Findings In Multiple Sclerosis Research Articles

Association between CD20+ T lymphocytes and neuropsychological findings in multiple sclerosis.

CD20+ T lymphocytes are a subset of circulating T cells presenting the CD20+ receptor, a molecular marker of B lineage. CD20+ T lymphocytes are thought to play a pivotal role in multiple sclerosis (MS) pathology, especially at progressive stages. We aimed to investigate the correlation between CD20+ T lymphocytes and neuropsychological features (i.e., cognition, depression, anxiety, fatigue, and sleep quality) in MS patients. We enrolled 90 MS patients. Each patient underwent cognitive assessment (Brief International Cognitive Assessment for Multiple Sclerosis) and psychometric assessment (modified Fatigue Impact Scale, Beck Anxiety Inventory, Beck Depression Inventory, Pittsburgh Sleep Quality Index). Cognitive status was defined through the cerebral functional score. Forty-four of 90 patients were relapsing-remitting (49%) and 46 were progressive patients (51%). Seventy patients (18.9%) showed CD20+ T lymphocytes in peripheral blood with a mean level of 0.38 ± 1.2%. Patients with CD20+ T lymphocytes were more likely to be at progressive phases (76.5% vs. 23.5%, p = 0.02) and showed a higher Expanded Disability Status Scale score (median [range] = 6.0 [1.5-7.5] vs. 3.5 [1-7.5], p = 0.001). Moreover, patients with CD20+ T lymphocytes showed worse cognitive functioning (p = 0.004), higher global fatigue symptoms (p = 0.02), higher cognitive fatigue (p = 0.01), higher psychosocial fatigue (p = 0.005), and a trend toward worse sleep quality (p = 0.06). The presence of CD20+ T lymphocytes in the peripheral blood of MS patients was associated with worse neuropsychological functioning and progressive disease stages. Peripheral CD20+ T lymphocytes could potentially serve as markers for both disease progression and development of fatigue in MS patients.

Heterogeneous Nuclear Ribonucleoprotein A1 Knockdown Alters Constituents of Nucleocytoplasmic Transport.

Changes in nuclear morphology, alterations to the nuclear pore complex (NPC), including loss, aggregation, and dysfunction of nucleoporins (Nups), and nucleocytoplasmic transport (NCT) abnormalities have become hallmarks of neurodegenerative diseases. Previous RNA sequencing data utilizing knockdown of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified enrichment for pathways and changes in RNAs related to nuclear morphology and showed differential expression of key nuclear targets. This suggests that dysfunction of hnRNP A1, which is observed in neurodegenerative diseases, may contribute to abnormalities in nuclear morphology, NPC, and NCT. We performed knockdown of hnRNP A1 in Neuro-2A cells, a neuronal cell line, to examine nuclear morphology, NPC, and NCT. First, we examined nuclear morphology using Lamin B, wherein we observed increased nuclear envelope abnormalities in cells with hnRNP A1 knockdown as compared to control. To quantify changes in Lamin B, we designed and validated an automated computer-based model, which quantitatively confirmed our observations. Next, we investigated the impact of hnRNP A1 knockdown on components of the NPC and NCT. In line with the previous literature, we found changes in Nups, including altered distribution and reduced protein expression, as well as disrupted NCT. Finally, we validated our findings in multiple sclerosis (MS) brains, a disease with a significant neurodegenerative component caused by hnRNP A1 dysfunction, where neuronal nuclear envelope alterations were significantly increased as compared to controls. Together, these data implicate hnRNP A1 as an important contributor to nuclear morphology, Nup expression and distribution, and NCT and suggest that hnRNP A1 dysfunction may lead to defects in these processes in neurodegenerative diseases.

Association of MicroRNA Expression and Serum Neurofilament Light Chain Levels with Clinical and Radiological Findings in Multiple Sclerosis.

microRNAs (miRNAs) are promising biomarkers for many diseases, including multiple sclerosis (MS). The neurofilament light chain (NfL) is a biomarker that can detect axonal damage in different neurological diseases. The objective of this study was to evaluate the association of the expression profile of pre-selected miRNAs and NfL levels with clinical and radiological variables in MS patients. We conducted a 1-year longitudinal prospective study in MS patients with different clinical forms. We measured clinical disability using the expanded disability status scale (EDSS), the magnetic resonance imaging (MRI) volumetry baseline, and cognitive functioning using the processing speed test (PST) at baseline and 1 year later. Selected serum miRNAs and serum NfL (sNfL) levels were quantified. Seventy-three patients were recruited. MiR-126.3p correlated with EDSS and cognitive status at baseline and miR-126.3p and miR-9p correlated with cognitive deterioration at 1 year. Correlations with regional brain volumes were observed between miR-126.3p and the cortical gray matter, cerebellum, putamen, and pallidum; miR-146a.5p with the cerebellum and pallidum; miR-29b.3p with white matter and the pallidum; miR-138.5p with the pallidum; and miR-9.5p with the thalamus. sNfL was correlated with miR-9.5p. miR-146a.5p was also associated with the MS phenotype. These data justify future studies to further explore the utility of miRNAs (mirR-126.3p, miR-146.5p, and miR.9-5p) and sNfL levels as biomarkers of MS.

Visually evoked potentials in Neuro‐Ophthalmology

The first major development in the visually evoked potentials (VEP) was the move from flash to pattern stimulation in the 1970's. The neurophysiological basis of the responses to flash and to pattern stimuli will be reviewed to explain the superiority of the pattern VEP. The following questions will be considered: Why were the early findings in multiple sclerosis so influential? In what situations does the pVEP continue to be useful clinically, with particular emphasis on the classification of optic neuritis? Should VEP and ERG always be carried out in combination? When is flash VEP useful? Is there a role for a chromatic VEP?

Sensitivity and Specificity of Central Vein Sign as a Diagnostic Biomarker in Egyptian Patients with Multiple Sclerosis.

PurposeMagnetic resonance imaging (MRI) findings in multiple sclerosis (MS) overlap with numerous MS mimics. The central vein sign (CVS) can help to differentiate MS from other mimics. This study aimed to determine the value of CVS as a diagnostic biomarker for distinguishing MS from its mimics.Patients and MethodsPatients were prospectively recruited into two groups: a typical clinical (TC) MS presentation with an atypical MRI for MS and an atypical clinical (ATC) MS presentation with a typical MRI for MS. Patients underwent a 1.5T MRI brain scan with a T2*-weighted gradient-echo sequence. The presence of the central vein was assessed by a radiologist blinded to patients’ clinical presentation. The MS consultant made the final diagnosis without reviewing the T2*-weighted gradient-echo sequence or the CVS analysis results.ResultsForty-two patients were included. Ten (40%) out of 25 TC patients were diagnosed with clinically definite MS (CDMS), with a mean percentage of CV-positive lesions of 65.5% among CDMS patients. Four (23.5%) out of 17 ATC patients were diagnosed with CDMS with a mean CV-positive lesions percentage of 68.25% among CDMS patients. TC patients who were not diagnosed as CDMS had a mean CV-positive lesions percentage of 10.13%, while ATC patients who were not diagnosed as CDMS had a mean CV-positive lesions percentage of 16.38%. The CVS showed 85.7% sensitivity and 100% specificity (95% confidence interval: 0.919–1.018) for diagnosis of MS at a cut off value of 45% (p < 0.001). The percentage of CV-positive lesions was significantly higher in oligoclonal bands (OCBs) positive patients compared to OCBs negative patients (p < 0.001) and those with spinal cord lesions compared to patients with no spinal cord lesions (p = 0.017).ConclusionThe CVS has 85.7% sensitivity and 100% specificity for the diagnosis of MS at a cutoff value of 45%.

Predominant domains and associated demographic and clinical characteristics in multiple sclerosis-related cognitive impairment in mildly disabled patients

BackgroundCognitive impairment (CI) is a common finding in multiple sclerosis (MS); however, there is a limited information about its prevalence in mildly disabled cases. We aimed to determine the most affected domains, and also the relation between the demographic factors and cognitive outcomes in mildly disabled relapsing–remitting MS (RRMS).ResultsNinety-one mildly disabled RRMS patients with expanded disability status scale (EDSS) < 4 and literacy level above 9 years, were recruited. Based on Minimal Assessment of Cognitive Function in MS (MACFIMS) battery, CI was observed in 19.8% of the patients while 40.60% of the patients had at least one failure in cognitive tests. The most common impaired cognitive domain was information processing speed and working memory (27.5%). There was no significant difference between men and women in terms of CI in our sample (p-values > 0.05). Disease duration (p = 0.01), EDSS (p = 0.01), and education (p < 0.01) were significantly different between CI and non-CI patients, while age (p = 0.72), sex (p = 0.50), diagnostic gap (p = 0.89), and frequency of relapses (p = 0.22), did not differ considerably.ConclusionsRRMS patients experience some degrees of CI that may present even before the onset of remarkable physical disability; nevertheless, a higher EDSS score and longer disease duration increases the risk of CI. These findings suggest routine cognitive assessment of MS patients.

Cardiovascular autonomic dysfunction in multiple sclerosis-findings and relationships with clinical outcomes and fatigue severity.

This study evaluates cardiovascular autonomic dysfunction (CAD) in multiple sclerosis (MS) and explores if CAD is related to clinical outcomes and fatigue severity. A total of 53 MS patients (30 relapsing-remitting, RRMS; 23 progressive, PMS) and 30 healthy controls were evaluated. TaskForce® Monitor was used to assess impedance cardiography parameters, heart rate (HRV), and blood pressure (BPV) variability during head-up tilt test (HUTT). Expiration/inspiration (E/I) ratio was assessed in response to a deep breathing test. Fatigue severity was evaluated using Chalder Fatigue Scale (CFQ). Compared to controls, PMS patients were characterized by increased sympathetic-parasympathetic ratio at rest (p < 0.01), decreased resting values of parasympathetic parameters (high-frequency HRV, p < 0.05; E/I ratio, p < 0.001), and index of contractility (p < 0.05), whereas RRMS patients showed reduced E/I ratio (p < 0.01). Compared to RRMS group, PMS patients had higher sympathovagal ratio and lower cardiac inotropy parameters (p < 0.05). No intergroup differences were observed for cardiovascular and autonomic function test parameters after HUTT. PMS and low CFQ physical score were identified as independent predictors of sympathetic hyper-reactivity as measured with HRV. Greater disability and male sex were predictors of diastolic BP increase and reduced cardiac inotropy parameters, and older age was predictor of decreased vagal tone (E/I ratio, high-frequency HRV). Cardiovascular autonomic modulation is altered in MS and highly dependent on disease variant, disability level, fatigue severity, and patients' demographics.

Correlation of corpus callosum index and optic coherence tomography findings in multiple sclerosis with or without optic nerve involvement

Correlation of corpus callosum index and optic coherence tomography findings in multiple sclerosis with or without optic nerve involvement

Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis.

Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1β1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1β1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1β1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1β1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1β1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1β1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1β1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1β1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1β1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.

Amyloid PET findings in multiple sclerosis are associated with cognitive decline at 18 months

ObjectiveTo study the clinical, cognitive, and radiological progression of a cohort of patients with MS, taking into account the amyloid PET with 18F-florbetaben analyses. MethodsTwenty-nine patients with MS were assessed with longitudinal structural MRI and a clinical and comprehensive neuropsychological protocol, with a mean interval between assessments of 18 ± 3.31 months. 18F-florbetaben PET was performed at baseline. Uptake was analysed in demyelinating plaques (DWM) and normal-appearing white matter (NAWM). Results were correlated with clinical, cognitive and MRI data. ResultsPatients with cognitive decline over the follow-up period showed a lower standardised uptake value ratio in NAWM and lower thalamic volume and a higher lesion load in the baseline MRI. Myelin status was correlated with EDSS and cognitive tests mainly evaluating visuospatial function and working memory. Lower uptake in NAWM at baseline was also associated with a growth in white matter lesion volume over time. ConclusionsLower white matter uptake in amyloid PET is associated with cognitive decline and an increase in white matter lesion volume during the follow-up. Our study suggests that 18F-florbetaben may be a useful biomarker in assessing myelin status in MS, understanding MS pathophysiology, and predicting cognitive outcomes.

Modification of CSF findings in multiple sclerosis in the era of rapidly expanding treatment options

ABSTRACTBackground: The detection of cerebrospinal fluid (CSF)-specific oligoclonal bands (OCB) as well as an elevated antibody production directed against neurotrophic viruses remain hallmark findings in multiple sclerosis (MS). In general, individual patients show a unique pattern of OCB, which is believed to persist over time. Here, the authors revisited this assumption and investigated to what extent common anti-inflammatory MS medications can alter the level of immunoglobulins produced within the CSF.Methods: The authors analyzed three patients and compared CSF findings longitudinally. Two of these patients received corticosteroids, either systemically or intrathecally, the third patient was treated continuously with natalizumab.Results: In line with reports from other groups, the authors observed that continuous natalizumab treatment dampened the intrathecal immunoglobulin production in our patient. Exceeding this anticipated scenario, the authors detected that the continued administration of corticosteroids similarly reduced the production of CSF immunoglobulins, down to a level at which these parameters are considered normal.Conclusion: These observations suggest that inflammatory CSF findings are more accessible to immunomodulatory MS treatment than previously thought, and that accordingly, their significance may transition from a sole diagnostic finding to a valuable therapeutic biomarker which may help to assess effective targeting of CNS-established inflammation in MS.

Lyme Disease or Multiple Sclerosis? Two cases with overlapping features.

Background, The etiology of multiple sclerosis is unclear and infectious agents have been considered. Borrelia infections can cause an intrathecal inflammatory response with accompanying cerebral and spinal imaging findings.&#x0D; Cases. Two children with acute or subacute initial neurological presentation, subsequent relapsing course, and MR imaging features suggestive of multiple sclerosis are presented. A history of tick bite or dramatic response to antibiotic treatment supported Lyme disease in the beginning, but requirement of disaese-modifying treatment later in the course supported multiple sclerosis.&#x0D; Results. These cases carrying features supportive of both multiple sclerosis and Lyme disease caused clinical dilemma and were treated for both disorders. Borrelia-specific IgG index testing before any treatment could have prevented the difficulty in differential diagnosis.&#x0D; Conclusions. Clinical, imaging and CSF findings of multiple sclerosis and acute or chronic progressive borrelia encephalomyelitis may overlap and testing for Borrelia-specific intrathecal antibody synthesis should not be omitted in endemic areas.

Recurrent optic neuritis – Different patterns in multiple sclerosis, neuromyelitis optica spectrum disorders and MOG-antibody disease

BackgroundOptic neuritis is a frequent finding in multiple sclerosis (MS) and in neuromyelitis optica spectrum disorder (NMOSD), as well as in Myelin-Oligodendrocyte Glycoprotein (MOG) –positive disease. While both NMOSD and MOG-antibody disease are known to be associated with a humoral, antibody-mediated attack against a specific antigen, much less is known about the etiology and pathogenesis of MS. The aim of this study was to determine if the localization of recurrent episodes of ON follows the same pattern in MS as in NMOSD and in MOG-positive recurrent ON. MethodsWe retrospectively reviewed our database to identify patients with recurrent ON. The eye affected in each episode of ON was recorded, and the findings were analyzed. ResultsForty-seven patients met the inclusion criteria. In the MS group, all episodes of ON recurred on the same side in 15 of the 29 patients (51.7%), accounting for 32 of the total 78 episodes (41%).In the NMSOD group, all episodes of ON recurred on the same side in 2 of the 12 patients (16.6%), accounting for 6 of the total 49 episodes (12.5%).In the MOG-positive group, all episodes of ON recurred on the same side in 1 out of 6 patients (16.6%), accounting for 2 of 21 episodes (9.5%).The between-group difference in the rate of recurrences affecting the ipsilateral side was statistically significant (p = .0007 and p = .0085 for the MS-NMOSD and MS-MOG groups, respectively). ConclusionsThe pattern of recurrent ON differs significantly between MS and NMOSD and MOG-positive recurrent ON. This finding suggests that in MS recurrences may be provoked by previous tissue damage, disruption of the blood-brain barrier, and other local factors while in NMOSD and MOG-antibody disease attacks are indeed due to localization of the auto antigen.

Increases in fatigue do not change spasticity scores in persons with multiple sclerosis.

Fatigue is a common finding in multiple sclerosis (MS) which may result in worsening of gait, function and other MS symptoms, like spasticity. Although the worsening of spasticity with fatigue has been reported by persons with MS, the effect of fatigue on spasticity has not been measured. The purpose of this study was to compare lower extremity Modified Ashworth Scale (MAS) scores of persons with mild-to-moderate MS symptoms before and after fatigued and unfatigued conditions. Using a randomized crossover design, MS subjects underwent 6-min walk to induce fatigue and 6-min supine rests, with lower extremity spasticity measured before and after each condition. Friedman tests gave paired comparisons of MAS before and after each condition. 16 subjects with mild-to-moderate MS completed the study (mean age=56; standard deviation =11.7). Friedman tests showed a significant decrease in mean rank for overall average MAS for both lower extremities (p= 0.031) when comparing fatigued to unfatigued conditions. This appeared to be driven by the right lower extremity average MAS (p= 0.002) and, more specifically, in post hoc pre to post-test comparisons for right knee flexor (p= 0.002 fatigued; p= 0.059 unfatigued) and right knee extensor (p= 0.001 fatigued; p= 0.020 unfatigued) MAS mean rank differences. Fatigue did not result in increased spasticity. Spasticity in these subjects with MS was not worsened by fatigue suggesting that worsening of gait with fatigue may be due to causes other than spasticity.

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study.

To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo‐cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far.

Prognostic significance of free light chains for long-term and short term disability progression in multiple sclerosis

Background: Intrathecal activation of B-cell is a major pathological finding in multiple sclerosis (MS) that is characterized by increased intrathecal synthesis and oligoclonal banding of immunoglobulins in cerebrospinal fluid (CSF). Free light chains (FLC) are fragments of immunoglobulins that are produced in parallel with OCB.

Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice.

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35–55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35–55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35–55.

White Matter Tract Injury is Associated with Deep Gray Matter Iron Deposition in Multiple Sclerosis.

With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to <.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM. Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients.

Psychological Growth and Benefit Finding in Multiple Sclerosis (MS) and Their Relationship to Symptom Burden (P2.184)

Psychological Growth and Benefit Finding in Multiple Sclerosis (MS) and Their Relationship to Symptom Burden (P2.184)

Report on the 1st International Razavi Multiple Sclerosis Congress Held in Mashhad, Iran, September 18th - 20th

From September 18th - 20th, 2015, the 1st international Razavi multiple sclerosis congress was held in Mashhad, Iran. The meeting was designated as a platform especially for young scientists to get internationally connected, discuss recent scientific findings and develop further ideas for strategic collaborations between Germany and Iran. Physicians and scientists from research groups working in Muenster (Germany), Tehran, and Mashhad attended the meeting to discuss their latest findings in Multiple Sclerosis. The meeting was very well organized in a stimulating environment and demonstrating the developments of Razavi hospital, Razavi neuroscience center, and the working environment in Mashhad, Iran.