Search

BackgroundThe circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain.ObjectiveTo determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS.MethodsWe collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale [EDSS]) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively.ResultsWe found that serum acylcarnitines (relapse rate: normalized enrichment score [NES] = 2.1, q = 1.03E-04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = -2.3, q = 0.002; EDSS: NES = -2.1, q = 0.004), plasmalogens (relapse rate: NES = -2.5, q = 5.81E-04; EDSS: NES = -2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = -2.0, q = 0.02; EDSS: NES = -1.9, q = 0.02) were associated with lower relapse rates and lower EDSS.ConclusionThis study supports the role of some lipid metabolites in pediatric MS relapses and disability.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Background: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. Objective: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. To assess changes in the circulating metabolome produced by ocrelizumab treatment in people with relapsing–remitting MS (RRMS). Methods: Thirty‐one individuals with RRMS eligible for beginning treatment with ocrelizumab were recruited and followed with demographic, clinical, quality‐of‐life, and global metabolomics data collected at each visit. Modules of highly correlated metabolites were identified using the weighted correlation network analysis approach. Changes in each module's eigenmetabolite values and individual metabolites during the study were evaluated using linear mixed‐effects models. Results: Patients with a mean age of 40.8 (SD = 10.30) years, and median disease duration of 4.0 (IQR = 8.5) years, were monitored for a median of 3.36 (IQR = 1.43) years. Two out of twelve identified sets of metabolites were altered significantly. The first module mainly contained androgenic and pregnenolone steroids (p‐value <0.001, coefficient: −0.10). The second module primarily consisted of several lysophospholipids, arachidonic acid, some endocannabinoids, and monohydroxy fatty acid metabolites (p‐value = 0.016, coefficient: −0.12), which its reduction was significantly associated with improvement based on overall disability response score (OR 3.09e‐01, 95% CI: 6.83e‐02, 9.09e‐01, p‐value = 3.15E‐02). Interpretation: In this longitudinal observational study, using a global untargeted metabolomics approach, we showed significant alteration in circulating metabolome in RRMS patients undergoing ocrelizumab treatment. In particular, we observed a significant reduction in metabolites involved in the lysophospholipid pathway, which was associated with patients' improvement. [ABSTRACT FROM AUTHOR]

BackgroundVitamin D insufficiency is a risk factor for multiple sclerosis (MS), and patients do not always show the expected response to vitamin D supplementation.ObjectiveWe aimed to determine if vitamin D supplementation leads to a similar increase in serum 25-hydroxyvitamin-D (25(OH)D) levels in patients with MS and healthy controls (HCs).MethodsParticipants in this open-label study were female, white, aged 18-60 years, had 25(OH)D levels ⩽ 75 nmol/l at screening, and had relapsing-remitting MS (RRMS) or were HCs. Participants received 5000 IU/day of vitamin D3 for 90 days. Utilizing generalized estimating equations we examined the relationship between the primary outcome (serum 25(OH)D level) and the primary (MS versus HC status) and secondary predictors.ResultsFor this study 27 MS patients and 30 HCs were enrolled. There was no significant difference in baseline 25(OH)D level or demographics except for higher body mass index (BMI) in the MS group (25.3 vs. 23.6 kg/m(2), p=0.035). In total, 24 MS subjects and 29 HCs completed the study. In a multivariate model accounting for BMI, medication adherence, and oral contraceptive use, MS patients had a 16.7 nmol/l (95%CI: 4.2, 29.2, p=0.008) lower increase in 25(OH)D levels compared with HCs.ConclusionsPatients with MS had a lower increase in 25(OH)D levels with supplementation, even after accounting for putative confounders.

Introduction Multiple sclerosis (MS) is a chronic demyelinating disorder characterized by inflammation and neurodegeneration (1). Both genetic and environmental factors play a role in the etiopathogenesis of this disease (2-4). [...], Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Background: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). Objective: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. Methods: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. Results: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = −0.113%, 95% confidence interval (CI): −0.204% to −0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. Conclusions: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect. [ABSTRACT FROM AUTHOR]