The association of menopausal hormone levels with progression-related biomarkers in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) progression coincides temporally with menopause. However, it remains unclear whether the changes in disease course are related to the changes in reproductive hormone concentrations. We assessed the association of menopausal hormonal levels with progression-related biomarkers of MS and evaluated the changes in serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels during menopausal hormone therapy (MHT) in a prospective baseline-controlled design. METHODS: The baseline serum estradiol, follicle stimulating hormone, and luteinizing hormone levels were measured from menopausal women with MS (n = 16) and healthy controls (HC, n = 15). SNfL and sGFAP were measured by single-molecule array. The associations of hormone levels with sNfL and sGFAP, and with Expanded Disability Status Scale (EDSS) and lesion load and whole brain volumes (WBV) in MRI were analyzed with Spearman's rank correlation and age-adjusted linear regression model. Changes in sNfL and sGFAP during one-year treatment with estradiol hemihydrate combined with cyclic dydrogesterone were assessed with Wilcoxon Signed Ranks Test. RESULTS: In MS group, baseline estradiol had a positive correlation with WBV in MRI and an inverse correlation with lesion load, sNfL and sGFAP, but no correlation with EDSS. The associations of low estradiol with high sGFAP and low WBV were independent of age. During MHT, there was no significant change in sNfL and sGFAP levels in MS group while in HC, sGFAP slightly decreased at three months but returned to baseline at 12 months. CONCLUSION: Our preliminary findings suggest that low estradiol in menopausal women with MS has an age-independent association with more pronounced brain atrophy and higher sGFAP and thus advanced astrogliosis which could partially explain the more rapid progression of MS after menopause. One year of MHT did not alter the sGFAP or sNfL levels in women with MS.

Temporal variability of serum miR-191, miR-223, miR-128, and miR-24 in multiple sclerosis: A 4-year follow-up study.

BACKGROUND: Circulating microRNAs (miRNA) are suggested to be a promising biomarker for multiple sclerosis (MS). Previously, miR-128-3p, miR-24-3p, miR-191-5p and miR-223-3p have been reported to associate with MS pathology. However, their longitudinal changes and association with the disease activity have not been studied. OBJECTIVES: To evaluate the serum temporal variability of miR-128-3p, miR-191-5p, miR-24-3p, and miR-223-3p and their association with disability and disease activity in MS. METHODS: The expression of four miRNAs in serum was studied in 57 MS patients, 18 clinically isolated syndrome patients, and 32 healthy controls over the four-year follow-up. RESULTS: At the baseline, miR-191-5p was overexpressed in RRMS in comparison to controls, and its levels correlated positively with EDSS and progression index (PI) in RRMS. Increased levels of miR-128-3p were detected in PPMS in comparison to controls, and increased levels correlated with EDSS and PI in RRMS. The expression of miR-24-3p and miR-223-3p did not differ between the subtypes, but miR-223-3p correlated negatively with T1 lesions volumes in SPMS and PPMS. Over the four-years follow-up period, the expression of miR-128-3p and miR-24-3p was stable longitudinally, while temporal changes of miR-191-5p and miR-223-3p were observed in MS. Temporal changes in miR-191-5p were observed to be associated with an increase of EDSS or MRI activity, while the variability of miR-223-3p was associated with relapses. CONCLUSION: Temporal variability of miR-191-5p and miR-223-3p are associated with changes in disability accumulation and disease activity. While, miR-128-3p was stably expressed and associated with the PPMS subtype and correlated with disability accumulation.

Establishment of a human induced pluripotent stem cell line (TAUi008-A) derived from a multiple sclerosis patient.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system where the main pathogenetic events include demyelination and axonal degeneration. Here, we generated a human induced pluripotent stem cell (hiPSC) line from peripheral blood mononuclear cells of an MS patient utilizing Sendai virus reprogramming. The produced hiPSC line expressed pluripotency markers, differentiated into three germ layers, showed a normal karyotype and was free of virus vectors, transgenes and mycoplasma. Established hiPSCs are a valuable source for studies of MS disease modeling and drug discovery.

A kainic acid-induced seizure model in human pluripotent stem cell-derived cortical neurons for studying the role of IL-6 in the functional activity.

Human pluripotent stem cell (hPSC)-derived neural cultures have attracted interest for modeling epilepsy and seizure-like activity in vitro. Clinical and experimental evidence have shown that the multifunctional inflammatory cytokine interleukin (IL)-6 plays a significant role in epilepsy. However, the role of IL-6 in neuronal networks remains unclear. In this study, we modelled seizure-like activity in hPSC-derived cortical neurons using kainic acid (KA) and explored the effects of IL-6 and its counterpart, hyper-IL-6 (H-IL-6), a fusion protein consisting of IL-6 and its soluble receptor, IL-6R. In the seizure-like model, functionally mature neuronal networks responded to KA induction with an increased bursting phenotype at the single electrode level, while network level bursts decreased. The IL-6 receptors, IL6R and gp130, were expressed in hPSC-derived cortical neurons, and the gene expression of IL6R increased during maturation. Furthermore, the expression of IL-6R increased not only after IL-6 and H-IL-6 treatment but also after KA treatment. Stimulation with IL-6 or H-IL-6 was not toxic to the neurons and cytokine pretreatment did not independently modulate neuronal network activity or KA-induced seizures. Furthermore, the increased expression of IL-6R in response to IL-6, H-IL-6 and KA implies that neurons can respond through both classical and trans-signaling pathways. Acute treatment with IL-6 and H-IL-6 did not alter functional activity, suggesting that IL-6 does not affect the induction or modulation of newly induced seizures in healthy cultures. Overall, we propose this model as a useful tool to study seizure-like activity in neuronal networks in vitro.

In Vitro Oxygen-Glucose Deprivation-Induced Stroke Models with Human Neuroblastoma Cell- and Induced Pluripotent Stem Cell-Derived Neurons.

Stroke is a devastating neurological disorder and one of the leading causes of mortality and disability. To understand the cellular and molecular mechanisms of stroke and to develop novel therapeutic approaches, two different in vitro human cell-based stroke models were established using oxygen-glucose deprivation (OGD) conditions. In addition, the effect of adipose stem cells (ASCs) on OGD-induced injury was studied. In the present study, SH-SY5Y human neuroblastoma cells and human induced pluripotent stem cells (hiPSCs) were differentiated into neurons, cultured under OGD conditions (1% O2) for 24 h, and subjected to a reperfusion period for 24 or 72 h. After OGD, ASCs were cocultured with neurons on inserts for 24 or 72 h to study the neuroprotective potential of ASCs. The effect of OGD and ASC coculture on the viability, apoptosis, and proliferation of and axonal damage to neuronal cells was studied. The results showed that OGD conditions induced cytotoxicity and apoptosis of SH-SY5Y- and hiPSC-derived neurons, although more severe damage was detected in SH-SY5Y-derived neurons than in hiPSC-derived neurons. Coculture with ASCs was protective for neurons, as the number of dead ASC-cocultured neurons was lower than that of control cells, and coculture increased the proliferation of both cell types. To conclude, we developed in vitro human cell-based stroke models in SH-SY5Y- and hiPSC-derived neurons. This was the first time hiPSCs were used to model stroke in vitro. Since OGD had different effects on the studied cell types, this study highlights the importance of using several cell types in in vitro studies to confirm the outcomes of the study. Here, ASCs exerted a neuroprotective effect by increasing the proliferation and decreasing the death of SH-SY5Y- and hiPSC-derived neurons after OGD.

Co-stimulation with IL-1ß and TNF-α induces an inflammatory reactive astrocyte phenotype with neurosupportive characteristics in a human pluripotent stem cell model system.

Astrocyte reactivation has been discovered to be an important contributor to several neurological diseases. In vitro models involving human astrocytes have the potential to reveal disease-specific mechanisms of these cells and to advance research on neuropathological conditions. Here, we induced a reactive phenotype in human induced pluripotent stem cell (hiPSC)-derived astrocytes and studied the inflammatory natures and effects of these cells on human neurons. Astrocytes responded to interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) treatment with a typical transition to polygonal morphology and a shift to an inflammatory phenotype characterized by altered gene and protein expression profiles. Astrocyte-secreted factors did not exert neurotoxic effects, whereas they transiently promoted the functional activity of neurons. Importantly, we engineered a novel microfluidic platform designed for investigating interactions between neuronal axons and reactive astrocytes that also enables the implementation of a controlled inflammatory environment. In this platform, selective stimulation of astrocytes resulted in an inflammatory niche that sustained axonal growth, further suggesting that treatment induces a reactive astrocyte phenotype with neurosupportive characteristics. Our findings show that hiPSC-derived astrocytes are suitable for modeling astrogliosis, and the developed in vitro platform provides promising novel tools for studying neuron-astrocyte crosstalk and human brain disease in a dish.

Gene expression profiles of TNF-like cytokine 1A (TL1A) and its receptors death receptor 3 (DR3) and decoy receptor 3 (DcR3) in multiple sclerosis.

TL1A/DR3/DcR3 pathway is an important mediator of inflammatory responses and contributes to the pathogenesis of several chronic inflammatory diseases. Therefore, we analysed PBMC gene expression of these molecules in 30 relapsing-remitting multiple sclerosis (RRMS) patients, 8 secondary progressive MS (SPMS), 9 primary progressive MS (PPMS), 11 clinically isolated syndrome (CIS) patients, and 16 healthy controls (HCs), to evaluate their biomarker potential in MS. The results showed significant decrease in TL1A expression in RRMS compared to other study groups. TL1A as a marker of inflammation, we found its higher expression among treatment näive RRMS patients as compared to HCs and among patients who were treated with DMTs. Moreover, TL1A expression was found to be associated with the clinical and MRI findings of MS patients suggesting its possible involvement in the establishment or preservation of immune system homeostasis or in the regulation of inflammatory activity. Taken together, these findings suggest the TL1A should be evaluated further for its potential as a candidate biomarker of inflammatory activity and the marker of therapeutic response to immunomodulatory treatments in MS.

Effects of inflammatory cytokines IFN-γ, TNF-α and IL-6 on the viability and functionality of human pluripotent stem cell-derived neural cells.

Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease, where neural progenitor cell (NPC) transplantation has been suggested as a potential neuroprotective therapeutic strategy. Since the effect of inflammation on NPCs is poorly known, their effect on the survival and functionality of human NPCs were studied. Treatment with interleukin (IL)-6, tumor necrosis factor (TNF)-α and interferon (IFN)-γ did not induced cytotoxicity, but IFN-γ treatment showed decreased proliferation and neuronal migration. By contrast, increased proliferation and inhibition of electrical activity were detected after TNF-α treatment. Treatments induced secretion of inflammatory factors. Inflammatory cytokines appear to modulate proliferation as well as the cellular and functional properties of human NPCs.

Diffusion tensor imaging and disability progression in multiple sclerosis: A 4-year follow-up study.

OBJECTIVES: Diffusion tensor imaging (DTI) is sensitive technique to detect widespread changes in water diffusivity in the normal-appearing white matter (NAWM) that appears unaffected in conventional magnetic resonance imaging. We aimed to investigate the prognostic value and stability of DTI indices in the NAWM of the brain in an assessment of disability progression in patients with a relapsing-onset multiple sclerosis (MS). METHODS: Forty-six MS patients were studied for DTI indices (fractional anisotropy (FA), mean diffusivity (MD), radial (RD), and axial (AD) diffusivity) in the NAWM of the corpus callosum (CC) and the internal capsule at baseline and at 1 year after. DTI analysis for 10 healthy controls was also performed at baseline. Simultaneously, focal brain lesion volume and atrophy measurements were done at baseline for MS patients. Associations between DTI indices, volumetric measurements, and disability progression over 4 years were studied by multivariate logistic regression analysis. RESULTS: At baseline, most DTI metrics differed significantly between MS patients and healthy controls. There was tendency for associations between baseline DTI indices in the CC and disability progression (p < 0.05). Changes in DTI indices over 1 year were observed only in the CC (p < 0.008), and those changes were not found to predict clinical worsening over 4 years. Clear-cut association with disability progression was not detected for baseline volumetric measurements. CONCLUSION: Aberrant diffusivity measures in the NAWM of the CC may provide additional information for individual disability progression over 4 years in MS with the relapsing-onset disease. CC may be a good target for DTI measurements in monitoring disease activity in MS, and more studies are needed to assess the related prognostic potential.

JCPyV microRNA in plasma inversely correlates with JCPyV seropositivity among long-term natalizumab-treated relapsing-remitting multiple sclerosis patients.

Sensitive biomarkers are needed to better manage multiple sclerosis (MS) patients for natalizumab (NTZ)-associated risk of progressive multifocal leukoencephalopathy (PML). A currently used risk stratification algorithm, mainly based on JC polyomavirus (JCPyV) serology, has not led to a reduction of PML incidence. Therefore, this study was designed to evaluate the presence and prevalence of JCPyV miRNAs in plasma of NTZ-treated MS patients, and to explore their biomarker potential for NTZ-associated PML risk assessment. Altogether, 102 plasma samples from 49 NTZ-treated and 28 interferon-beta (IFN-ß)-treated relapsing-remitting MS patients, and 25 healthy controls (HCs) were analyzed for jcv-miR-J1-5p (5p miRNA) and jcv-miR-J1-3p (3p miRNA) expression. The overall detection rate of 5p miRNA was 84% (41/49) among NTZ-treated patients, 75% (21/28) among IFN-ß-treated patients, and 92% (23/25) in HCs. Relative 5p miRNA expression levels were lower in NTZ-treated patients as compared to patients treated with IFN-ß (p = 0.027) but not to HCs. Moreover, 5p miRNA expression inversely correlated with anti-JCPyV antibody index among JCPyV seropositive long-term NTZ-treated patients (r = -0.756; p = 0.002). The overall detection rate of 3p miRNA was low. Our results suggest that JCPyV miRNA in plasma may be linked to the reactivation of persistent JCPyV, to enhanced virus replication, and eventually to the risk of developing PML among NTZ-treated MS patients. However, further study is warranted in a larger data set including samples from PML patients to confirm the clinical relevance of JCPyV miRNA as a sign of/in viral reactivation, and to identify its potential to predict developing PML risk.

Circulating microRNAs as biomarkers in progressive multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), microRNA (miRNA) dysregulation is mostly reported in different immune cells, but less information is available on circulating miRNAs that exert strong biomarker potential due to their exceptional stability in body fluids. OBJECTIVE: The aim of this study was to profile expression of circulating miRNAs in primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS) and assess their association with neurological worsening. METHODS: The expressions of 84 different miRNAs were profiled in serum of 83 subjects (62 MS and 21 controls) using miScript miRNA techniques. First, they were screened on 18 PPMS and 10 controls; thereafter, 10 most aberrantly expressed miRNAs were validated on a larger cohort. RESULTS: In comparison with controls, upregulation of miR-191-5p was found in both progressive MS subtypes, while miR-376c-3p was overexpressed only in PPMS. Additionally, upregulation of miR-128-3p and miR-24-3p was detected in PPMS when compared to controls and SPMS. Progression index correlated with miR-128-3p in PPMS and miR-375 in SPMS. CONCLUSION: We detected overexpression of four miRNAs that have not been previously associated with progressive forms of MS. The increased expression of circulating miR-191-5p seems to be associated with progressive forms of MS, while miR-128-3p seems to be associated mostly with PPMS.

Adipsin Is Associated with Multiple Sclerosis: A Follow-Up Study of Adipokines.

Background and Objective. The role of adipokines in regulation of immune responses has been recognized, but very little is known about their impact on multiple sclerosis (MS). In this study, we analysed whether the major adipokines are differentially expressed in plasma of patients with different MS subtypes and clinically isolated syndrome (CIS) and explored their association with major disease characteristics. Methods. The levels of adiponectin, adipsin, leptin, and resistin in the plasma of 80 patients with different subtypes of MS and CIS were followed up annually over the two years. The data obtained were correlated with disease activity, EDSS and volumes of T1-weighted lesions (T1-LV), and fluid attenuation inversion recovery lesions (FLAIR-LV) on MRI. Results. In MS group, a correlation was found between the level of adipsin and EDSS score at baseline (r = 0.506, p < 0.001). In RRMS, the levels of adipsin correlated with EDSS scores (r = 0.542, p = 0.002), T1-LV (r = 0.410, p = 0.034), and FLAIR-LV (r = 0.601, p = 0.0001) at baseline and an increase in the T1-LV over the follow-up (r = 0.582, p = 0.003). Associations with other adipokines were not detected. Conclusion. Our exploratory study provides novel insights on the impact of adipokines in MS and suggests that adipsin exerts predictive potential as a biomarker of neurodegeneration.

Association between soluble L-selectin and anti-JCV antibodies in natalizumab-treated relapsing-remitting MS patients.

OBJECTIVE: In relapsing-remitting MS (RRMS) patients treated with natalizumab, the low level of L-selectin-expressing CD4+ T cells has been associated with the risk of progressive multifocal leukoencephalopathy (PML). In this study, our aim was to correlate the levels of soluble L-selectin and the anti-JCV antibody index in the sera of RRMS patients treated with natalizumab. METHODS: This study included 99 subjects, including 44 RRMS patients treated with natalizumab, 30 with interferon beta (IFN-ß) and 25 healthy controls. The levels of soluble L-selectin (sL-selectin) in sera were measured by ELISA, and the anti-JC Virus (JCV) antibody index was determined by the second-generation ELISA (STRATIFY JCV™ DxSelect™) assay. RESULTS: A significant correlation was found between the levels of sL-selectin and anti-JCV antibody indices in sera in the natalizumab-treated patients (r=0.402; p=0.007; n=44), but not in those treated with IFN-ß. This correlation became even stronger in JCV seropositive patients treated with natalizumab for longer than 18 months (r=0.529; p=0.043; n=15). CONCLUSION: The results support the hypothesis of sL-selectin being connected to the anti-JCV antibody index values and possibly cellular L-selectin. Measurement of serum sL-selectin should be evaluated further as a potential biomarker for predicting the risk of developing PML.

Analysis of apoptosis-related genes in patients with clinically isolated syndrome and their association with conversion to multiple sclerosis.

To analyse whether the expression of apoptotic transcripts is associated with the conversion from clinically isolated syndrome (CIS) to multiple sclerosis (MS). Eleven candidate transcripts belonging to the death receptor pathway, BCL-2, the inflammasome complex and NF-ΚB family were studied in the nonconverting and converting CIS patients during the four-year follow-up period. Conversion to MS was associated with marked variability in the expression of proapoptotic genes that were linked to TGF-B1 gene levels. The predominant expression of proapoptotic genes in patients with CIS suggests an increased potential to undergo apoptosis with the goal of terminating immune responses and regulating immune system homeostasis.

Longitudinal assessment of clinically isolated syndrome with diffusion tensor imaging and volumetric MRI.

The potential of diffusion tensor imaging (DTI) indices and volumes of focal lesions on conventional magnetic resonance imaging to predict conversion to multiple sclerosis (MS) was analyzed in subjects with clinically isolated syndrome (CIS) over 4 years. Twenty patients with CIS and 10 healthy controls were included in the study. The data showed an association between the volumes of T1 and fluid-attenuated inversion recovery (FLAIR) lesions and conversion to MS (T1: P=.02; FLAIR: P=.02). The worsening of DTI indices (mean diffusivity and fractional anisotropy) was primarily seen in patients progressing to MS, but clear-cut association with conversion could not be detected.

Hemispheric asymmetry measured by texture analysis and diffusion tensor imaging in two multiple sclerosis subtypes.

BACKGROUND: This paper addresses two subtypes of multiple sclerosis (MS), primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS). The separation of PPMS and RRMS is challenging in certain cases. PURPOSE: To quantitatively determine MS subtypes using texture analysis (TA) and diffusion tensor imaging (DTI). MATERIAL AND METHODS: T1-weighted (T1W) magnetic resonance imaging (MRI) and DTI of the left and right brain hemispheres of 17 patients with PPMS and 19 patients with RRMS were studied. Areas of the caudate nucleus and thalamus were investigated as normal appearing gray matter (NAGM), and areas of the cerebral peduncle and centrum semiovale were investigated as normal appearing white matter (NAWM). The described locations were symmetrical and were accurately marked. TA was performed on the T1W images, and the fractional anisotropy and apparent diffusion coefficient were determined from the DTI data. RESULTS: Hemispherical differences were found with both TA and DTI. Several texture and diffusion tensor parameter values calculated for the left and right hemispheres of the patients showed statistically significant differences. The patients with RRMS had greater significant differences (P < 0.01) in the thalamus between the hemispheres than did the patients with PPMS. The TA classification accuracy of the PPMS and RRMS subtypes was above 80%. CONCLUSION: TA can be helpful when distinguishing between PPMS and RRMS, while DTI appears to reveal the hemispherical asymmetry of RRMS patients.

Healthy human CSF promotes glial differentiation of hESC-derived neural cells while retaining spontaneous activity in existing neuronal networks.

The possibilities of human pluripotent stem cell-derived neural cells from the basic research tool to a treatment option in regenerative medicine have been well recognized. These cells also offer an interesting tool for in vitro models of neuronal networks to be used for drug screening and neurotoxicological studies and for patient/disease specific in vitro models. Here, as aiming to develop a reductionistic in vitro human neuronal network model, we tested whether human embryonic stem cell (hESC)-derived neural cells could be cultured in human cerebrospinal fluid (CSF) in order to better mimic the in vivo conditions. Our results showed that CSF altered the differentiation of hESC-derived neural cells towards glial cells at the expense of neuronal differentiation. The proliferation rate was reduced in CSF cultures. However, even though the use of CSF as the culture medium altered the glial vs. neuronal differentiation rate, the pre-existing spontaneous activity of the neuronal networks persisted throughout the study. These results suggest that it is possible to develop fully human cell and culture-based environments that can further be modified for various in vitro modeling purposes.

Diffusion Tensor Imaging in NAWM and NADGM in MS and CIS: Association with Candidate Biomarkers in Sera.

The aim of this study was to evaluate diffusion tensor imaging (DTI) indices in the corpus callosum and pyramidal tract in normal-appearing white matter (NAWM) and the caudate nucleus and thalamus in deep grey matter (NADGM) in all MS subtypes and clinically isolated syndrome (CIS). Furthermore, it was determined whether these metrics are associated with clinical measures and the serum levels of candidate immune biomarkers. Apparent diffusion coefficients (ADC) values were significantly higher than in controls in all six studied NAWM regions in SPMS, 4/6 regions in RRMS and PPMS and 2/6 regions in CIS. In contrast, decreased fractional anisotropy (FA) values in comparison to controls were detected in 2/6 NAWM regions in SPMS and 1/6 in RRMS and PPMS. In RRMS, the level of neurological disability correlated with thalamic FA values (r = 0.479, P = 0.004). In chronic progressive subtypes and CIS, ADC values of NAWM and NADGM were associated with the levels of MIF, sFas, and sTNF- α . Our data indicate that DTI may be useful in detecting pathological changes in NAWM and NADGM in MS patients and that these changes are related to neurological disability.

Melatonin pathway genes are associated with progressive subtypes and disability status in multiple sclerosis among Finnish patients.

In this study we investigated the relationship between melatonin pathway and multiple sclerosis (MS) in a high-risk Finnish population by studying the single nucleotide polymorphisms (SNPs) in the genes coding for critical enzymes and receptors involved in the melatonin pathway. A total of 590 subjects (193 MS patients and 397 healthy controls) were genotyped for seven SNPs in four genes including tryptophan hydroxylases (TPH)1 and 2, arylalkylamine N-acetyltransferase (AANAT) and melatonin receptor 1B (MTNR1B). An overrepresentation of T allele carriers of a functional polymorphism (G-703T, rs4570625) in the promoter region of TPH2 gene was observed in the progressive MS subtypes. The haplotype rs4570625-rs10506645TT of TPH2 gene was associated with the risk of severe disability in primary progressive MS (PPMS), while haplotype rs4570625-rs10506645TC appeared to be protective against disability in secondary progressive MS (SPMS). In the MTNR1B gene, the haplotype rs10830963-rs4753426GC was associated with the risk of SPMS, whereas another haplotype rs10830963-rs4753426GT showed an association with the risk of PPMS. These data showing the association of polymorphisms in the TPH2 and MTNR1B genes with the progressive subtypes of MS and disability suggest dysregulation in melatonin pathway. Melatonin pathway seems to be involved in disease progression, and therefore its potential effects in overcoming MS-related neurodegeneration may be worth evaluating in future clinical trials.

Disease-associated inflammatory biomarker profiles in blood in different subtypes of multiple sclerosis: prospective clinical and MRI follow-up study.

To identify biomarkers of disease activity and progression in multiple sclerosis (MS), we analyzed the serum profiles of cytokines, chemokines and apoptotic molecules in different subtypes of MS including clinically isolated syndrome (CIS) and correlated their levels with clinical and volumetric MRI findings obtained over a one-year follow up. Upregulated levels of apoptotic sFas molecule were found in MS patients with a worsening EDSS score and an accumulation of hypointense lesions in MRI. In such patients, the levels of MIF appeared to be higher than in non-progressing patients. In addition, increased levels of serum TNF-α and CCL2 were found especially in primary progressive MS (PPMS). These observations suggest that serum Fas and MIF are candidate biomarkers of neurological worsening related to progressive neurodegeneration, while serum TNF-α and CCL2 reflect the presence of inflammatory responses in PPMS.