Is the walk ratio a window to the cerebellum in multiple sclerosis? A structural magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Existing research studies have demonstrated a relationship between magnetic resonance imaging (MRI) neuroimaging measures and walking speed in people with multiple sclerosis (PwMS). However, to date there are no data as to the brain structures involved in gait coordination and control in PwMS. Therefore, the aim of our study was to investigate the association between walk ratio, an indicator of gait coordination, and related brain structures in PwMS. METHODS: A brain MRI was performed by a 3.0-T MR scanner in conjunction with a volumetric analysis based on three-dimensional T1-weighted images. Regions of interest were volumes of the hippocampus, amygdala, putamen, caudate, pallidum, thalamus, cerebellum and the corpus callosum regions. Walking speed and walk ratio, defined as step length divided by step rate, was measured whilst walking on an electronic walkway. RESULTS: In all, 343 PwMS (41.1 ± 13.4 years, 69.1% female, median Expanded Disability Status Scale 2.5) were included in the study. A significant association was found between the left cerebellum volume and walk ratio after controlling for age, gender, total cranial volume and disability; R2  = 0.379, P = 0.002. A similar association was found between the right cerebellum volume and walk ratio, R2  = 0.364, P = 0.002. No correlations were observed between walk ratio and the thalamus, basal ganglia, hippocampus, amygdala and the corpus callosum volumes. No association was found between walking speed and all brain measures. CONCLUSIONS: The walk ratio should be considered when evaluating and assessing PwMS presenting with ataxia. Furthermore, it is also hypothesized that a low walk ratio indicates a lower cerebellum volume in the MS population.

Neural correlates of gait variability in people with multiple sclerosis with fall history.

BACKGROUND AND PURPOSE: The aim was to investigate the association between step time variability and related brain structures in accordance with fall status in people with multiple sclerosis (PwMS). METHODS: The study included 225 PwMS. Whole-brain magnetic resonance imaging was performed with a high-resolution 3.0 T magnetic resonance scanner in addition to volumetric analysis based on 3D T1-weighted images using the FreeSurfer image analysis suite. Step time variability was measured with an electronic walkway. Participants were defined as 'fallers' (at least two falls during the previous year) and 'non-fallers'. RESULTS: In all, 105 PwMS were defined as fallers and had a greater step time variability compared to non-fallers [5.6% (SD = 3.4) vs. 3.4% (SD = 1.5); P = 0.001]. MS fallers exhibited a reduced volume in the left caudate and both cerebellum hemispheres compared to non-fallers. On using a linear regression analysis no association was found between gait variability and related brain structures in the total cohort and the non-fallers group. However, the analysis found an association between the left hippocampus and left putamen volumes with step time variability in the faller group: P = 0.031, 0.048, respectively, controlling for total cranial volume, walking speed, disability, age and gender. Nevertheless, according to the hierarchical regression model, the contribution of these brain measures to predict gait variability was relatively small compared to walking speed. CONCLUSIONS: An association between low left hippocampal, putamen volumes and step time variability was found in PwMS with a history of falls, suggesting that brain structural characteristics may be related to falls and increased gait variability in PwMS.

Retinal layers thickness changes following epiretinal membrane surgery.

PurposeTo evaluate the time course of changes in the thickness of retinal layers after epiretinal membrane (ERM) removal surgery.MethodsA retrospective cohort study of patients following surgery for idiopathic ERM. We used new specialized image analysis software to create a thickness map of each retinal layer and analyzed changes during one year follow-up. Healthy fellow eyes were used as negative controls and the retina prior to surgery as positive control.ResultsTwenty-one patients were included with a mean age of 68±13 years. Central macular thickness decreased steadily until 6 months after surgery (25% decrease, 516±76 to 386±73 µm, P<0.001) with no further decrease between 6 and 12 months (386±73 to 390±73 µm, P=0.291). The retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIPL) were most affected (57%, P<0.001 and 27%, P=0.010, respectively). The thickest region showed a more abrupt decrease of 21% at first follow-up (504±61 to 399±58 µm, P=0.001) with subsequent decrements of about 3%. Prior to surgery all retinal layers were thicker in study eyes compared with healthy control eyes (6-63%, all P<0.05).ConclusionsFollowing ERM surgery, in the course of 6 months, the macula gradually becomes thinner after which a stable state is reached. All layers appear to be affected, with the RNFL and GCIPL impacted the most. Our results provide a unique view on how the thickness of different retinal layers changes following ERM surgery.

Experimental Autoimmune Encephalomyelitis Ameliorated by Passive Transfer of Polymerase 1-Silenced MOG35-55 Lymphatic Node Cells: Verification of a Novel Therapeutic Approach in Multiple Sclerosis.

In the current study, we present an innovative concept based on the knowledge that enhancing naturally occurring biological mechanisms is effective in preventing neuronal damage and maintaining low disease activity in about 15% of multiple sclerosis (MS) patients presenting the benign type of MS. Recently, we have demonstrated that low disease activity in benign MS is associated with suppression of RNA polymerase 1 (POL1) pathway; therefore, targeting POL1 transcription machinery as a strategy for suppressing active forms of MS is suggested. To further establish our approach, we aimed to suppress POL1 pathway by silencing of the POL1-related RRN3, POLR1D and LRPPRC genes in specific MOG35-55-activated lymphocytes and assess their capacity to induce experimental autoimmune encephalomyelitis (EAE) by passive transfer. We have demonstrated that silencing of specific POL1 pathway-related genes significantly decreased viability and increased the proportion of CD4+/AnnexinV+/PI+ apoptotic cells in MOG35-55-primed lymphocytes. POL1-gene silencing significantly decreased the proportion of CD4+IL17+ and increased proportion of CD4+IL10+ and CD4+TNFa+ lymphocytes that occurred simultaneously with over-presentation of Treg CD4+CD25+FoxP3+ cells. Passive transfer of MOG35-55-primed lymphocytes after POL1-gene silencing suppressed EAE development in mice as demonstrated by delayed onset and peak of disease accompanied by significantly lower maximal and cumulative EAE scores. Our study supports a basis for direct targeting of POL1 transcription pathway as a strategy for selective induction of apoptosis and suppression of inflammation in EAE and consequently paves the way for innovative and targeted MS therapeutic strategy that is based on naturally existing biological mechanism.

Psoriasis comorbidity affects multiple sclerosis neurological progression: a retrospective case - control analysis.

BACKGROUND: Multiple sclerosis (MS) and psoriasis are inflammatory disorders, with epidemiological and biological associations. The impact of one disease on the course of the other has not been studied. OBJECTIVE: To characterize patients with psoriasis and MS, and to assess whether psoriasis comorbidity affected the progression of MS. METHODS: A retrospective case-control study. Patients with psoriasis comorbidity were identified from 3456 patients included in the Sheba Hospital Multiple Sclerosis Center database. Clinical and demographical characteristics and MS progression-related outcomes in patients whose follow-up exceeded 5 years were analysed and compared to those of a matched control cohort of MS-only (MSO) patients. RESULTS: Forty-five (1.3%) MS patients had psoriasis comorbidity. Psoriasis preceded MS in 35 (78%) cases. The psoriasis was defined as mild, moderate and severe in 24 (53%), twelve (27%) and nine (20%) cases respectively. MS progression-related outcomes were evaluated in 35 patients that had follow-up over 5 years. Patients with psoriasis onset preceding relapsing-remitting MS (RRMS) had slower progression of disease compared to MSO patients, as manifested by a longer time to second relapse (P < 0.01) and a longer time to significant neurological disability scores (P < 0.03). CONCLUSION: Psoriasis comorbidity preceding the onset of MS is associated with slower progression of disability.

RAM-589.555 a new Polymerase-1 inhibitor as innovative targeted-treatment for multiple sclerosis.

Targeting Polymerase-1 (POL1) transcription machinery is a new strategy for suppression of multiple sclerosis (MS) disease activity that is based on suppression of ribosomal biogenesis and subsequent activation of apoptosis. We developed an oral POL1 inhibiting compound RAM-589.555, that suppress ribosomal biogenesis as an innovative therapeutic approach to ameliorate MS. RAM-589.555 shows high permeability, specificity to POL1 pathway, ability to induce apoptosis and to inhibit proliferation and viability of activated lymphocytes both in-vitro and in-vivo. Moreover, oral administration of RAM-589.555 blocks ribosomal RNA transcription and significantly suppresses and ameliorates experimental autoimmune encephalomyelitis (EAE).

Intraocular pressure measurement after DSAEK by iCare, Goldmann applanation and dynamic contour tonometry: A comparative study.

PURPOSE: Corneal thickness inevitably increases following Descemet's stripping automated endothelial keratoplasty (DSAEK), owing to the addition of a donor graft. The current study compares different devices in assessing post-DSAEK intraocular pressure (IOP). METHODS: We compared IOP values measured by the Goldmann tonometry (GAT), iCare rebound tonometry (iCare) and Pascal dynamic contour tonometry (PDCT) in eyes following DSAEK. Agreement between measurements was calculated with correlation analysis and Bland-Altman plots. Effects of keratometry, central, thickness (CCT), endothelial cell density (ECD) and axial length on IOP measurements were assessed with Pearson's correlation. RESULTS: Twenty eyes of 20 patients (mean age 74.3±14.4, 14 females) post-DSAEK were included in this study. There was a high concordance between the IOP readings obtained by the three devices: a strong and significant correlation was found between GAT and PDCT (r=0.94, P<0.001) GAT and iCare (r=0.86, P<0.001) and iCare with PDCT (r=0.81, P<0.001). However, the iCare measurements were significantly and consistently lower than that obtained with GAT (ΔIOP=1.68±2.0, P=0.002, 95% CI: 0.7-2.6) and with PDCT (ΔIOP=1.61±2.5, P=0.01, 95% CI: 0.4-2.8). CCT, ECD, CCT, AXL, corneal curvature or astigmatism did not influence IOP measurement by any instrument. CONCLUSIONS: IOP measurement with three different techniques (applanation, rebound and dynamic contour) showed good correlations, despite an increased corneal thickness following DSAEK. However, the iCare, which is based on a rebound tonometry showed significant lower IOP then the two other methods. This should be taken into account when evaluating patients post DSAEK.

The role of laquinimod in modulation of the immune response in relapsing-remitting multiple sclerosis: Lessons from gene expression signatures.

Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down-regulation of inflammatory responses mainly via TGFb signaling, and of pro-inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients.

Prevalence of overweight, obesity and metabolic syndrome components in multiple sclerosis patients with significant disability.

BACKGROUND AND PURPOSE: Information about metabolic comorbidities in patients with multiple sclerosis (MS) is scarce. Our aim was to examine the prevalence of the metabolic syndrome (MetS) and its components in patients with long duration of MS and significant disability. METHODS: Demographic and clinical data, weight, height, waist circumference, blood pressure, and levels of fasting glucose, triglycerides and high density lipoprotein cholesterol (HDL-C) were obtained from 130 MS patients with Extended Disability Status Scale (EDSS) score ≥3.0. RESULTS: Seventy-two percent were female, mean ± SD age 55.8 ± 6.0, range 45-65 years, disease duration 18.2 ± 10.1 years, EDSS 5.5 ± 1.0. Obesity [body mass index (BMI) ≥ 30 kg/m(2) ] was present in 18.5% and overweight (BMI 25.0-29.9 kg/m(2) ) in 34.6%. The prevalence of the MetS was 30% with no gender difference. Fifty-six percent had central obesity by waist circumference, 28% treated hypertension, 45.8% elevated blood pressure, 11% type 2 diabetes mellitus, 31.4% treated dyslipidemia, 28.8% elevated triglyceride levels and 31.4% had low HDL-C. MS patients with MetS were significantly older (59.0 ± 5.5 vs. 53.8 ± 5.5, P < 0.0001) and heavier (BMI 29.0 ± 6.9 vs. 25.1 ± 4.7, P = 0.0009). There were no differences between the groups in neurological disability by the EDSS (5.7 ± 1.0 vs. 5.4 ± 1.0), disease duration (18.4 ± 9.9 vs. 18.2 ± 10.2 years) and number of steroid courses received (6.6 ± 9.5 vs. 6.3 ± 8.4). CONCLUSIONS: Compared to the general population, adult disabled MS patients had lower rates of obesity and overweight, as assessed by BMI. Despite these reduced rates, the prevalence of the MetS was similar to the general population. Specifically higher rates of increased waist circumference were found, suggesting that the lower BMI may be misleading in terms of health risk.

Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases.

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/ß-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.

Effect of a cognitive task on postural control in patients with a clinically isolated syndrome suggestive of multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) frequently experience poor postural control affecting mobility and/or cognitive impairment, even in the early stages of the disease. As postural control consumes attentional resources, it is essential to test stability during a cognitive task. AIM: To assess postural control and determine the effect of a cognitive task on balance in patients with a clinically isolated syndrome (CIS) suggestive of MS, within 3 months from onset. DESIGN: Observational case control study SETTING: Multiple Sclerosis Center and Institute of Motor Functions, Sheba Medical Center, Tel Hashomer, Israel POPULATION: Fifty-two CIS patients, aged 35.2±1.3 years, disease duration of 54±6.2 days and Expanded Disability Status Scale (EDSS) of 1.7±0.2, participated in the study. The control group consisted of 28 age and gender matched healthy subjects. METHODS: Stability was evaluated by the quantifying movement of the center of pressure (CoP) during standing under three conditions: eyes open, eyes closed, and while performing the modified Stroop test. Sway rate and CoP data was collected by a computerized force platform device. RESULTS: After combining major postural control parameters, only 50% of the patients performed normally. Differences in postural variables were found between patients and healthy subjects (P<0.01). Both sway rate and standard deviation of the CoP in all test conditions were significantly higher in patients compared to controls. The cognitive task resulted in an elevated sway rate both in CIS patients and the control group when compared with the eyes open task. Within 3 months of the onset of neurological symptomatology, postural instability was detected in 50% of CIS patients using a dedicated balance measurement device. CONCLUSION: As these findings are associated with the very early phase of MS, it appears that the ongoing pathological disease process is already taking place with regard to the balance control system. CLINICAL REHABILITATION IMPACT: Identification of postural abnormalities in the early stages is important in order to establish proper intervention programs.

Laquinimod suppress antigen presentation in relapsing-remitting multiple sclerosis: in-vitro high-throughput gene expression study.

Laquinimod (LAQ) is a new immunomodulatory drug shown to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS); however, its molecular target pathways are not well recognized. In this study we characterized in-vitro the molecular effects of LAQ in peripheral blood mononuclear cells (PBMC) of healthy subjects and RRMS patients by gene expression microarrays. We demonstrated that LAQ induced suppression of genes related to antigen presentation and corresponding inflammatory pathways. These findings were demonstrated mainly via the NFkB pathway. Analysis of PBMC subpopulations identified activation of Th2 response in CD14+ and CD4+ cells and suppression of proliferation in CD8+ cells.

Gender effects in relapsing-remitting multiple sclerosis: correlation between clinical variables and gene expression molecular pathways.

Gene expression profiles were assessed in patients with relapsing-remitting multiple sclerosis (RRMS) to identify gender effects. Clear gender differences in time to second relapse and time to EDSS=6.0 progression in patients with late onset of the disease (>40years) were evident, and occurred more rapidly in female RRMS patients. Identified molecular biological mechanisms were related to increased immune activation associated with prominent inhibition of apoptosis that enhanced inflammatory processes and were more evident in female RRMS patients. Our findings open possibilities to explore gender-dependent immunomodulatory treatments that will be based on gene expression mechanisms that set the difference between male and female RRMS patients.

Prolonged response times characterize cognitive performance in multiple sclerosis.

Cognitive impairment is amongst the main symptoms affecting multiple sclerosis (MS) and should be comprehensively and accurately assessed. To study the added value of a computerized neuropsychological battery enabling the measurement of response times in the cognitive domains, 58 randomly selected MS patients and 71 age-, gender- and education-matched healthy subjects were evaluated. Construct and discriminant validity were assessed for the standard Neuropsychological Screening Battery for Multiple Sclerosis (NSBMS) and the Mindstreams Computerized Cognitive Battery (MCCB). The MCCB demonstrated good construct validity in comparison with the NSBMS in memory (P < 0.001), executive function (P < 0.001), attention (P < 0.05) and information processing (P < 0.05) domains. In addition, it showed high discriminant validity most prominently for executive function, attention and motor skills (P < 0.001). Response times measured by the computerized battery were longer in all cognitive domains and varied with cognitive load, demonstrating that response time deficits in MS are associated with particular task demands. We conclude that in MS prolonged response times on a range of cognitive tasks signify abnormal conduction within demyelinative tracts.

Zinc-ion binding and cytokine activity regulation pathways predicts outcome in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease characterized by an unpredictable clinical course with intermittent relapses that lead over time to significant neurological disability. Clinical and radiological variables are limited in the ability to predict disease course. Peripheral blood genome scale analyses were used to characterize MS patients with different disease types, but not for prediction of outcome. Using complementary-DNA microarrays we studied peripheral-blood gene expression patterns in 53 relapsing-remitting MS patients. Patients were classified into good, intermediate and poor clinical outcome established after 2-year follow-up. A training set of 26 samples was used to identify clinical outcome differentiating gene-expression signature. Supervised learning and feature selection algorithms were applied to identify a predictive signature that was validated in an independent group of 27 patients. Key genes within the predictive signature were confirmed by quantitative reverse transcription-polymerase chain reaction in an additional 10 patients. The analysis identified 431 differentiating genes between patients with good and poor clinical outcome (change in neurological disability by the expanded disability status scale was -0.33 +/- 0.24 and 1.6 +/- 0.35, P = 0.0002, total number of relapses were 0 and 1.80 +/- 0.35, P = 0.00009, respectively). An optimal set of 29 genes was depicted as a clinical outcome predictive gene expression signature and classified appropriately 88.9% of patients. This predictive signature was enriched by genes related biologically to zinc-ion binding and cytokine activity regulation pathways involved in inflammation and apoptosis. Our findings provide a basis for monitoring patients by prediction of disease outcome and can be incorporated into clinical decision-making in relapsing-remitting MS.

Peripheral blood gene expression signature mirrors central nervous system disease: the model of multiple sclerosis.

Global gene expression analysis using cDNA microarrays has proven to be a sensitive method to gain insight into molecular pathways mediating multiple sclerosis (MS) activity and to develop and refine the molecular taxonomy of the disease. This method was applied as a tool to investigate molecular heterogeneity of MS related gene transcripts in the aim of distinguishing between transcripts that trigger disease activity and account for direct genotype-phenotype correlation, and those whose expression is altered as a downstream effect of other genes. This review summarizes the current state of gene expression microarray applications for the study of MS, and specifically emphasizes the results of gene expression studies using peripheral blood mononuclear cells (PBMC) that were shown to be useful for better understanding of disease related pathways, monitoring of therapeutic responses to various drugs and prediction of clinical outcome. In the long run it is expected that the information provided by cDNA microarrays experiments will allow the determination of key molecular players involved in MS pathogenesis, and lead to better management of the disease using targeted treatments that will prevent its progression.

Gene expression studies in systemic lupus erythematosus.

In a single assay, gene microarrays generate tens of thousands of measurements for the relative levels of messenger RNA expression, and thus hold promise to uncover the regulation of transcriptional responses behind clinical phenotypes of various diseases. Systemic lupus erythematosus (SLE) offers a unique opportunity to study gene expression both systemically and organ specific, as the tissues involved and specifically peripheral blood cells are readily accessible for molecular analysis. In the current review we highlight the current knowledge related to gene microarray in SLE. We approached the following questions: 1) Can gene microarray technology be used to translate molecular profiles into meaningful and applicable clinical information? 2) Does the assessment of differential gene expression provide specific signatures that may contribute to diagnostic and prognostic markers of SLE? 3) Can clinicians be helped in monitoring disease activity by identification of drug response gene profile? 4) Does evaluation of differential gene expression provide clues to detect previously unrecognized genes associated with the disease? It is evident that though not all questions can be currently answered appropriately, gene expression studies in SLE have important implications and will not only be beneficial for SLE patients, but will also lead to a better understanding of other autoimmune inflammatory diseases, thereby leading to novel diagnostic and therapeutic strategies in autoimmunity.