Search

Axonal and neuronal pathologies are a central constituent of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), induced by the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. In this study, we investigated neurodegenerative manifestations in chronic MOG 35-55 induced EAE and the effect of glatiramer acetate (GA) treatment on these manifestations. We report that the neuronal loss seen in this model is not attributed to apoptotic neuronal cell death. In EAE-affected mice, axonal damage prevails from the early disease phase, as revealed by analysis of neurofilament light (NFL) leakage into the sera along the disease duration, as well as by immunohistological examination. Elevation of interstitial glutamate concentrations measured in the cerebrospinal fluid (CSF) implies that glutamate excess plays a role in the damage processes inflicted by this disease. GA applied as a therapeutic regimen to mice with apparent clinical symptoms significantly reduces the pathological manifestations, namely apoptotic cell death, NFL leakage, histological tissue damage, and glutamate excess, thus corroborating the neuroprotective consequences of this treatment.

Specific inflammatory pathways and specifically Tumor Necrosis Factor alpha (TNF-α) have been associated with the neurodegeneration in Parkinson's disease (PD). TNFα is also known to play an important role in the pathogenesis of sarcoidosis and TNF blockers can ameliorate the disease. In contrast, multiple sclerosis (MS) is clearly exacerbated by anti- TNF-α medications. We have therefore hypothesized that Parkinson-like disease would be more common in neurosarcoidosis (NS) compared to MS. The aim of this case-control study was therefore to assess the frequency of extrapyramidal signs in patients with NS compared to MS patients. In order to do so the medical records of NS patients and of age and gender matched MS patients were reviewed and data regarding the clinical features, ancillary tests performed, treatment, and outcome were documented. Patients were then examined in a uniform manner for the presence of extrapyramidal signs. We found that in the NS group 8 patients had minor signs, one had mild functional disability and 3 subjects had significant extrapyramidal signs compatible with the diagnosis of Parkinson's disease. All extrapyramidal signs found in 5 of the MS group were minor. The proportional severity of extrapyramidal signs was significantly higher (p=0.045, chi square test) in the NS group compared to the MS group. We conclude that the specificity of extrapyramidal to NS raises the intriguing question of whether specific inflammatory pathways involving TNF-α play a role in the pathogenesis of PD and therefore may be a therapeutic target., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background/aims: Large-scale population studies measuring rates and dynamics of cognitive decline in multiple sclerosis (MS) are lacking. In the current cross-sectional study we evaluated the patterns of cognitive impairment in MS patients with disease duration of up to 30 years., Methods: 1,500 patients with MS were assessed by a computerized cognitive battery measuring verbal and non-verbal memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Cognitive impairment was defined as below one standard deviation (SD) and severe cognitive impairment as below 2SD for age and education matched healthy population norms., Results: Cognitive performance in our cohort was poorer than healthy population norms. The most frequently impaired domains were information processing speed and executive function. MS patients with secondary-progressive disease course performed poorly compared with clinically isolated syndrome, relapsing-remitting and primary progressive MS patients. By the fifth year from disease onset, 20.9% of patients performed below the 1SD cutoff for impairment, p=0.005, and 6.0% performed below the 2SD cutoff for severe cognitive impairment, p=0.002. By 10 years from onset 29.3% and 9.0% of patients performed below the 1SD and 2SD cutoffs, respectively, p=0.0001. Regression modeling suggested that cognitive impairment may precede MS onset by 1.2 years., Conclusions: The rates of cognitive impairment in this large sample of MS patients were lower than previously reported and severe cognitive impairment was evident only in a relatively small group of patients. Cognitive impairment differed significantly from expected normal distribution only at five years from onset, suggesting the existence of a therapeutic window during which patients may benefit from interventions to maintain cognitive health.

Objectives: To compare treatment persistence between two dosages of interferon β-1a in a large observational multiple sclerosis registry and assess disease outcomes of first line MS treatment at these dosages using propensity scoring to adjust for baseline imbalance in disease characteristics., Methods: Treatment discontinuations were evaluated in all patients within the MSBase registry who commenced interferon β-1a SC thrice weekly (n = 4678). Furthermore, we assessed 2-year clinical outcomes in 1220 patients treated with interferon β-1a in either dosage (22 µg or 44 µg) as their first disease modifying agent, matched on propensity score calculated from pre-treatment demographic and clinical variables. A subgroup analysis was performed on 456 matched patients who also had baseline MRI variables recorded., Results: Overall, 4054 treatment discontinuations were recorded in 3059 patients. The patients receiving the lower interferon dosage were more likely to discontinue treatment than those with the higher dosage (25% vs. 20% annual probability of discontinuation, respectively). This was seen in discontinuations with reasons recorded as "lack of efficacy" (3.3% vs. 1.7%), "scheduled stop" (2.2% vs. 1.3%) or without the reason recorded (16.7% vs. 13.3% annual discontinuation rate, 22 µg vs. 44 µg dosage, respectively). Propensity score was determined by treating centre and disability (score without MRI parameters) or centre, sex and number of contrast-enhancing lesions (score including MRI parameters). No differences in clinical outcomes at two years (relapse rate, time relapse-free and disability) were observed between the matched patients treated with either of the interferon dosages., Conclusions: Treatment discontinuations were more common in interferon β-1a 22 µg SC thrice weekly. However, 2-year clinical outcomes did not differ between patients receiving the different dosages, thus replicating in a registry dataset derived from "real-world" database the results of the pivotal randomised trial. Propensity score matching effectively minimised baseline covariate imbalance between two directly compared sub-populations from a large observational registry.

Patients with neurological disease of unknown etiology sometimes present with antigliadin and antitissue transglutaminase antibodies. The association between these antibodies and multiple sclerosis has been previously suggested. The purpose of this study was to determine the prevalence of these antibodies in multiple sclerosis patients. We determined the level of serum immunoglobulin A and immunoglobulin G antigliadin and antitissue transglutaminase antibodies in 98 patients with multiple sclerosis. We found a highly significant increase in titers of immunoglobulin G antibodies against gliadin and tissue transglutaminase in the multiple sclerosis patients. Seven patients had a positive IgG AGA, whereas only 2 controls presented positive titers (P = 0.03). Four patients had positive IgG anti-tTG while all the controls tested negative (P = 0.02). However, immunoglobulin A antibodies against gliadin and tissue transglutaminase were not statistically higher in the multiple sclerosis group in comparison to the control group. Our findings support the associations between antibodies against gliadin and tissue transglutaminase to multiple sclerosis. The specific role of these antibodies in the pathogenesis of multiple sclerosis remains uncertain and requires additional research. A gluten free diet should be considered in specific cases of patients who present with gluten antibodies.

Inflammatory brain diseases such as multiple sclerosis (MS) include hyperactivation of the coagulation pathway which includes thrombin. In the experimental autoimmune encephalomyelitis (EAE) model we have found significantly higher levels of thrombin inhibitors which include the very early elevation of protease nexin 1. The physiological importance of excess thrombin in neural tissue is demonstrated by recent experiments which link thrombin with conduction block in the sciatic nerve.

Objective: To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging ("q-space" imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM)., Design: In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps., Results: We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8+/-0.2 to 4.6+/-0.6 microm (P<.02), the q-space probability values decreased from 7.4+/-0.3 to 6.8+/-0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40+/-0.02 to 0.37+/-0.02 (P<.05)., Conclusion: High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques.

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS). Activated coagulation factors are associated with inflammation and are elevated in the plasma of animals with EAE. Thrombin is a key coagulation factor and its major endogenous inhibitors are antithrombin III (ATIII) in the plasma and protease nexin 1 (PN-1) in the brain. We measured the capacity of brain homogenates to inhibit exogenous thrombin and the CNS levels of ATIII and PN-1 during the course of EAE. Acute EAE was induced in SJL/J mice by immunization with mouse spinal cord homogenates. On Days 8, 13, and 22 post-immunization, inhibition of exogenous thrombin activity was measured by a recently developed fluorimetric assay. PN-1 and ATIII were assayed both by immunohistochemistry and by immunoblots in the brain and spinal cord. Total brain thrombin inhibitory activity increased (32%) in EAE mice at the peak of clinical disease (Day 13, P=0.04 compared to controls). Brain ATIII also increased at the peak of disease (2.5-fold higher than controls, P=0.0001), and correlated significantly with clinical scores at all stages of disease (r=0.72, P=0.0068). In contrast, PN-1 elevations were more pronounced at the preclinical stage on Day 8 (3-fold higher than controls, P=0.01) than on Day 13 (1.4-fold higher, P=0.005). Increased brain thrombin inhibition at the clinical peak of EAE probably reflects increased influx of plasma thrombin inhibitors. Early PN-1 changes represent a potential target for thrombin modulating drugs in EAE and MS.

The interface between multiple sclerosis (MS) and the antiphospholipid syndrome (APS) is of great clinical relevance and may also shed some light on their pathogenesis. Although formal diagnostic criteria of these two immune syndromes are ostensibly mutually exclusive, many patients with subcortical white matter brain lesions share features of both MS and APS. The main diagnostic feature of APS, the antiphospholipid antibodies (aPLAb), is relatively common in multiple sclerosis and increased fibrin deposition is a feature of both APS lesions and MS plaques. A closer examination of the clinical and laboratory data reveals, however, fundamental differences between the syndromes: MS is a diffuse disease of white matter compared to a much more patchy disease in APS as demonstrated by recent studies in imaging and electrophysiology. Furthermore, a closer examination of the specific aPLAb profile reveals significant differences: we have found that although aPLAb were common in MS patients (32%), these antibodies did not depend on the presence of serum factors for binding to phospholipids and none of the MS patients had antibodies to beta2-glycoprotein-I (beta2-GPI), the major autoantigen in APS. Animal models of the two syndromes are induced by very different antigens and may serve to assess overlapping pathogenic mechanisms. The most common treatment used in MS are beta-interferons which theoretically may exacerbate APS, while anticoagulation, the mainstay of APS treatment, is of unknown value in MS. The relationship of MS to APS remains to be clarified by focused large collaborative studies.

This paper aims to present the results of a study that explores the use of uncontrolled and unexamined alternative treatment methods with 37 MS patients, and to compare these results with previous studies. The studied variables were: (a) reasons and circumstances of referral, (b) self reported outcome effectiveness of alternative treatment, and (c) satisfaction with the conventional physician and alternative healer. From a group of 37 patients, 17 were referred to alternative healers. In comparison with those who were not referred to alternative medicine, the sub-group referred for alternative treatment reported more familial support and lower levels of satisfaction from their rapport with their conventional physicians.

Thrombin and other proteases involved in coagulation also have the potential to stimulate inflammation in the brain to a large extent through the protease-activated receptors (PARs). Such exposure of the brain to increased levels of coagulation factors is more likely to occur during vasculitis and activation of intrinsic coagulation in the brain and may cause inflammatory diseases such as multiple sclerosis. There is growing evidence from animal models and human brain samples that links upregulation of coagulation factors to inflammatory central nervous system (CNS) disease. Evidence includes measures of thrombin-like activity, levels of its receptors, PARs, and inhibitors of the coagulation pathway. The major receptor for thrombin, PAR-1, has now been definitively located to the synapse and node of Ranvier and its excessive activation leads to blocks in long-term potentiation and in nerve conduction. There is growing evidence that modulating coagulation in models of CNS inflammatory disease has beneficial clinical effects. These findings suggest that coagulation-like pathways play a significant role in the pathogenesis of inflammatory diseases in the CNS and present a viable target for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To explore the diagnostic usefulness of high b-value diffusion magnetic resonance brain imaging (“q-space” imaging) in multiple sclerosis (MS). More specifically, we aimed at evaluating the ability of this methodology to identify tissue damage in the so-called normal-appearing white matter (NAWM). Design: In this study we examined the correlation between q-space diffusion imaging and magnetic resonance spectroscopy (MRS)-based two-dimensional 1H chemical shift imaging. Eight MS patients with different degree of disease severity and seven healthy subjects were scanned in a 1.5-T magnetic resonance imaging (MRI) scanner. The MRI protocol included diffusion tensor imaging (DTI) (with bmax of 1000 s/mm2), high b-value diffusion-weighted imaging (with bmax of 14,000 s/mm2) and 2D chemical shift imaging. The high b-value data set was analyzed using the q-space methodology to produce apparent displacement and probability maps. Results: We found that the q-space diffusion displacement and probability image intensities correlated well with N-acetylaspartate levels (r=.61 and .54, respectively). Furthermore, NAWM that was abnormal on MRS was also found to be abnormal using q-space diffusion imaging. In these areas, the q-space displacement values increased from 3.8±0.2 to 4.6±0.6 μm (P<.02), the q-space probability values decreased from 7.4±0.3 to 6.8±0.3 (P<.002), while DTI revealed only a small, but still significant, reduction in fractional anisotropy values from 0.40±0.02 to 0.37±0.02 (P<.05). Conclusion: High b-value diffusion imaging can detect tissue damage in the NAWM of MS patients. Despite the theoretical limitation of this method, in practice it provides additional information which is clinically relevant for detection of tissue damage not seen in conventional imaging techniques. [Copyright &y& Elsevier]

Background: Apolipoprotein E expression is increased in regenerating neural tissue and the APOE ε4 allele is associated with impaired neuronal repair. Since repair is essential for the restoration of central nervous system function following multiple sclerosis (MS) relapses, APOE genotype may influence clinical progression of the disease. Objective: To examine the association of the APOE genotype with disease susceptibility and progression in MS. Patients and Methods: APOE genotyping was determined by polymerase chain reaction and restriction enzyme digestion in 47 patients with MS who had been followed up every 3 months for 2 years as part of an open-label clinical trial with glatiramer acetate. The Expanded Disability Status Scale (EDSS) was used to assess clinical progression. Results: Nine patients were heterozygous and 1 patient was homozygous for the APOE ε4 allele, for a frequency of 12% (11/94), which is similar to that of the general Israeli population. The APOE ε4 carriers had a mean ± SE EDSS score of 3.10 ± 0.45 at entry, which was not significantly different from the remaining 37 patients (2.62 ± 0.25). During the observation period, the EDSS score of the APOE ε4 carriers deteriorated to 4.00 ± 0.63 while the other patients remained stable with an EDSS score of 2.74 ± 0.31. The interaction of genotype with disability over time was significant (P = .02 by repeated-measures analysis of variance). There were no differences in the number of relapses occurring in the 2 groups. Conclusions: These preliminary observations suggest that APOE genotype may influence disease progression in MS. The APOE ε4 allele was not associated with an increased risk of MS or relapses. [ABSTRACT FROM AUTHOR]

Abstract: Neuromyelitis optica (NMO) is an autoimmune disorder, predominantly characterized by severe optic neuritis (ON) and transverse myelitis (TM). Historically considered a variant of Multiple sclerosis, the discovery that most NMO patients have autoantibodies against aquaporin-4 (AQP4) or NMO-IgG, dramatically changed our understanding of the disease. The finding of NMO-IgG revealed wider array of clinical presentations, including patients with recurrent ON of TM alone, now considered part of the NMO spectrum. Furthermore, symptoms other than optic-spinal involvement and the presence of brain lesions, do not exclude the diagnosis of NMO as traditionally accepted. We present an overview of the epidemiology, clinical manifestations and current diagnostic criteria for NMO and NMO spectrum disorders. [Copyright &y& Elsevier]

Abstract: EAE is a common animal model for multiple sclerosis (MS). Immunomodulatory treatments such as glatiramer acetate (GA, Copaxone) are beneficial in EAE but are not universally effective in the clinic. The Ras inhibitor farnesylthiosalycylic acid (FTS, Salirasib), efficiently ameliorate EAE as well. Here we demonstrate a synergistic beneficial effect of the combined GA and FTS treatment on EAE; 22.5% of the combined-treatment mice developed disease compared to 87.5%, 77.5% and 82.5% of mice treated with vehicle, GA and FTS, respectively, results supported by MRI, histological, immunological and biochemical data. Such a combined treatment may improve clinical outcome in MS patients. [ABSTRACT FROM AUTHOR]