Brain atrophy and lesion load in a large population of patients with multiple sclerosis

OBJECTIVE: To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. METHODS: The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). RESULTS: Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. CONCLUSIONS: Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disabilit

The still under-investigated role of cognitive deficits in PML diagnosis.

Background Despite cognitive deficits frequently represent the first clinical manifestations of Progressive Multifocal Leukoencephalopathy (PML) in Natalizumab-treated MS patients, the importance of cognitive deficits in PML diagnosis is still under-investigated. The aim of the current study is to investigate the cognitive deficits at PML diagnosis in a group of Italian patients with PML. Methods Thirty-four PML patients were included in the study. The demographic and clinical data, the lesion load and localization, and the longitudinal clinical course was compared between patients with (n = 13) and without (n = 15) cognitive deficit upon PML suspicion (the remaining six patients were asymptomatic). Clinical presentation of cognitive symptoms was described in detail. Result After symptoms detection, the time to diagnosis resulted to be shorter for patients presenting with cognitive than for patients with non cognitive onset (p = 0.03). Within patients with cognitive onset, six patients were presenting with language and/or reading difficulties (46.15%); five patients with memory difficulties (38.4%); three patients with apraxia (23.1%); two patients with disorientation (15.3%); two patients with neglect (15.3%); one patients with object agnosia (7.7%), one patient with perseveration (7.7%) and one patient with dementia (7.7%). Frontal lesions were less frequent (p = 0.03), whereas temporal lesions were slightly more frequent (p = 0.06) in patients with cognitive deficits. The longitudinal PML course seemed to be more severe in cognitive than in non cognitive patients (F = 2.73, p = 0.03), but differences disappeared (F = 1.24, p = 0.29) when balancing for the incidence of immune reconstitution syndrome and for other treatments for PML (steroids, plasma exchange (PLEX) and other therapies (Mefloquine, Mirtazapine, Maraviroc). Conclusion Cognitive deficits at PML onset manifest with symptoms which are absolutely rare in MS. Their appearance in MS patients should strongly suggest PML. Clinicians should be sensitive to the importance of formal neuropsychological evaluation, with particular focus on executive function, which are not easily detected without a formal assessment

Small non-coding RNA signature in multiple sclerosis patients after treatment with interferon-β

Background: Non-coding small RNA molecules play pivotal roles in cellular and developmental processes by regulating gene expression at the post-transcriptional level. In human diseases, the roles of the non-coding small RNAs in specific degradation or translational suppression of the targeted mRNAs suggest a potential therapeutic approach of post-transcriptional gene silencing that targets the underlying disease etiology. The involvement of non-coding small RNAs in the pathogenesis of neurodegenerative diseases such as Alzheimer's, Parkinson's disease and Multiple Sclerosis has been demonstrated. Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by chronic inflammation, demyelination and scarring as well as a broad spectrum of signs and symptoms. The current standard treatment for SM is interferon ß (IFNß) that is less than ideal due to side effects. In this study we administered the standard IFN-ß treatment to Relapsing-Remitting MS patients, all responder to the therapy; then examined their sncRNA expression profiles in order to identify the ncRNAs that were associated with MS patients' response to IFNß. Methods. 40 IFNß treated Relapsing-Remitting MS patients were enrolled. We analyzed the composition of the entire small transcriptome by a small RNA cloning method, using peripheral blood from Relapsing-Remitting MS patients at baseline and 3 and 6 months after the start of IFNß therapy. Real-time qPCR from the same patients group and from 20 additional patients was performed to profile miRNAs expression. Results: Beside the altered expression of several miRNAs, our analyses revealed the differential expression of small nucleolar RNAs and misc-RNAs.For the first time, we found that the expression level of miR-26a-5p changed related to INF-β response. MiR-26a-5p expression was significantly higher in IFN-β treated RRMS patients at 3 months treatment, keeping quite stable at 6 months treatments. Conclusions: Our results might provide insights into the mechanisms of action of IFN-β treatment in MS and provide fundamentals for the development of new biomarkers and/or therapeutic tools. © 2014 De Felice et al.; licensee BioMed Central Ltd

A multicenter, observational, prospective study of self- and parent-reported quality of life in adolescent multiple sclerosis patients self-administering interferon-β1a using RebiSmartâ\u84¢â\u80\u94the FUTURE study

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-β1a (Rebif; 22 μg), administered subcutaneously three times weekly using the RebiSmartâ\u84¢ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being â\u80\u9cEmotional functioning.â\u80\u9d In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported â\u80\u9cPsychosocial health summary scoreâ\u80\u9d (+ 5.90 points; p = 0.015) and â\u80\u9cSchool functioningâ\u80\u9d (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmartâ\u84¢ for self-administration of Rebif® can experience long-term improvements in QL

The IFN-β 1b effect on Cu Zn superoxide dismutase (SOD1) in peripheral mononuclear blood cells of relapsing-remitting multiple sclerosis patients and in neuroblastoma SK-N-BE cells

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease leading to axonal injury. Even if the etiology of MS is still unknown the disease begins with inflammation involving autoreactive T lymphocytes activation in genetically susceptible subjects. Interferon beta-1b (IFN β 1b) is one of the most used drug in the MS therapy.The results obtained in this study show that the concentration of SOD1 in CSF of relapsing-remitting MS (RR-MS) patients, evaluated by enzyme-linked immunosorbent assay (ELISA), is decreased compared to pathological controls. Moreover, the Western blotting analysis demonstrated that SOD1 in human peripheral blood mononuclear cells (PBMC) in healthy controls was significantly higher compared to MS subjects before starting DMT therapy. In addition IFN β 1b therapy causes an increase of intracellular SOD1 protein as well as mRNA levels in PBMC. Moreover, the treatment of neuroblastoma SK-N-BE cells with IFN β 1b increased SOD1 protein and mRNA levels; these data also suggest that neuroprotective effect of this physiological molecule is, at least in part, carried out through its effect on SOD1. This study demonstrate that DMT therapy is able to increase SOD1 expression in PBMC of RR-MS patients. Therefore, the effectiveness of DMT therapy can be ascribed, at least in part, to an increased levels of this antioxidant enzyme as further confirmed by in vitro studies in SK-N-BE cells

Treatment of multiple sclerosis with interferon beta in clinical practice:2-year follow-up data from the South Italy Mobile MRI Project

This follow-up study assessed the 2-year clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) originally enrolled in an MRI study conducted at eight centres in south Italy (the South Italy Mobile MRI Project). Of the 597 MS patients recruited at baseline, 391 returned for the follow-up study. Of these, 363 provided 2-year clinical and MRI follow-up data, and 215 were still undergoing treatment with one of four interferon beta regimens: Avonex, 30 mcg intramuscularly once weekly; Betaferon, 250 mcg subcutaneously (sc) every other day; Rebif 22 mcg sc three times weekly (tiw; Rebif 22); or Rebif 44 mcg sc tiw (Rebif 44). Over the 2-year follow-up period, patients receiving the higher dose of Rebif were more likely to remain free from relapses [odds ratio (OR) = 2.23] and from developing both new T2 (OR = 0.15) and new T1 black hole lesions (OR = 0.22), when compared with patients in the Avonex group. Despite some limitations in the trial design, the results from this follow-up study provide helpful clinical and MRI data on the efficacy of interferon beta regimens in MS patients treated in the clinical setting

Treatment of multiple sclerosis with interferon beta in clinical practice: 2-year follow-up data from the South Italy Mobile MRI Project.

This follow-up study assessed the 2-year clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) originally enrolled in an MRI study conducted at eight centres in south Italy (the South Italy Mobile MRI Project). Of the 597 MS patients recruited at baseline, 391 returned for the follow-up study. Of these, 363 provided 2-year clinical and MRI follow-up data, and 215 were still undergoing treatment with one of four interferon beta regimens: Avonex, 30 mcg intramuscularly once weekly; Betaferon, 250 mcg subcutaneously (sc) every other day; Rebif 22 mcg sc three times weekly (tiw; Rebif 22); or Rebif 44 mcg sc tiw (Rebif 44). Over the 2-year follow-up period, patients receiving the higher dose of Rebif were more likely to remain free from relapses [odds ratio (OR) = 2.23] and from developing both new T2 (OR = 0.15) and new T1 black hole lesions (OR = 0.22), when compared with patients in the Avonex group. Despite some limitations in the trial design, the results from this follow-up study provide helpful clinical and MRI data on the efficacy of interferon beta regimens in MS patients treated in the clinical setting