Analysis Of Multiple Sclerosis Research Articles

The clinico-radiological paradox of cognitive function and MRI burden of white matter lesions in people with multiple sclerosis: A systematic review and meta-analysis.

BackgroundModerate correlation exists between the imaging quantification of brain white matter lesions and cognitive performance in people with multiple sclerosis (MS). This may reflect the greater importance of other features, including subvisible pathology, or methodological limitations of the primary literature.ObjectivesTo summarise the cognitive clinico-radiological paradox and explore the potential methodological factors that could influence the assessment of this relationship.MethodsSystematic review and meta-analysis of primary research relating cognitive function to white matter lesion burden.ResultsFifty papers met eligibility criteria for review, and meta-analysis of overall results was possible in thirty-two (2050 participants). Aggregate correlation between cognition and T2 lesion burden was r = -0.30 (95% confidence interval: -0.34, -0.26). Wide methodological variability was seen, particularly related to key factors in the cognitive data capture and image analysis techniques.ConclusionsResolving the persistent clinico-radiological paradox will likely require simultaneous evaluation of multiple components of the complex pathology using optimum measurement techniques for both cognitive and MRI feature quantification. We recommend a consensus initiative to support common standards for image analysis in MS, enabling benchmarking while also supporting ongoing innovation.

Linked Patient-Reported Outcomes Data From Patients With Multiple Sclerosis Recruited on an Open Internet Platform to Health Care Claims Databases Identifies a Representative Population for Real-Life Data Analysis in Multiple Sclerosis.

BackgroundAn enormous amount of information relevant to public health is being generated directly by online communities.ObjectiveTo explore the feasibility of creating a dataset that links patient-reported outcomes data, from a Web-based survey of US patients with multiple sclerosis (MS) recruited on open Internet platforms, to health care utilization information from health care claims databases. The dataset was generated by linkage analysis to a broader MS population in the United States using both pharmacy and medical claims data sources.MethodsUS Facebook users with an interest in MS were alerted to a patient-reported survey by targeted advertisements. Eligibility criteria were diagnosis of MS by a specialist (primary progressive, relapsing-remitting, or secondary progressive), ≥12-month history of disease, age 18-65 years, and commercial health insurance. Participants completed a questionnaire including data on demographic and disease characteristics, current and earlier therapies, relapses, disability, health-related quality of life, and employment status and productivity. A unique anonymous profile was generated for each survey respondent. Each anonymous profile was linked to a number of medical and pharmacy claims datasets in the United States. Linkage rates were assessed and survey respondents’ representativeness was evaluated based on differences in the distribution of characteristics between the linked survey population and the general MS population in the claims databases.ResultsThe advertisement was placed on 1,063,973 Facebook users’ pages generating 68,674 clicks, 3719 survey attempts, and 651 successfully completed surveys, of which 440 could be linked to any of the claims databases for 2014 or 2015 (67.6% linkage rate). Overall, no significant differences were found between patients who were linked and not linked for educational status, ethnicity, current or prior disease-modifying therapy (DMT) treatment, or presence of a relapse in the last 12 months. The frequencies of the most common MS symptoms did not differ significantly between linked patients and the general MS population in the databases. Linked patients were slightly younger and less likely to be men than those who were not linkable.ConclusionsLinking patient-reported outcomes data, from a Web-based survey of US patients with MS recruited on open Internet platforms, to health care utilization information from claims databases may enable rapid generation of a large population of representative patients with MS suitable for outcomes analysis.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.

Subcortical gray matter segmentation and voxel-based analysis using transverse relaxation and quantitative susceptibility mapping with application to multiple sclerosis.

To investigate subcortical gray matter segmentation using transverse relaxation rate (R2 *) and quantitative susceptibility mapping (QSM) and apply it to voxel-based analysis in multiple sclerosis (MS). Voxel-based variation in R2 * and QSM within deep gray matter was examined and compared to standard whole-structure analysis using 37 MS subjects and 37 matched controls. Deep gray matter nuclei (caudate, putamen, globus pallidus, and thalamus) were automatically segmented and morphed onto a custom atlas based on QSM and standard T1 -weighted images. Segmentation accuracy and scan-rescan reliability were tested. When considering only significant regions as returned by the multivariate voxel-based analysis, increased R2 * and QSM was found in MS subjects compared to controls in portions of all four nuclei studied (P < 0.002). For R2 *, regional analysis yielded at least 66-fold improved P-value significance in all nuclei over standard whole-structure analysis, while for QSM only thalamus benefited, with 5-fold improvement in significance. Improved segmentation over standard methods, particularly for globus pallidus (2.8 times higher Dice score), was achieved by incorporating high-contrast QSM into the atlas. Voxel-based reliability was highest for QSM (<1% variation). Automatic segmentation of iron-rich deep gray matter can be improved by incorporating QSM. Voxel-based evaluation yielded increased R2 * and QSM in MS subjects in all four nuclei studied with R2 *, benefiting the most from localized analysis over whole-structure measures.

Does cerebrospinal fluid analysis add predictive value to magnetic resonance imaging for long term irreversible disability in patients with early multiple sclerosis?

BackgroundThe independent prognostic value of cerebrospinal fluid analysis in multiple sclerosis is not established. ObjectiveTo determine the prognostic value of intrathecal synthesis in a cohort of patients with relapsing-onset MS taking into consideration demographic and imaging parameters. MethodsIn this prospective cohort study conducted from 1993 to 2013, we analyzed the time to confirmed disability (persistent above 6months) and irreversible disability (persistent for the entire disease course) of two disability milestones, Expanded Disability Status Scale score ≥4 or 6, and the time to secondary progressive onset in 579 patients with relapsing-onset multiple sclerosis. Demographic parameters (age at onset, gender) and imaging parameters (periventricular lesions) were included in the Cox models. Results447 patients (77.2%) had intrathecal synthesis (oligoclonal bands and/or increased immunoglobulin G index value). No statistically significant relation was found between intrathecal synthesis and the time to reach each disability milestone or secondary progressive onset. An age older than 40years and more than 3 periventricular lesions predicted a worse prognosis. ConclusionsCerebrospinal fluid analysis did not predict the time to disability milestones in relapsing-onset multiple sclerosis independently of age and imaging data.

Using perceptive computing in multiple sclerosis - the Short Maximum Speed Walk test.

BackgroundWe investigated the applicability and feasibility of perceptive computing assisted gait analysis in multiple sclerosis (MS) patients using Microsoft Kinect™. To detect the maximum walking speed and the degree of spatial sway, we established a computerized and observer-independent measure, which we named Short Maximum Speed Walk (SMSW), and compared it to established clinical measures of gait disability in MS, namely the Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk (T25FW).MethodsCross-sectional study of 22 MS patients (age mean ± SD 43 ± 9 years, 13 female) and 22 age and gender matched healthy control subjects (HC) (age 37 ± 11 years, 13 female). The disability level of each MS patient was graded using the EDSS (median 3.0, range 0.0-6.0). All subjects then performed the SMSW and the Timed 25-Foot Walk (T25FW). The SMSW comprised five gait parameters, which together assessed average walking speed and gait stability in different dimensions (left/right, up/down and 3D deviation).ResultsSMSW average walking speed was slower in MS patients (1.6 ± 0.3 m/sec) than in HC (1.8 ± 0.4 m/sec) (p = 0.005) and correlated well with EDSS (Spearman’s Rho 0.676, p < 0.001). Furthermore, SMSW revealed higher left/right deviation in MS patients compared to HC. SMSW showed high recognition quality and retest-reliability (covariance 0.13 m/sec, ICC 0.965, p < 0.001). There was a significant correlation between SMSW average walking speed and T25FW (Pearson’s R = -0.447, p = 0.042).ConclusionOur data suggest that ambulation tests using Microsoft Kinect™ are feasible, well tolerated and can detect clinical gait disturbances in patients with MS. The retest-reliability was on par with the T25FW.

Epidemiological analysis of multiple sclerosis in Goias and in Brazil from 2008 to 2011

Epidemiological analysis of multiple sclerosis in Goias and in Brazil from 2008 to 2011

Indications, interests and limits of quantified motion analysis in multiple sclerosis: Review of the literature

Indications, interests and limits of quantified motion analysis in multiple sclerosis: Review of the literature

Retinal nerve fibre layer thickness by OCT3 provides direct assessment of axonal loss in optic neuritis and may help in the early diagnosis and progression analysis of multiple sclerosis

Context: Retinal nerve fibre layer (RNFL) being unmyelinated, RNFL thickness (RNFLT) provides direct evidence of axonal loss in optic neuritis (ON) and may prove to be a valuable diagnostic and prognostic tool in the development of multiple sclerosis (MS). Aims: Assessment of RNFLT by OCT3 in patients with recent onset retrobulbar ON, comparison of obtained values based on presence or absence of the periventricular white matter lesion (PVWML) on magnetic resonance imaging (MRI), comparison with the RNFLT of a control group, and analysis of the obtained results. Settings and Design: Cross-sectional study. Materials and Methods: Eighteen patients with Statistical Analysis Used: ANOVA and Student's t test. Results: ON eyes in group B had thinnest RNFLT (average temporal = 39.75 μ), followed by group A (average temporal = 44.3 μ), and finally by group C (average temporal-OU = 80.78 μ). Conclusions: Our study shows that patients with ON, irrespective of detection of PVWML on MRI, have thinner RNFL compared to age-matched controls (P < 0.001). The average RNFLT values are lowest in patients with PVWML. The aspect of RNFL thinning in non-ON eyes should be further studied as a possible subclinical indicator of MS.

Lipidome analysis in multiple sclerosis reveals protein lipoxidative damage as a potential pathogenic mechanism

Metabolomic and lipidomic analyses have been used for the profiling of neurodegenerative processes, both in targeted and untargeted approaches. In this work we have applied these techniques to the study of CSF samples of multiple sclerosis (MS) patients (n = 9), compared with samples of non-MS individuals (n = 9) using mass-spectrometry. We have used western-blot and analyzed cell culture to confirm pathogenic pathways suggested by mass-spectrometric measurements. The results of the untargeted approach of metabolomics and lipidomics suggest the existence of several metabolites and lipids discriminating both populations. Applying targeted lipidomic analyses focused to a pathogenic pathway in MS, oxidative stress, reveal that the lipid peroxidation marker 8-iso-prostaglandin F2α is increased in CSF from MS patients. Furthermore, as lipid peroxidation exerts its pathogenical effects through protein modification, we studied the incidence of protein lipoxidation, revealing specific increases in carboxymethylated, neuroketal and malondialdehyde-mediated protein modifications in proteins of CSF from MS patients, despite the absence of their precursors glyoxal and methylglyoxal. Finally, we report that the level of neuroketal-modified proteins correlated with a hitherto unknown increased amount of autoantibodies against lipid peroxidation-modified proteins in CSF, without compensation by signaling induced by lipid peroxidation via peroxisome proliferator-activated receptor γ (PPARγ). The results, despite the limitation of being obtained in a small population, strongly suggest that autoimmunity against in situ produced epitopes derived from lipid peroxidation can be a relevant pathogenic factor in MS.

Biochemical Markers of Autoimmune Diseases of the Nervous System

Biochemical biomarkers are important candidates for the diagnosis and prognosis of neurological diseases of autoimmune etiology, since they may reflect the presence, nature and intensity of certain immune responses caused by both genetic and environmental processes. Different body fluids such as cerebrospinal fluid (CSF), serum, urine, and tears have been used to identify useful biomarkers. Autoimmune neurological diseases associated with pathology of cell surface structures such as myasthenia gravis, Lambert-Eaton myasthenic syndrome, neuromyotonia, stiff person syndrome, limbic encephalitis, Guillain-Barré syndrome (GBS), and neuromyelitis optica (NMO) are amenable to serum antibody tests which can be used to support the diagnosis. In several of these disorders, new specific autoantibodies have been detected that are directed against proteins complexed with potassium channels in both the central and peripheral nervous system such as contactin-2 associated protein (Caspr2) or the protein leucine-rich, glioma-inactivated 1 (LGI1). Recently, a number of central nervous system disorders like limbic encephalitis and multiple sclerosis (MS) have also been associated with the presence of specific serum autoantibodies. In MS and GBS CSF analysis is still essential to support the diagnosis and to rule out other diseases. We provide an overview over the widening field of autoimmune diseases of the central and peripheral nervous system and discuss the current state of biomarker research and its relevance for clinical practice.

Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis

Interferon beta (IFNβ) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNβ-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNβ's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS- and IFNβ-associated gene expression suggests an IFNβ insufficiency in MS. We observed more gene expression changes in long-term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNβ treatment effects were developed and subsequently confirmed in independent IFNβ-1b-treated MS studies, but not in glatiramer acetate-treated patients.

MRI texture analysis in multiple sclerosis.

Multiple sclerosis (MS) is a complicated disease characterized by heterogeneous pathology that varies across individuals. Accurate identification and quantification of pathological changes may facilitate a better understanding of disease pathogenesis and progression and help identify novel therapies for MS patients. Texture analysis evaluates interpixel relationships that generate characteristic organizational patterns in an image, many of which are beyond the ability of visual perception. Given its promise detecting subtle structural alterations texture analysis may be an attractive means to evaluate disease activity and evolution. It may also become a new tool to assess therapeutic efficacy if technique issues are resolved and pathological correlates are further confirmed. This paper describes the concept, strategies, and considerations of MRI texture analysis; summarizes applications of texture analysis in MS as a measure of tissue integrity and its clinical relevance; then discusses potentially future directions of texture analysis in MS.

Metabolic Profiling in Multiple Sclerosis and Other Disorders by Quantitative Analysis of Cerebrospinal Fluid Using Nuclear Magnetic Resonance Spectroscopy

Cerebrospinal fluid (CSF) is being analyzed for the diagnosis of a variety of neurological diseases. Among the methods employed, metabolomics and proteomics are increasingly gaining popularity. At present, sensitivity and, in particular, specificity are limited in CSF metabolomics by nuclear magnetic resonance (NMR) spectroscopy. Nonetheless, progress is being made by studying more and more well-defined and homogeneous patient cohorts. This review starts off with a brief overview of classical CSF analysis in multiple sclerosis (MS), followed by a description of NMR spectroscopy in general metabolic CSF analysis. The subsequent sections focus on metabolomic profiling of CSF by NMR spectroscopy in MS and other neurological disorders. Currently existing results are reviewed and compared, and the potential and limits of this approach are discussed. In addition, several methodological questions are addressed, and the prospects for future developments are briefly outlined.

MRI Texture Analysis in Multiple Sclerosis: Toward a Clinical Analysis Protocol

Magnetic resonance imaging (MRI)-based texture analysis has been shown to be effective in classifying multiple sclerosis lesions. Regarding the clinical use of texture analysis in multiple sclerosis, our intention was to show which parts of the analysis are sensitive to slight changes in textural data acquisition and which steps tolerate interference. The MRI datasets of 38 multiple sclerosis patients were used in this study. Three imaging sequences were compared in quantitative analyses, including a comparison of anatomical levels of interest, variance between sequential slices and two methods of region of interest drawing. We focused on the classification of white matter and multiple sclerosis lesions in determining the discriminatory power of textural parameters. Analyses were run with MaZda software for texture analysis, and statistical tests were performed for raw parameters. MRI texture analysis based on statistical, autoregressive-model and wavelet-derived texture parameters provided an excellent distinction between the image regions corresponding to multiple sclerosis plaques and white matter or normal-appearing white matter with high accuracy (nonlinear discriminant analysis 96%-100%). There were no significant differences in the classification results between imaging sequences or between anatomical levels. Standardized regions of interest were tolerant of changes within an anatomical level when intra-tissue variance was tested. The MRI texture analysis protocol with fixed imaging sequence and anatomical levels of interest shows promise as a robust quantitative clinical means for evaluating multiple sclerosis lesions.

Persistence of Immunopathological and Radiological Traits in Multiple Sclerosis

Multiple sclerosis (MS) is a heterogeneous autoimmune disease of the central nervous system. The identification of 4 different immunopathological subtypes of MS raises the question of whether these subtypes represent different patient subgroups that can be distinguished according to their leading mechanism of myelin destruction or whether this is a stage-dependent process in the development of lesions in a given patient. To document intraindividual immunopathological and radiological homogeneity of 2 different lesions in a single patient with relapsing-remitting MS over time. Case report. A neuropathological referral center for inflammatory demyelinating diseases of the central nervous system. A 49-year-old woman with clinically definite relapsing-remitting MS. Radiological and immunopathological analysis of MS lesions. Identical pathological findings in 2 different MS lesions separated by more than 2 years were identified. These lesions displayed similar and distinct radiological features on cranial imaging. In this patient we were able to show the same antibody/complement-mediated lesion pathological findings with compatible identical ring enhancement on T1-weighted magnetic resonance images and hypointense rims on T2-weighted images after an interval of 26 months. Our observations support the concept of intraindividual homogeneity of a given immunopathological MS subtype.

Liquordiagnostik der Multiplen Sklerose – Diagnose und Differenzialdiagnose

Bei der Multiplen Sklerose handelt es sich um eine chronisch–entzündliche Erkrankung des zentralen Nervensystems mit funktionellen Defiziten vorwiegend aufgrund multipler demyelinisierender Läsionen unterschiedlichen Alters. Grundkonzept der Diagnosestellung ist der Nachweis einer Dissemination des Krankheitsprozesses in Bezug auf Ort und Zeit. Die diagnostischen Kriterien der Multiplen Sklerose wurden wiederholt revidiert. Der Artikel gibt einen Überblick über verschiedene Kriteriensysteme und diskutiert die derzeit verwendeten McDonald–Kriterien in ihrer revidierten Fassung von 2005. Die Diagnosestellung der Multiplen Sklerose beruht auf dem Ausschluss anderer entzündlicher, infektiöser, granulomatöser und hereditärer Erkrankungen, die nachfolgend skizziert werden. Ein klinischer Abklärungsalgorithmus bei Verdacht auf Multiple Sklerose wird vorgestellt. Im Rahmen der Diagnosestellung ist die Liquoranalyse essenziell, charakteristische Liquorbefunde und ihre Bedeutung werden diskutiert.

La sclérose en plaques : quelles possibilités de régénération ?

Disability in multiple sclerosis is related to demyelination and axonal injury. Remyelination has been shown to occur in the different forms of the disease. In addition to restoring nerve conduction, myelin repair has a major role in preventing neurodegeneration. However, although sometimes extensive, remyelination is usually insufficient. Our understanding of the cellular and molecular mechanisms underlying the success or failure of myelin repair has benefited from lesion analysis in multiple sclerosis, and from in vivo and in vitro models of myelination and remyelination. This also provides potential targets for therapeutic intervention aimed at promoting endogenous remyelination.

Recent advances in genetic analysis of multiple sclerosis: genetic associations and therapeutic implications

Epidemiological studies have confirmed that genetic factors are a key component in the pathogenesis of multiple sclerosis (MS) and that those determining MS susceptibility have been extensively studied. Many papers have been published regarding the heritable differences useful in genetic studies; these include variations in DNA, such as single-nucleotide polymorphisms, microsatellites and insertion/deletion polymorphisms. However, to date, among other regions, HLA is the only region confirmed to possess genes that determine MS susceptibility. In this article, we review the progress during the last 5 years in the studies on the susceptibility genes and the pharmacogenetics of MS. Newer techniques and methods of analysis will hopefully result in better screening of individuals who are at highest risk and novel treatments.

Multiple sclerosis: Postlinkage genetics

Because of the relative failure of linkage analysis in multiple sclerosis, despite the investigation of more than 700 affected relative pairs, we have applied four alternative strategies to identify genes that confer susceptibility to the disease. First, we have reported two clusters of MS patients from isolated populations where 19 and 13 patients, respectively, could be shown to have common ancestry tracing back several centuries. Three and five haplotypes, respectively, were shown to be shared by affected individuals, however, these haplotypes were extended and the statistical evidence modest. Second, we have recently reported the results of a two-stage candidate gene analysis of 66 selected genes, mostly of immune function. The IL-7 receptor alpha gene and LAG-3 both had three SNP markers associated with MS. Third, we recently identified the MHC class II transactivator gene in an animal model with inflammatory properties and later confirmed it to be of importance for MS, rheumatoid arthritis and acute myocardial infarction. Finally, in collaboration with the Serono Genetics Institute, we have completed a genome-wide screen with over 100,000 markers in three sets of 300 MS patients and 300 matched controls. Eighty genes showed evidence of importance in all three populations. These strategies appear to hold some promise of success where linkage analysis has proven less successful than anticipated.