Clinical Subtypes Of Multiple Sclerosis Research Articles

The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing-remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis.

Association between LAG3/CD4 Genes Variants and Risk for Multiple Sclerosis

Several recent works have raised the possibility of the contribution of the lymphocyte activation gene 3 (LAG3) protein in the inflammatory processes of multiple sclerosis (MS). Results of studies on the possible association between LAG3 gene variants and the risk of MS have been inconclusive. In this study, we tried to show the possible association between the most common single nucleotide variants (SNVs) in the CD4 and LAG3 genes (these two genes are closely related) and the risk of MS in the Caucasian Spanish population. We studied the genotypes and allelic variants CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 in 300 patients diagnosed with MS and 400 healthy patients using specific TaqMan-based qPCR assays. We analyzed the possible influence of the genotype frequency on age at the onset of MS, the severity of MS, clinical evolutive subtypes of MS, and the HLADRB1*1501 genotype. The frequencies of the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants were not associated with the risk of MS and were unrelated to gender, age at onset and severity of MS, the clinical subtype of MS, and HLADRB1*1501 genotype. The results of the current study showed a lack of association between the CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 SNVs and the risk of developing MS in the Caucasian Spanish population.

Phenotyping of multiple sclerosis lesions according to innate immune cell activation using 18 kDa translocator protein-PET.

Chronic active lesions are promotors of neurodegeneration and disease progression in multiple sclerosis. They harbour a dense rim of activated innate immune cells at the lesion edge, which promotes lesion growth and thereby induces damage. Conventional MRI is of limited help in identifying the chronic active lesions, so alternative imaging modalities are needed. Objectives were to develop a PET-based automated analysis method for phenotyping of chronic lesions based on lesion-associated innate immune cell activation and to comprehensively evaluate the prevalence of these lesions in the various clinical subtypes of multiple sclerosis, and their association with disability. In this work, we use 18 kDa translocator protein-PET imaging for phenotyping chronic multiple sclerosis lesions at a large scale. For this, we identified 1510 white matter T1-hypointense lesions from 91 multiple sclerosis patients (67 relapsing–remitting patients and 24 secondary progressive patients). Innate immune cell activation at the lesion rim was measured using PET imaging and the 18 kDa translocator protein-binding radioligand 11C-PK11195. A T1-hypointense lesion was classified as rim-active if the distribution volume ratio of 11C-PK11195-binding was low in the plaque core and considerably higher at the plaque edge. If no significant ligand binding was observed, the lesion was classified as inactive. Plaques that had considerable ligand binding both in the core and at the rim were classified as overall-active. Conventional MRI and disability assessment using the Expanded Disability Status Scale were performed at the time of PET imaging. In the secondary progressive cohort, an average of 19% (median, interquartile range: 11–26) of T1 lesions were rim-active in each individual patient, compared to 10% (interquartile range: 0–20) among relapsing–remitting patients (P = 0.009). Secondary progressive patients had a median of 3 (range: 0–11) rim-active lesions, versus 1 (range: 0–18) among relapsing–remitting patients (P = 0.029). Among those patients who had rim-active lesions (n = 63), the average number of active voxels at the rim was higher among secondary progressive compared to relapsing–remitting patients (median 158 versus 74; P = 0.022). The number of active voxels at the rim correlated significantly with the Expanded Disability Status Scale (R = 0.43, P < 0.001), and the volume of the rim-active lesions similarly correlated with the Expanded Disability Status Scale (R = 0.45, P < 0.001). Our study is the first to report in vivo phenotyping of chronic lesions at large scale, based on 18 kDa translocator protein-PET. Patients with higher disability displayed a higher proportion of rim-active lesions. The in vivo lesion phenotyping methodology offers a new tool for individual assessment of smouldering (rim-active) lesion burden.

Understanding quality of life across different clinical subtypes of multiple sclerosis: a thematic analysis.

Multiple sclerosis (MS) is a neurological disease that has different clinical presentations and illness trajectories. The aim of this study was to explore factors that are important for quality of life (QoL) of people with MS (pwMS), and to understand how they may differ across three subtypes. Both convenience and purposive sampling were employed. Semi-structured interviews were conducted with people with relapsing-remitting MS (n = 16), secondary progressive MS (n = 14), and primary progressive MS (n = 13). All interviews were audio recorded and then transcribed verbatim for thematic analysis involving both inductive and deductive processes. A separate analysis for each subtype was made during the inductive process before examining for similarities and differences across the three subtypes in the deductive process. Four factors were identified to have an important influence on QoL of pwMS: restricted and disrupted enjoyment, disturbed future, challenged sense of self, and well-being of significant others. The themes reflect how pwMS commonly perceived enjoyment as a purpose of life, while also illustrating how their QoL may be questioned because of new perspectives going forward with MS, challenges to their sense of self, and increased concerns for their significant others as a result of MS. Subtype differences were attributed to different illness trajectories: relapsing or progressive. There are subtype differences in the negative impact of MS on QoL. Clinicians are encouraged to understand the challenges of different illness trajectories, in particular the traumatic nature of relapses and steady worsening of symptoms among those with progressive subtypes of MS.

Astrocyte Heterogeneity in Multiple Sclerosis: Current Understanding and Technical Challenges.

The emergence of single cell technologies provides the opportunity to characterize complex immune/central nervous system cell assemblies in multiple sclerosis (MS) and to study their cell population structures, network activation and dynamics at unprecedented depths. In this review, we summarize the current knowledge of astrocyte subpopulations in MS tissue and discuss the challenges associated with resolving astrocyte heterogeneity with single-nucleus RNA-sequencing (snRNA-seq). We further discuss multiplexed imaging techniques as tools for defining population clusters within a spatial context. Finally, we will provide an outlook on how these technologies may aid in answering unresolved questions in MS, such as the glial phenotypes that drive MS progression and/or neuropathological differences between different clinical MS subtypes.

Classification of multiple sclerosis based on patterns of CNS regional atrophy covariance.

There is evidence that multiple sclerosis (MS) pathology leads to distinct patterns of volume loss over time (VLOT) in different central nervous system (CNS) structures. We aimed to use such patterns to identify patient subgroups. MS patients of all classical disease phenotypes underwent annual clinical, blood, and MRI examinations over 6 years. Spinal, striatal, pallidal, thalamic, cortical, white matter, and T2‐weighted lesion volumes as well as serum neurofilament light chain (sNfL) were quantified. CNS VLOT patterns were identified using principal component analysis and patients were classified using hierarchical cluster analysis. 225 MS patients were classified into four distinct Groups A, B, C, and D including 14, 59, 141, and 11 patients, respectively). These groups did not differ in baseline demographics, disease duration, disease phenotype distribution, and lesion‐load expansion. Interestingly, Group A showed pronounced spinothalamic VLOT, Group B marked pallidal VLOT, Group C small between‐structure VLOT differences, and Group D myelocortical volume increase and pronounced white matter VLOT. Neurologic deficits were more severe and progressed faster in Group A that also had higher mean sNfL levels than all other groups. Group B experienced more frequent relapses than Group C. In conclusion, there are distinct patterns of VLOT across the CNS in MS patients, which do not overlap with clinical MS subtypes and are independent of disease duration and lesion‐load but are partially associated to sNfL levels, relapse rates, and clinical worsening. Our findings support the need for a more biologic classification of MS subtypes including volumetric and body‐fluid markers.

Endothelial nitric oxide synthase (NOS3) rs2070744 polymorphism and risk for multiple sclerosis.

The possible role of oxidative stress and nitric oxide (NO) in the pathogenesis of multiple sclerosis (MS) has been suggested by several neuropathological, biochemical, and experimental data. Because the single-nucleotide polymorphism (SNP) rs2070744 in the endothelial nitric oxide synthase (eNOS or NOS3) gene (chromosome 7q36.1) showed association with the risk for MS in Iranians, we attempted to replicate the possible association between this SNP and the risk for MS in the Caucasian Spanish population. The frequencies of NOS3rs2070744 genotypes and allelic variants in 300 patients diagnosed with MS and 380 healthy controls were assessed with a TaqMan-based qPCR assay. The possible influence of the genotype frequency on age at onset of MS, the severity of MS, clinical evolutive subtypes of MS, and HLA-DRB1*1501 genotype were also analyzed. The frequencies of rs2070744 genotypes and allelic variants were not associated with the risk of developing MS and were not influenced by gender, age at onset and severity of MS, the clinical subtype of MS or the HLA-DRB1*1501 genotype. This study found a lack of association between NOS3 rs2070744 SNP and the risk for MS in Caucasian Spanish people.

Diffusion basis spectrum imaging for identifying pathologies in MS subtypes.

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal‐appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and nonrestricted isotropic fraction (representing edema). This study provides preliminary evidence supporting the ability of DBSI as a potential noninvasive biomarker of MS neuropathology.

Peripapillary retinal nerve fiber layer thickness measured by optical coherence tomography in different clinical subtypes of multiple sclerosis

BackgroundMultiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the central nervous system (CNS) with axonal degeneration as major determinant of neurological disability. Assessment of unmyelinated retinal nerve fibers using optical coherence tomography (OCT) may be useful for diagnosing the onset and rate of progression of neurodegeneration. ObjectiveTo assess the incidence and severity of damage of the peripapillary retinal nerve fiber layer (RNFL) in two different MS subtypes: non-progressive [Prog(-)MS] and progressive [Prog(+)MS]. Methods48 patients (96 eyes) with MS were included: 13 males, 35 females; aged 22–62 years (mean 38.8; SD ± 10.02) in two subgroups: 26 Prog(-)MS and 22 Prog(+)MS. 3 subtypes of Prog(+)MS were identified by neurologist, according to Lublin criteria: 3 patients had PPMS (14%), 7 had SPMS(32%), 12 had PRMS(54%). RRMS subtype was considered a non-progressive phenotype, designated as Prog(-)MS. All 22 patients with progressive MS phenotypes were included in one group, designated as Prog(+)MS. Progressive disease can be defined over 1 year. The expanded EDSS score was determined by the treating MS specialist and confirmed by the study investigators through the records review. Definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step≥4 and pyramidal score≥2. 11 Prog(-)MS (16 eyes) and 10 Prog(+)MS (13 eyes) patients had a history of optic neuritis (ON). EDSS score was 1.5–6.5 (mean 3.83 ± 1.62) in the Prog(+)MS group and 1.0–3.5 (mean 1.40 ± 0.57) in the Prog(-)MS. Control group: 31 healthy volunteers (3 males, 28 females), aged 20–62 years (mean 37.4 ± 10.88). Peripapillary RNFL thickness was measured around the optic nerve head (ONH) using spectral-domain OCT (Topcon OCT 1000 MarkII, FastMap v. 3.40, Topcon, Japan). Scans were obtained according to OSCAR-IB consensus criteria.The generalized estimating equation model (GEE) was used in the statistical analysis to assess differences in RNFL thickness between Prog(-)MS and Prog(+)MS patients, taking into consideration history of ON, EDSS score, immunomodulatory therapy, MS progression, MS duration, age and gender.The protocol was approved by the Ethical Committee of the Medical Centre of Postgraduate Education, Warsaw, Poland and informed consent was obtained from all subjects. ResultsThere was a significant difference between Prog(-)MS and Prog(+)MS groups for mean, nasal and superior quadrant of RNFL thickness. For individuals with a history of ON, significant differences were found between the two MS phenotypes regardless of RNFL thickness measurements. ConclusionsA significant correlation was established between RNFL thickness and progression of neurodegeneration in MS patients with no regard to history of ON. RNFL thickness may be considered a MS biomarker and potential diagnostic tool for assessment of disease progression.

A Pilot Investigation of Natural Killer Cell Function and Phenotypes in Stable and Active Multiple Sclerosis Patients

Background: Previous studies have reported impaired cytotoxic activity in Natural Killer (NK) CD56Dim and CD56Bright cell phenotypes in peripheral blood associated with Multiple Sclerosis (MS). Recently it has been suggested that NK cell phenotype could be associated with new lesions on Magnetic resonance imaging (MRI) and may be used as an immunological indicator of disease activity. This project, for the first time, investigates NK cell cytotoxicity in MS patients with active and stable lesions.Methods: NK cell cytotoxic activity and NK CD56Dim and CD56Bright cell phenotypes were examined in MS patients using flow cytometry. Isolated NK cells were labelled with antibodies to determine CD56Dim and CD56Bright NK cells and cytotoxic function using target cells (K562). Seven patients (aged 38.0 ± 3.21) with stable Relapsing Remitting MS (RRMS) who had previously received alemtuzumab (Lemtrada®), five patients with active MS (aged 32.66 ± 5.17) on nil medication and five healthy controls (aged 34.4 ± 6.12) participated.Results: There were no significant differences for NK cell cytotoxic activity and NK CD56Dim and CD56Bright phenotypes between stable RRMS, active RRMS and healthy controls.Conclusion: Clear associations between NK cell cytotoxicity and clinical MS subtypes in this study were not identified.

Cerebrospinal fluid B cells and disease progression in multiple sclerosis - A longitudinal prospective study.

BackgroundThere is evidence that B cells play an important role in disease pathology of multiple sclerosis (MS). The aim of this prospective observational study was to determine the predictive value of cerebrospinal fluid (CSF) B cell subtypes in disease evolution of patients with MS.Materials and methods128 patients were included between 2004 and 2012. Median follow up time was 7.9 years (range 3.3–10.8 years). 10 patients were lost to follow-up. 32 clinically isolated syndrome- (CIS), 25 relapsing remitting MS- (RRMS), 2 secondary progressive MS- (SPMS) and 9 primary progressive MS- (PPMS) patients were included. The control group consisted of 40 patients with other neurological diseases (OND). CSF samples were analyzed for routine diagnostic parameters. B cell phenotypes were characterized by flow cytometry using CD19 and CD138 specific antibodies. Standardized baseline brain MRI was conducted at the time of diagnostic lumbar puncture. Main outcome variables were likelihood of progressive disease course, EDSS progression, conversion to clinical definite MS (CDMS) and relapse rate.ResultsCSF mature B cells (CD19+CD138-) were increased in bout-onset MS compared to PPMS (p<0.05) and OND (p<0.001), whereas plasma blasts (CD19+CD138+) were increased in bout-onset MS (p<0.001) and PPMS (p<0.05) compared to OND. CSF B cells did not predict a progressive disease course, EDSS progression, an increased relapse rate or the conversion to CDMS. Likelihood of progressive disease course (p<0.05) and EDSS (p<0.01) was predicted by higher age at baseline, whereas conversion to CDMS was predicted by a lower age at onset (p<0.01) and the presence of ≥9 MRI T2 lesions (p<0.05).ConclusionWe detected significant differences in the CSF B cell subsets between different clinical MS subtypes and OND patients. CSF B cells were neither predictive for disease and EDSS progression nor conversion to CDMS after a CIS.

The association between retinal nerve fibre layer thickness and corpus callosum index in different clinical subtypes of multiple sclerosis.

The objective of this paper is to evaluate the association between physical disability in multiple sclerosis (MS) patients, the thickness of the retinal nerve fibre layer (RNFL) and corpus callosum volumes, as expressed by the corpus callosum index (CCI). This study was based on a cohort of 212 MS patients and 52 healthy control subjects, who were age and gender matched. The MS patients included 144 women and 177 relapsing-remitting MS (RRMS) patients. Peripapillary and volumetric optical coherence tomography (OCT) scans of the macula were performed using spectral-domain OCT technology. All magnetic resonance imaging (MRI) scans were performed using 1.5-T systems. CCI and RNFL were lower in MS than healthy control subjects (0.341 versus 0.386, p<0.01 and 92.1 versus 105.0, p<0.01). In addition, CCI correlated with RNFL (r=0.464, p<0.01). This was also true for the subgroup of patients with no history of optic neuritis (ON). There is a correlation between the thickness of the RNFL and CCI values in MS patients with no history of ON, which suggests that OCT might be a suitable marker for neurodegeneration in MS clinical trials.

Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression

Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers.

Effects of dietary supplementation with lemon verbena extracts on serum inflammatory markers of multiple sclerosis patients.

Inflammation is one of the main contributory factors to the etiopathogenesis of multiple sclerosis (MS). Dietary interventions with Lipia citriadora (lemon verbena) extracts have been proved to be effective in the prevention of inflammatory diseases. The aim of this study is to evaluate the effect of lemon verbena supplementation in pro- and anti- inflammatory serum biomarkers of patients with different clinical subtypes of multiple sclerosis. The effect of lemon verbena supplementation (10% w/w verbascoside) was evaluated in a randomized, double-blinded placebo-controlled study with 30 participants classified in relapsing-remitting (n=10), primary progressive (n=5) and secondary progressive (n=15) MS presentations. Serum cytokine and C reactive protein levels were assessed in intervention and control groups for each MS clinical subtype after 28 days of dietary supplementation. Serum levels of C reactive protein and 8 cytokines/ inflammatory (IFN-γ, IL-12, IL-23, IL-6, TNF-α, TGF-β, IL-4 and IL-10) markers were studied. Secondary progressive MS- supplemented patients showed C reactive protein concentrations significantly lower compared to the placebo group (p.

Gradient echo magnetic resonance imaging correlates with clinical measures and allows visualization of veins within multiple sclerosis lesions

Background: Conventional magnetic resonance imaging (MRI) methods do not quantify the severity of multiple sclerosis (MS) white matter lesions or measure pathology within normal-appearing white matter (NAWM). Objective: Gradient Echo Plural Contrast Imaging (GEPCI), a fast MRI technique producing inherently co-registered images for qualitative and quantitative assessment of MS, was used to 1) correlate with disability; 2) distinguish clinical MS subtypes; 3) determine prevalence of veins co-localized within lesions in WM. Methods: Thirty subjects representing relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS) subtypes were scanned with clinical and GEPCI protocols. Standard measures of physical disability and cognition were correlated with magnetic resonance metrics. Lesions with central veins were counted for RRMS subjects. Results: Tissue damage load (TDL-GEPCI) and lesion load (LL-GEPCI) derived with GEPCI correlated better with MS functional composite (MSFC) measures and most other neurologic measures than lesion load derived with FLAIR (LL-FLAIR). GEPCI correctly classified clinical subtypes in 70% subjects. A central vein could be identified in 76% of WM lesions in RRMS subjects on GEPCI T2*-SWI images. Conclusion: GEPCI lesion metrics correlated better with neurologic disability than lesion load derived using FLAIR imaging, and showed promise in classifying clinical subtypes of MS. These improvements are likely attributable to the ability of GEPCI to quantify tissue damage.

Low Serum Urate Levels Are Associated to Female Gender in Multiple Sclerosis Patients

BackgroundUrate is a natural antioxidant and may prevent CNS tissue damage and the clinical manifestations of experimental autoimmune encephalitis. Results from clinical studies are conflicting and the contribution of urate to the pathogenesis of Multiple Sclerosis (MS) remains uncertain.ObjectiveTo evaluate serum urate levels in MS patients and their relationships with clinical, demographic and MRI variables.MethodsLevels of non-fasting serum uric acid and creatinine were determined by an automated enzymatic assay and glomerular filtration rate was assessed in 245 MS patients, in 252 age/sex-matched neurological controls (NC) and in 59 Healthy controls (HC).ResultsMedian serum urate levels did not differ between MS patients (3.8 mg/dL), HC (4.0 mg/dl) and NC (4.0 mg/dL). Serum urate levels were lower in females than in males in all groups (p = <0.0001). In female-MS, serum urate levels (3.2 mg/dL) were lower compared to those in female HC (3.8; p = 0.01) and NC (3.5 mg/dL; p = 0.02), whereas in male-MS they(4.8 mg/dL) did not differ from those in male HC (4.5 mg/dl) and NC (4.8 mg/dL). Urate concentrations trended to be lower in Clinically isolated syndromes suggestive of MS (3.7 mg/dL) and in relapsing MS (3.7 mg/dL), compared to patients with progressive MS (4.4 mg/dL; p = 0.06), and in patients with an annual relapse rate (ARR) >2 (3.3 mg/dL) than in those with an ARR ≤2: 3.9 mg/dL; p = 0.05). Significant lower serum urate levels were found in females than in males in all clinical MS subtypes (p<0.01), separately evaluated. Female sex (beta: −0.53; p<0.00001) was the most significant determinant of serum urate concentrations in MS patients on multivariate regression analysis.ConclusionsOur findings suggest that low urate levels could be of significance in predominantly inflammatory phases of MS even at the early stage and mainly in females.

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

BackgroundSeveral lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls.Methodology/Principal FindingsWe have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5).Conclusions/SignificanceOur analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.

Regional White Matter Atrophy−Based Classification of Multiple Sclerosis in Cross-Sectional and Longitudinal Data

The different clinical subtypes of multiple sclerosis (MS) may reflect underlying differences in affected neuroanatomic regions. Our aim was to analyze the effectiveness of jointly using the inferior subolivary medulla oblongata volume (MOV) and the cross-sectional area of the corpus callosum in distinguishing patients with relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis (PPMS). We analyzed a cross-sectional dataset of 64 patients (30 RRMS, 14 SPMS, 20 PPMS) and a separate longitudinal dataset of 25 patients (114 MR imaging examinations). Twelve patients in the longitudinal dataset had converted from RRMS to SPMS. For all images, the MOV and corpus callosum were delineated manually and the corpus callosum was parcellated into 5 segments. Patients from the cross-sectional dataset were classified as RRMS, SPMS, or PPMS by using a decision tree algorithm with the following input features: brain parenchymal fraction, age, disease duration, MOV, total corpus callosum area and areas of 5 segments of the corpus callosum. To test the robustness of the classification technique, we applied the results derived from the cross-sectional analysis to the longitudinal dataset. MOV and central corpus callosum segment area were the 2 features retained by the decision tree. Patients with MOV >0.94 cm(3) were classified as having RRMS. Patients with progressive MS were further subclassified as having SPMS if the central corpus callosum segment area was <55.12 mm(2), and as having PPMS otherwise. In the cross-sectional dataset, 51/64 (80%) patients were correctly classified. For the longitudinal dataset, 88/114 (77%) patient time points were correctly classified as RRMS or SPMS. Classification techniques revealed differences in affected neuroanatomic regions in subtypes of multiple sclerosis. The combination of central corpus callosum segment area and MOV provides good discrimination among patients with RRMS, SPMS, and PPMS.

Dietary patterns in clinical subtypes of multiple sclerosis: an exploratory study

BackroundMultiple sclerosis is a neurodegenerative disorder with a wide range in disease course severity. Many factors seem to be implicated in multiple sclerosis disease course, and diet has been suggested to play a role. Because limited data is present in the literature it was investigated whether variations in dietary intake may be related to the severity of the disease course in multiple sclerosis.MethodsUsing a food diary during 14 days, the dietary intake of 23 nutrients and vitamins was measured in patients with primary progressive (n = 21), secondary progressive (n = 32), and benign multiple sclerosis (n = 27) and compared to each other. The intake measured was also compared to the intake of the Dutch population and to the recommended daily allowance.ResultsCompared to the other MS groups, the secondary progressive MS patients had a lower intake of magnesium, calcium and iron. The total group of MS patients had, compared to the Dutch population, a lower intake of folate, magnesium and copper and a lower energy intake. Compared to the daily recommended allowance, the MS patients had a lower than recommended intake of folic acid, magnesium, zinc and selenium.ConclusionMagnesium, calcium and iron intake may possibly be related to MS disease progression, and should receive further attention. This is important because no effective neuroprotective treatment for MS patients is available.

The diagnosis of multiple sclerosis and the clinical subtypes.

The diagnosis of multiple sclerosis (MS) requires objective findings referable to the central nervous system. A wide differential diagnosis often has to be considered. Magnetic resonance imaging and electrophysiologic and cerebrospinal fluid studies can all contribute to an early definitive diagnosis. The McDonald diagnostic criteria for MS (2005) are the currently recognized MS diagnostic criteria. The clinical subtypes of MS and their diagnosis are discussed in this article. Being informed of the diagnosis may be a stressful experience for the patient and this is also dealt with.