Sanna Hagman

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.

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.

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.

Anti-JC virus seroprevalence in a Finnish MS cohort

The risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV) is increased in patients with multiple sclerosis receiving biological therapies.

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-β) 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-β. 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.

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.

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

Summary 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.

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.

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.