying the basis of this dysequilibrium may provide insight into the pathogenesis of RRMS.

Effects of lipoic acid on migration of human B cells and monocyte-enriched peripheral blood mononuclear cells in relapsing remitting multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system characterized by inflammation and demyelination resulting in clinical disability. The rodent MS model suggests that infiltration of monocytes and B cells contributes to disease pathogenesis. Here, we compared the migratory capacity of human monocytes and B cells from healthy control (HC) and relapsing-remitting MS (RRMS) subjects, with or without lipoic acid (LA) treatment. Basal migration of monocyte-enriched PBMCs from RRMS subjects is significantly higher than HC PBMCs. LA treatment significantly inhibits monocyte and B cell migration in both cohorts, and may thus be therapeutically effective for treatment of MS.

Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial

Background: The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive. Objective: To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO). Methods: A total of 16 disease-modifying treatment (DMT) naive RRMS subjects were studied in a baseline versus treatment (BVT) controlled prospective study. MRI scans were performed during 5 months of screening-observation, 10 months of treatment, and 4 months of post-treatment surveillance. Results: No serious symptoms or adverse events occurred during treatment. For the cohort, there was a trend consistent with a 35% diminution in active lesions when observation MRIs were compared to treatment MRIs (p = 0.08), and at the level of individuals, 12 of 16 subjects improved during TSO treatment. T regulatory lymphocytes were increased during TSO treatment. Conclusion: TSO is safe in RRMS subjects. Potentially favorable MRI outcomes and immunoregulatory changes were observed during TSO treatment; however, the magnitude of these effects was modest, and there was considerable variation among the responses of individual subjects.