Involvement In Multiple Sclerosis Research Articles

Long noncoding RNAs APOA1-AS, IFNG-AS1, RMRP and their related biomolecules in Egyptian patients with relapsing-remitting multiple sclerosis: Relation to disease activity and patient disability

Lately, long noncoding (lnc) RNAs are increasingly appreciated for their involvement in multiple sclerosis (MS). In inflammation and autoimmunity, a role of apoprotein A1 (ApoA1), mediated by sphingosine 1-phosphate receptors (S1PRs), was reported. However, the epigenetic mechanisms regulating these biomolecules and their role in MS remains elusive. This case control study investigated the role of ApoA1, sphingosine kinase 1 and 2 (SPHK1 & 2), S1PR1 & 5, interferon-γ (IFN-γ) and interleukin 17 (IL17) in MS, beside three lncRNA: APOA1-AS, IFNG-AS1, and RMRP. Expression of SPHKs, S1PRs, and lncRNAs were measured in 72 relapsing-remitting MS patients (37 during relapse and 35 in remission) and 28 controls. Plasma levels of ApoA1, IFN-γ and IL17 were determined. The impact of these parameters on MS activity, relapse rate and patient disability was assessed. APOA1-AS, IFNG-AS1, SPHK1 & 2, and S1PR5 were upregulated in RRMS patients. Differences in ApoA1, SPHK2, and IL17 were observed between relapse and remission. Importantly, ApoA1, SPHK2, and IL17 were related to activity, while S1PR1 and IFN-γ were linked to disability, though, only IFN-γ was associated with relapse rate. Finally, an excellent diagnostic power of IFN-γ, IL17, SPHK1 and APOA1-AS was demonstrated, whereas SPHK2 showed promising prognostic power in predicting relapses.

The role of interleukin 22 in multiple sclerosis and its association with c-Maf and AHR.

The aim of this paper was to summarise knowledge of IL-22 involvement in multiple sclerosis (MS) and the possible link between IL-22 and two transcription factors - AHR and c-Maf. The conclusion is that despite numerous studies, the exact role of IL-22 in the pathogenesis of MS is still unknown. The expression and function of c-Maf in MS have not been studied. It seems that the functions of c-Maf and AHR are at least partly connected with IL-22, as both directly or indirectly influence the regulation of IL-22 expression. This possible connection has never been studied in MS.

A pilot study on the efficacy of transcranial direct current stimulation applied to the pharyngeal motor cortex for dysphagia associated with brainstem involvement in multiple sclerosis

Objective: we investigated the effect of anodal transcranial direct current stimulation (tDCS) applied over the pharyngeal motor area in dysphagia associated with multiple sclerosis (MS). Methods: Eighteen MS patients with dysphagia associated with brainstem involvement were randomized to receive either “real” or “sham” tDCS. Primary outcome: The Penetration/Aspiration Scale (PAS). Secondary outcomes: changes in electromyographic (EMG) parameters and pharyngeal cortical motor evoked potentials (MEPs). Patients were evaluated at baseline (T0), at the end of 5-session cycle of tDCS stimulations (T1), after two (T2), and four (T3) weeks.Results: the PAS values were significantly lower in the active group than in “sham” group at T1, and at T3. Over the post-stimulation periods, PAS significantly improved only in the “real” group. As regards the secondary outcomes, we observed a statistically significant difference between the 2 groups only in the MEPs amplitude at T1. The comparison between baseline and each of the post-stimulation times showed significant differences only of the “real” group across all the secondary parameters.Conclusions: Our findings support a beneficial effect of anodal tDCS applied to the pharyngeal motor cortex in MS-associated dysphagia.Significance: Considering its safety and efficacy, tDCS may represent an important resource in MS-associated dysphagia.

Angiopoietin-like proteins in multiple sclerosis

Angiopoietin-like proteins (ANGPTLs) are a group of proteins with functions in lipid metabolism, angiogenesis, and inflammation. Here, we investigated their involvement in multiple sclerosis (MS) progression and response to treatment in 100 MS patients and 77 healthy controls. ANGPTLs significantly associated with MS progression and response to therapy. High ANGPTL6 levels associated with slow disease progression and good response to fingolimod treatment and low ANGPTL4 associated with poor response to natalizumab treatment. Therefore, we propose high ANGPTL4 and 6 levels as markers for positive response to MS treatments either natalizumab or fingolimod respectively. Further investigations into their role in MS is warranted.

Optimal Intereye Difference Thresholds in Retinal Nerve Fiber Layer Thickness for Predicting a Unilateral Optic Nerve Lesion in Multiple Sclerosis.

The optic nerve is a frequent site for involvement in multiple sclerosis (MS). Optical coherence tomography (OCT) detects thinning of the retinal nerve fiber layer (RNFL) in eyes of patients with MS and in those meeting criteria for clinically or radiologically isolated demyelinating syndromes. Current international diagnostic criteria for MS do not include the optic nerve as an imaging lesion site despite the high prevalence of acute optic neuritis (ON), or occult optic neuropathy, among early MS and clinically isolated syndrome patients; as well as most MS patients over the course of the disease. We sought to determine optimal thresholds for intereye difference in peripapillary RNFL thickness that are most predictive of a unilateral optic nerve lesion. We analyzed spectral domain OCT data of 31 healthy volunteers and 124 patients with MS at a single center as part of an ongoing collaborative investigation of visual outcomes. Intereye differences in peripapillary (360°) RNFL thickness were calculated as the absolute value of the difference. First, we determined the 95th percentile value of intereye difference for the healthy volunteers. This value was applied to the convenience sample group of MS patients as a validation cohort determining how well this threshold could distinguish patients with vs without a history of unilateral ON. The relation of intereye differences in peripapillary RNFL thickness to binocular low-contrast letter acuity scores was also examined. Among healthy volunteer participants (n = 31), the 95th percentile value for intereye difference (upper boundary of expected for normal controls) was 6.0 μm. This value was applied to the convenience sample group of MS patients (n = 124, validation cohort). Positive predictive value, negative predictive value, sensitivity, and specificity for identifying MS patients with a history of unilateral ON were calculated for the 6-μm threshold value in a 2 × 2 table analysis with the application of χ tests (P < 0.0001). The 6-μm threshold was predictive of worse binocular low-contrast acuity scores at 2.5% (P = 0.03) and 1.25% (P = 0.002 by linear regression analyses). A receiver operating characteristic curve analysis demonstrated an optimal intereye difference threshold of 5 μm for identifying unilateral ON in the MS cohort. An intereye difference of 5-6 μm in RNFL thickness is a robust structural threshold for identifying the presence of a unilateral optic nerve lesion in MS.

Optical coherence tomography as a means to characterize visual pathway involvement in multiple sclerosis.

Optical coherence tomography (OCT) is a noninvasive in-vivo imaging tool that enables the quantification of the various retinal layer thicknesses. Given the frequent involvement of the visual pathway in multiple sclerosis, OCT has become an important tool in clinical practice, research and clinical trials. In this review, the role of OCT as a means to investigate visual pathway damage in multiple sclerosis is discussed. Evidence from recent OCT studies suggests that the peripapillary retinal nerve fibre layer (pRNFL) appears to be an ideal marker of axonal integrity, whereas the macular ganglion cell and inner plexiform layer (GCIP) thickness enables early detection of neuronal degeneration in multiple sclerosis. The thickness of the macular inner nuclear layer (INL) has been suggested as a biomarker for inflammatory disease activity and treatment response in multiple sclerosis. OCT parameters may also be used as an outcome measure in clinical trials evaluating the neuroprotective or regenerative potential of new treatments. OCT provides insights into multiple sclerosis beyond the visual pathway. It is capable of quantifying the major pathological hallmarks of the disease, specifically inflammation and neuroaxonal degeneration. OCT, therefore, has the potential to become another mainstay in the monitoring of multiple sclerosis patients.

Dysfunctional RNA binding proteins and stress granules in multiple sclerosis

Dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonuclear protein A1 (hnRNP A1) has been shown to contribute to the pathogenesis of neurodegenerative diseases, but its involvement in multiple sclerosis (MS) is largely unknown. In a neuronal cell line, interferon-γ caused hnRNP A1 nucleocytoplasmic mislocalization; colocalization of hnRNP A1 in stress granules (SGs); and inhibition of translation. Neurons in the brain of a MS patient showed pathogenic RBP dysfunction, including nuclear depletion of hnRNP A1, its mislocalization to the cytoplasm, and its colocalization in SGs. These data indicate a role for dysfunctional hnRNP A1 in the pathogenesis of MS.

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuroinflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. miRNAs regulate CD4+ T cells to differentiate toward various T cell subtypes including Th17 cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17 cells, and potential miRNA targets for current disease-modifying treatments.

Inner ear involvement in multiple sclerosis: An underestimated condition?

Inner ear involvement in multiple sclerosis: An underestimated condition?

Cervical vestibular-evoked myogenic potentials in patients with multiple sclerosis: sensitive in detecting brainstem involvement?

Cervical vestibular-evoked myogenic potentials (cVEMPs) are accepted to demonstrate the vestibulo-collic reflex. However, the brainstem pathway is still not fully understood. The aim of the study was to evaluate the contribution of cVEMPs to detection of brainstem involvement in multiple sclerosis (MS). Thirty patients fulfilling the criteria for definite MS were included in the study. All were newly diagnosed cases, admitted due to an attack with active lesions on MRI. Thirty-one age- and sex-matched healthy controls constituted the control group. The latencies of peaks p13 and n23 and peak-to-peak amplitude of p13-n23 were measured. Brainstem lesions on MRI were present in 13 of the patients (43.4%). Comparison of the overall results recorded from patients with the healthy controls did not reveal a statistically significant difference in any of the parameters studied (p > 0.05). A significant inter-side difference was not also present between groups (p > 0.05). When p13 and n23 latencies exceeding 2.5 standard deviations (SD) were taken into consideration, it was seen that there were seven patients (23.3%) with prolonged latencies mainly involving the p13 peak. Five of them had brainstem signs on examination and had brainstem lesions on MRI. In the other eight patients with abnormal MRI, normal results were recorded indicating that in only 38% of patients with brainstem lesions, cVEMPs were altered. Absence of a correlation between cVEMPs and brainstem clinical or MRI lesions defies their role in identifying lower brainstem involvement.

DTI metrics reflecting microstructural changes of normal appearing deep grey matter in multiple sclerosis

PurposeTo evaluate the role of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in detecting microstructural changes of normal-appearing deep grey matter (NDGM) in multiple sclerosis (MS). Patient and methodsWe examined 40 patients with MS and 20 healthy volunteers using DTI to correlate average ADC and FA of the thalami, lentiform and caudate nuclei between the two groups. Receiver operating characteristic analysis was used to test the diagnostic performance of ADC and FA in detecting NDGM involvement in multiple sclerosis. ResultsBetween the two study groups, there was statistically significant difference of ADC of thalami, lentiform, caudate nuclei, and FA of the thalami (p < .05). No statistically significant difference of FA of lentiform (p = .2) and caudate (p = .06) nuclei. For detection of microstructural changes of NDGM, ADC cut off values were 0.762 × 10−3 mm2/s for thalamus (90% sensitivity and 66% specificity), 0.529 × 10−3 mm2/s for lentiform (86% sensitivity and 60% specificity) and 0.784 × 10−3 mm2/s for caudate nuclei (83% sensitivity and 67% specificity). ConclusionADC has better diagnostic performance and is more accurate than FA as a measure to detect microstructural changes of NDGM.

Peripheral nerve involvement in multiple sclerosis: Demonstration by magnetic resonance neurography.

To detect and quantify peripheral nerve lesions in multiple sclerosis (MS) by magnetic resonance neurography (MRN). Thirty-six patients diagnosed with MS based on the 2010 McDonald criteria (34 with the relapsing-remitting form, 2 with clinically isolated syndrome) with and without disease-modifying treatment were compared to 35 healthy age-/sex-matched volunteers. All patients underwent detailed neurological and electrophysiological examinations. Three Tesla MRN with large anatomical coverage of both legs and the lumbosacral plexus was performed by using 2-dimensional (2D) fat-saturated, T2-weighted (T2w) and dual echo turbo spin echo sequences as well as a 3D T2-weighted, fat-saturated SPACE sequence. Besides qualitative visual nerve assessment, a T2w signal quantification was performed by calculation of proton spin density and T2 relaxation time. Nerve diameter was measured as a morphometric criterion. T2w hyperintense nerve lesions were detectable in all MS patients, with a mean lesion number at thigh level of 151.5 ± 5.7 versus 19.1 ± 2.4 in controls (p < 0.0001). Nerve proton spin density was higher in MS (tibial/peroneal: 371.8 ± 7.7/368.9 ± 8.2) versus controls (tibial/peroneal: 266.0 ± 11.0/276.8 ± 9.7, p < 0.0001). In contrast, T2 relaxation time was significantly higher in controls (tibial/peroneal: 82.0 ± 2.1/78.3 ± 1.7) versus MS (tibial/peroneal: 64.3 ± 1.0/61.2 ± 0.9, p < 0.0001). Proximal tibial and peroneal nerve caliber was higher in MS (tibial: 52.4 ± 2.1mm2 , peroneal: 25.4 ± 1.3mm2 ) versus controls (tibial: 45.2 ± 1.4mm2 , p < 0.0015; peroneal: 21.3 ± 0.7mm2 , p = 0.0049). Peripheral nerve lesions could be visualized and quantified in MS in vivo by high-resolution MRN. Lesions are defined by an increase of proton spin density and a decrease of T2 relaxation time, indicating changes in the microstructural organization of the extracellular matrix in peripheral nerve tissue in MS. By showing involvement of the peripheral nervous system in MS, this proof-of-concept study may offer new insights into the pathophysiology and treatment of MS. Ann Neurol 2017;82:676-685.

Transglutaminase-6 is an autoantigen in progressive multiple sclerosis and is upregulated in reactive astrocytes

Background: Transglutaminase-6 (TGM6), a member of the transglutaminase enzyme family, is found predominantly in central nervous system (CNS) neurons under physiological conditions. It has been proposed as an autoimmune target in cerebral palsy, gluten-sensitive cerebellar ataxia, and schizophrenia. Objective: To investigate TGM6 involvement in multiple sclerosis (MS). Methods: Antibody levels against TGM6 (TGM6-IgG) were measured in the cerebrospinal fluid (CSF) of 62 primary progressive multiple sclerosis (PPMS), 85 secondary progressive multiple sclerosis (SPMS), and 50 relapsing-remitting multiple sclerosis (RRMS) patients and 51 controls. TGM6 protein expression was analyzed in MS brain autopsy, murine experimental autoimmune encephalomyelitis (EAE), and cultured astrocytes. Results: CSF levels of TGM6-IgG were significantly higher in PPMS and SPMS compared to RRMS and controls. Notably, patients with clinically active disease had the highest TGM6-IgG levels. Additionally, brain pathology revealed strong TGM6 expression by reactive astrocytes within MS plaques. In EAE, TGM6 expression in the spinal cord correlated with disease course and localized in reactive astrocytes infiltrating white matter lesions. Finally, knocking down TGM6 expression in cultured reactive astrocytes reduced their glial fibrillary acidic protein (GFAP) expression. Conclusion: TGM6-IgG may be a candidate CSF biomarker to predict and monitor disease activity in progressive MS patients. Furthermore, TGM6 expression by reactive astrocytes within both human and mouse lesions suggests its involvement in the mechanisms of glial scar formation.

Deep grey matter MRI abnormalities and cognitive function in relapsing-remitting multiple sclerosis

Although deep grey matter (GM) involvement in multiple sclerosis (MS) is well documented, in-vivo multi-parameter magnetic resonance imaging (MRI) studies and association with detailed cognitive measures are limited. We investigated volumetric, diffusion and perfusion metrics in thalamus, hippocampus, putamen, caudate nucleus and globus pallidum, and neuropsychological measures, spanning 4 cognitive domains, in 60 relapsing-remitting MS patients (RRMS) (mean disease duration of 5.1 years, median EDSS of 1.5) and 30 healthy controls. There was significantly reduced volume of thalamus, hippocampus and putamen in the RRMS patients, but no diffusion or perfusion changes in these structures. Decreased volume in these deep GM volumes in RRMS patients was associated with a modest reduction in cognitive performance, particularly information processing speed, consistent with a subtle disruption of distributed networks, that subserve cognition, in these patients. Future longitudinal studies are needed to elucidate the influence of deep GM changes on the evolution of cognitive deficits in MS.

Gray matter involvement in multiple sclerosis; correlation of clinical and cognitive diasability with DTI magnetic resonance imaging findings

Gray matter involvement in multiple sclerosis; correlation of clinical and cognitive diasability with DTI magnetic resonance imaging findings

Improved Detection of Cortical Gray Matter Involvement in Multiple Sclerosis with Quantitative Susceptibility Mapping

Quantitative susceptibility mapping (QSM) is a novel technique which allows determining the bulk magnetic susceptibility distribution of tissue invivo from gradient echo magnetic resonance (MR) phase images. Our purpose was to evaluate if there is additional diagnostic value of QSM images in detecting the cortical gray matter involvement in multiple sclerosis (MS) patients. Our institutional review board approved this study. Conventional MR imaging, including T2-weighted imaging and two- or three-dimensional fluid-attenuated inversion recovery images, and QSM imaging examinations were performed in 27 patients (19 male and eight female) with MS. Two radiologists (radiologists 1 and 2) assessed the MS lesions in the following 3 anatomic regions: intracortical, mixed white matter-gray matter (WM-GM), and juxtacortical regions. The numbers of lesions per region category were compared between conventional MR images with and without QSM images. For radiologists 1 and 2, QSM images identified 6 (50.0%) and 7 (50.0%) additional lesions that were not seen in the conventional MR images, respectively. In a lesion-by-lesion analysis, the substantial fraction (20 [25.3%] of 79 at radiologist 1, 22 [29.7%] of 74 at radiologist 2) of juxtacortical white matter lesions on the conventional MR images were scored as mixed WM-GM lesions with QSM images. Our preliminary results suggest that the MR imaging with QSM may increase the sensitivity in cortical lesion detection in the MS brain and improved distinction between juxtacortical and mixed WM-GM lesions.

7T MRI‐Histologic Correlation Study of Low Specific Absorption Rate T2‐Weighted GRASE Sequences in the Detection of White Matter Involvement in Multiple Sclerosis

The high value of the specific absorption rate (SAR) of radio-frequency (RF) energy arising from the series of RF refocusing pulses in T2-weighted (T2-w) turbo spin echo (TSE) MRI hampers its clinical application at 7.0 Tesla (7T). T2-w gradient and spin echo (GRASE) uses the speed from gradient refocusing in combination with the chemical-shift/static magnetic field (B0) inhomogeneity insensitivity from spin-echo refocusing to acquire T2-w images with a limited number of refocusing RF pulses, thus reducing SAR. To investigate whether low SAR T2-w GRASE could replace T2-w TSE in detecting white matter (WM) disease in MS patients imaged at 7T. The .7 mm3 isotropic T2-w TSE and T2-w GRASE images with variable echo times (TEs) and echo planar imaging (EPI) factors were obtained on a 7T scanner from postmortem samples of MS brains. These samples were derived from brains of 3 female MS patients. WM lesions (WM-Ls) and normal-appearing WM (NAWM) signal intensity, WM-Ls/NAWM contrast-to-noise ratio (CNR) and MRI/myelin staining sections comparisons were obtained. GRASE sequences with EPI factor/TE = 3/50 and 3/75 ms were comparable to the SE technique for measures of CNR in WM-Ls and NAWM and for detection of WM-Ls. In all sequences, however, identification of areas with remyelination, Wallerian degeneration, and gray matter demyelination, as depicted by myelin staining, was not possible. T2-w GRASE images may replace T2-w TSE for clinical use. However, even at 7T, both sequences fail in detecting and characterizing MS disease beyond visible WM-Ls.

Thoracic spinal cord lesions are influenced by the degree of cervical spine involvement in multiple sclerosis.

Cross-sectional analyses. To determine whether cervical spinal cord lesions predict the presence of thoracic cord lesions in multiple sclerosis (MS) patients. Single MS Clinic, AZ, USA. All MS patients, with MRI studies of the brain, cervical and thoracic spine obtained during a single scanning session, were acquired during a 1-year period. Clinical, demographic and imaging covariates were used in a multivariate regression model to refine predictors of thoracic cord involvement. A total of 687 patients were evaluated, and patients were excluded because of a diagnosis of other neurological disorders, not meeting the 2010 McDonald criteria for MS (n=222) or incomplete neuraxis imaging (n=339). The study cohort comprised 126 patients. There was an increase in the odds ratio (OR) of thoracic spine involvement when any cervical spine lesion was present (OR=6.08, 95% confidence interval (2.21-16.68), P<0.001). The multivariate logistic regression model demonstrated a substantial and significant increase in the odds of thoracic spine involvement when more than two cervical spine lesions were present, two lesions (OR 4.44, (0.91-21.60), P=0.06), three lesions (OR 19.76, (3.51-111.17), P=0.001), four or more lesions (OR 20.49, (1.97-213.23), P=0.012) and diffuse lesions (OR 71.94, (5.28-979.88), P=0.001), when adjusting for significant covariates including clinical symptoms, brain lesions, disease duration and treatment exposure. Thoracic spinal cord lesions appear to be predicated on the degree of cervical spine involvement in patients with MS, a risk that appears to be independent of brain findings or clinical features.

Purkinje Cell Pathology and Loss in Multiple Sclerosis Cerebellum

Cerebellar ataxia commonly occurs in multiple sclerosis, particularly in chronic progressive disease. Previous reports have highlighted both white matter and grey matter pathological changes within the cerebellum; and demyelination and inflammatory cell infiltrates appear commonly. As Purkinje cell axons are the sole output of the cerebellar cortex, understanding pathologic processes within these cells is crucial to develop strategies to prevent their loss and thus reduce ataxia. We studied pathologic changes occurring within Purkinje cells of the cerebellum. Using immunohistochemic techniques, we found changes in neurofilament phosphorylation states within Purkinje cells, including loss of dephosphorylated neurofilament and increased phosphorylated and hyperphosphorylated neurofilament. We also found Purkinje axonal spheroids and Purkinje cell loss, both of which occurred predominantly within areas of leucocortical demyelination within the cerebellar cortex. These changes have important implications for the study of cerebellar involvement in multiple sclerosis and may help design therapies to reduce the burden of ataxia in the condition.

The vestibular evoked myogenic potentials (VEMP) score: a promising tool for evaluation of brainstem involvement in multiple sclerosis.

Concerning the great importance of brainstem involvement in multiple sclerosis (MS), the aim of this study was to explore the role of the newly developed vestibular evoked myogenic potentials (VEMP) score as a possible marker of brainstem involvement in MS patients. This was a prospective case-control study which included 100 MS patients divided into two groups (without and with clinical signs of brainstem involvement) and 50 healthy controls. Ocular VEMP (oVEMP) and cervical VEMP (cVEMP) measurements were performed in all participants and analyzed for latencies, conduction block and amplitude asymmetry ratio. Based on this the VEMP score was calculated and compared with Expanded Disability Status Scale (EDSS), disease duration and magnetic resonance imaging data. Multiple sclerosis patients with clinical signs of brainstem involvement (group 2) had a statistically significant higher percentage of VEMP conduction blocks compared with patients without clinical signs of brainstem involvement (group 1) and healthy controls (P = 0.027 and P < 0.0001, respectively). Similarly, the VEMP score was significantly higher in group 2 compared with group 1 (P = 0.018) and correlated with EDSS and disease duration (P = 0.011 and P = 0.032, respectively). Multivariate linear regression analysis showed that the VEMP score has a statistically significant influence on the EDSS score (P < 0.001, R(2) = 0.239). Interpretation of the oVEMP and cVEMP results in the form of the VEMP score enables better evaluation of brainstem involvement than either of these evoked potentials alone and correlates well with disability.