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Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system with inflammatory and degenerative components. The cause of MS remains unknown although genetic and environmental factors appear to play a role in its etiopathogenesis. Metabolomics is a new "omics" technology that aims at measuring small molecules in various biological matrices and can provide information that is not readily obtained from genomics, transcriptomics, or proteomics. Currently, several different analytical platforms exist for metabolomics, and both untargeted and targeted approaches are being employed. Methods of analysis of metabolomics data are also being developed and no consensus currently exists on the optimal approach to analysis and interpretation of these data. Metabolomics has the potential to provide putative biomarkers, insights into the pathophysiology of the disease, and to aid in precision medicine for patients with MS., (© The Author(s), 2016.)

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]

Background: Mitochondrial dysfunction plays an important role in multiple sclerosis (MS) disease progression. Plasma extracellular vesicles are a potential source of novel biomarkers in MS, and some of these are derived from mitochondria and contain functional mitochondrial components. Objective: To evaluate the relationship between levels of mitochondrial complex IV and V activity in neuronally enriched extracellular vesicles (NEVs) and brain and retinal atrophy as assessed using serial magnetic resonance imaging (MRI) and optical coherence tomography (OCT). Methods: Our cohort consisted of 48 people with MS. NEVs were immunocaptured from plasma and mitochondrial complex IV and V activity levels were measured. Subjects underwent OCT every 6 months and brain MRI annually. The associations between baseline mitochondrial complex IV and V activities and brain substructure and retinal thickness changes were estimated utilizing linear mixed-effects models. Results: We found that higher mitochondrial complex IV activity and lower mitochondrial complex V activity levels were significantly associated with faster whole-brain volume atrophy. Similar results were found with other brain substructures and retinal layer atrophy. Conclusion: Our results suggest that mitochondrial measures in circulating NEVs could serve as potential biomarkers of disease progression and provide the rationale for larger follow-up longitudinal studies. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic demyelinating disorder of the central nervous system with inflammatory and degenerative components. The cause of MS remains unknown although genetic and environmental factors appear to play a role in its etiopathogenesis. Metabolomics is a new “omics” technology that aims at measuring small molecules in various biological matrices and can provide information that is not readily obtained from genomics, transcriptomics, or proteomics. Currently, several different analytical platforms exist for metabolomics, and both untargeted and targeted approaches are being employed. Methods of analysis of metabolomics data are also being developed and no consensus currently exists on the optimal approach to analysis and interpretation of these data. Metabolomics has the potential to provide putative biomarkers, insights into the pathophysiology of the disease, and to aid in precision medicine for patients with MS. [ABSTRACT FROM AUTHOR]

Synaptic loss is a feature of multiple sclerosis pathology that can be seen even in normal-appearing gray matter. Opsonization of synapses with complement components may underlie pathologic synapse loss.We sought to determine whether circulating neuronal-enriched and astrocytic-enriched extracellular vesicles (NEVs and AEVs) provide biomarkers reflecting complement-mediated synaptic loss in multiple sclerosis.From plasma of 61 people with multiple sclerosis (46 relapsing–remitting multiple sclerosis (RRMS) and 15 progressive MS) and 31 healthy controls, we immunocaptured L1CAM + NEVs and GLAST + AEVs. We measured pre- and post-synaptic proteins synaptopodin and synaptophysin in NEVs and complement components (C1q, C3, C3b/iC3b, C4, C5, C5a, C9, Factor B, and Factor H) in AEVs, total circulating EVs, and neat plasma.We found lower levels of NEV synaptopodin and synaptophysin in MS compared to controls (p < 0.0001 for both). In AEVs, we found higher levels of multiple complement cascade components in people with MS compared to controls; these differences were not noted in total EVs or neat plasma. Strikingly, there were strong inverse correlations between NEV synaptic proteins and multiple AEV complement components in MS, but not in controls.Circulating EVs could identify synaptic loss in MS and suggest a link between astrocytic complement production and synaptic loss. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are involved in inter-cellular communication and their cargo may provide prognostic/diagnostic biomarkers. To discover EV-associated biomarkers for Multiple Sclerosis (MS), we used an immune marker array to identify surface proteins on circulating EVs that differ between MS patients and controls (n = 3 each). We identified toll-like receptor-3 (TLR3) as a potential target for further validation. We utilized prospectively collected serum from relapsing-remitting MS patients (n = 18) and controls (n = 16) and confirmed lower concentration of TLR3 and higher concentration of mechanistically related TLR4 in MS EVs compared to controls. Future studies may further evaluate the utility of EV-associated TLRs as MS biomarkers and uncover their mechanistic significance. [ABSTRACT FROM AUTHOR]