Spinal Cord Multiple Sclerosis Research Articles

The contribution of paramagnetic rim and cortical lesions to physical and cognitive disability at multiple sclerosis clinical onset: evaluating the power of MRI and OCT biomarkers.

In multiple sclerosis (MS), imaging biomarkers play a crucial role in characterizing the disease at the time of diagnosis. MRI and optical coherence tomography (OCT) provide readily available biomarkers that may help to define the patient's clinical profile. However, the evaluation of cortical and paramagnetic rim lesions (CL, PRL), as well as retinal atrophy, is not routinely performed in clinic. To identify the most significant MRI and OCT biomarkers associated with early clinical disability in MS. Brain, spinal cord (SC) MRI, and OCT scans were acquired from 45 patients at MS diagnosis to obtain: brain PRL and non-PRL, CL, SC lesion volumes and counts, brain volumetric metrics, SC C2-C3 cross-sectional area, and retinal layer thickness. Regression models assessed relationships with physical disability (Expanded Disability Status Scale [EDSS]) and cognitive performance (Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS]). In a stepwise regression (R2 = 0.526), PRL (β = 0.001, p = 0.023) and SC lesion volumes (β = 0.001, p = 0.017) were the most significant predictors of EDSS, while CL volume and age were strongly associated with BICAMS scores. Moreover, in a model where PRL and non-PRL were pooled, only the contribution of SC lesion volume was retained in EDSS prediction. OCT measures did not show associations with disability at the onset. At MS onset, PRL and SC lesions exhibit the strongest association with physical disability, while CL strongly contribute to cognitive performance. Incorporating the evaluation of PRL and CL into the initial MS patient assessment could help define their clinical profile, thus supporting the treatment choice.

Integrated elemental analysis supports targeting copper perturbations as a therapeutic strategy in multiple sclerosis

Multiple sclerosis (MS) is a debilitating affliction of the central nervous system (CNS) that involves demyelination of neuronal axons and neurodegeneration resulting in disability that becomes more pronounced in progressive forms of the disease. The involvement of neurodegeneration in MS underscores the need for effective neuroprotective approaches necessitating identification of new therapeutic targets. Herein, we applied an integrated elemental analysis workflow to human MS-affected spinal cord tissue utilising multiple inductively coupled plasma-mass spectrometry methodologies. These analyses revealed shifts in atomic copper as a notable aspect of disease. Complementary gene expression and biochemical analyses demonstrated that changes in copper levels coincided with altered expression of copper handling genes and downstream functionality of cuproenzymes. Copper-related problems observed in the human MS spinal cord were largely reproduced in the experimental autoimmune encephalomyelitis (EAE) mouse model during the acute phase of disease characterised by axonal demyelination, lesion formation, and motor neuron loss. Treatment of EAE mice with the CNS-permeant copper modulating compound CuII(atsm) resulted in recovery of cuproenzyme function, improved myelination and lesion volume, and neuroprotection. These findings support targeting copper perturbations as a therapeutic strategy for MS with CuII(atsm) showing initial promise.

A role for vessel-associated extracellular matrix proteins in multiple sclerosis pathology.

Multiple sclerosis (MS) is unsurpassed for its clinical and pathological hetherogeneity, but the biological determinants of this variability are unknown. HLA-DRB1*15, the main genetic risk factor for MS, influences the severity and distribution of MS pathology. This study set out to unravel the molecular determinants of the heterogeneity of MS pathology in relation to HLA-DRB1*15 status. Shotgun proteomics from a discovery cohort of MS spinal cord samples segregated by HLA-DRB*15 status revealed overexpression of the extracellular matrix (ECM) proteins, biglycan, decorin, and prolargin in HLA-DRB*15-positive cases, adding to established literature on a role of ECM proteins in MS pathology that has heretofore lacked systematic pathological validation. These findings informed a neuropathological characterisation of these proteins in a large autopsy cohort of 41 MS cases (18 HLA-DRB1*15-positive and 23 HLA-DRB1*15-negative), and seven non-neurological controls on motor cortical, cervical and lumbar spinal cord tissue. Biglycan and decorin demonstrate a striking perivascular expression pattern in controls that is reduced in MS (-36.5%, p = 0.036 and - 24.7%, p = 0.039; respectively) in lesional and non-lesional areas. A concomitant increase in diffuse parenchymal accumulation of biglycan and decorin is seen in MS (p = 0.015 and p = 0.001, respectively), particularly in HLA-DRB1*15-positive cases (p = 0.007 and p = 0.046, respectively). Prolargin shows a faint parenchymal pattern in controls that is markedly increased in MS cases where a perivascular deposition pattern is observed (motor cortex +97.5%, p = 0.001; cervical cord +49.1%, p = 0.016). Our findings point to ECM proteins and the vascular interface playing a central role in MS pathology within and outside the plaque area. As ECM proteins are known potent pro-inflammatory molecules, their parenchymal accumulation may contribute to disease severity. This study brings to light novel factors that may contribute to the heterogeneity of the topographical variation of MS pathology.

Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology

Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.

Characteristics of multiple sclerosis and demyelinating disease in an Asian American population

Background: Race and ancestry influence the course of multiple sclerosis (MS). Objectives: Explore clinical characteristics of MS and neuromyelitis optica spectrum disorder (NMOSD) in Asian American patients. Methods: Chart review was performed for 282 adults with demyelinating disease who self-identified as Asian at a single North American MS center. Demographics and clinical characteristics were compared to non-Asian MS patients and by region of Asian ancestry. Results: Region of ancestry was known for 181 patients. Most (94.7%) preferred English, but fewer East Asian patients did (80%, p = 0.0001). South Asian patients had higher neighborhood household income (p = 0.002). Diagnoses included MS (76.2%) and NMOSD (13.8%). More patients with NMOSD than MS were East and Southeast Asian (p = 0.004). For MS patients, optic nerve and spinal cord involvement were similar across regions of ancestry. Asian MS patients were younger at symptom onset and diagnosis than non-Asian MS patients. MS Severity Scale scores were similar to non-Asian MS patients but worse among Southeast Asians (p = 0.006). Conclusions: MS severity was similar between Asian American patients and non-Asian patients. Region of ancestry was associated with differences in sociodemographics and MS severity. Further research is needed to uncover genetic, socioeconomic, or environmental factors causing these differences.

Double inversion recovery to detect cervical spinal cord multiple sclerosis lesions.

Magnetic resonance imaging (MRI) plays a key role in diagnosing and monitoring multiple sclerosis (MS). Double inversion recovery (DIR) is a pulse sequence that has proven highly effective at detecting cortical lesions but is understudied in the spinal cord. We hypothesize that DIR images obtained during brain MRI can be of value in assessing the upper spinal cord of MS patients. We retrospectively examined brain MRI exams of 64 patients with established MS, who had also undergone cervical spine MRI. Two blinded MS expert readers, who assessed the scans for lesion numbers and rated lesion visibility and overall image quality, reviewed brain 3-dimensional DIR sagittal and coronal images. Standardized mean contrast-to-noise ratios (C/N) and standard deviation (SD) were calculated in representative lesions for each patient and compared to those of 3-dimensional FLAIR images. For the analysis of lesions categorized as "definite lesions," the sensitivity was 87%, specificity was 61%, and negative predictive value was 80%. On the other hand, for "definite" plus "probable" lesions, the sensitivity was 91%, the specificity was 54%, and negative predictive value was 86%. DIR demonstrated lesions with an average C/N of 7.56 with an SD of 1.77. FLAIR sequence demonstrated lesions with an average C/N of 0.67 and SD of 1.27. Sagittally acquired brain DIR can provide useful information on upper spinal cord lesions, with high C/N. In theory, this should facilitate the attainment of McDonald's or the Magnetic Resonance Imaging in MS (MAGNIMS) criteria in some cases, without a dedicated cervical spine MRI exam.

Great leaps in multiple sclerosis treatment but the holy grail is still ahead

Great leaps in multiple sclerosis treatment but the holy grail is still ahead MS is an autoimmune disease of the central nervous system (CNS), affecting the brain, optic nerve and spinal cord. In MS, the immune system mistakenly attacks the myelin sheath around the nerves, disrupting the conduction of nerve signals to other parts of the body. There are many symptoms that can be variable and unpredictable depending on which part of the CNS is damaged. They can be a one-off occurrence, come and go or change in severity over time, contributing to the uncertainty that MS brings. Here CEO of MS Australia Rohan Greenland highlights the breakthroughs in treating attacks on the brain and spinal cord in multiple sclerosis (MS). But his sights are set firmly on the great unmet needs: to repair damaged nerves, reverse disability, and ultimately, prevent MS.

Identification of potential regulatory long non-coding RNA-associated competing endogenous RNA axes in periplaque regions in multiple sclerosis.

Slow-burning inflammation at the lesion rim is connected to the expansion of chronic multiple sclerosis (MS) lesions. However, the underlying processes causing expansion are not clearly realized. In this context, the current study used a bioinformatics approach to identify the expression profiles and related lncRNA-associated ceRNA regulatory axes in the periplaque region in MS patients. Expression data (GSE52139) from periplaque regions in the secondary progressive MS spinal cord and controls were downloaded from the Gene Expression Omnibus database (GEO), which has details on mRNAs and lncRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also found using the DIANA-LncBase, miRTarBase, and HMDD databases. The Pearson correlation coefficient was used to determine whether there were any positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Finally, lncRNA-associated ceRNA axes were created based on co-expression and connections between DElncRNA, miRNA, and DEmRNA. We used the Enrichr tool to enrich the biological process, molecular function, and pathways for DEmRNAs and DElncRNAs. A network of DEmRNAs' protein-protein interactions was developed, and the top five hub genes were found using Cytoscape and STRING. The current study indicates that 15 DEmRNAs, including FOS, GJA1, NTRK2, CTNND1, and SP3, are connected to the MS ceRNA network. Additionally, four DElncRNAs (such as TUG1, ASB16-AS1, and LINC01094) that regulated the aforementioned mRNAs by sponging 14 MS-related miRNAs (e.g., hsa-miR-145-5p, hsa-miR-200a-3p, hsa-miR-20a-5p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-27a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-34a-5p) were found. In addition, the analysis of pathway enrichment revealed that DEmRNAs were enriched in the pathways for the "MAPK signaling pathway", "Kaposi sarcoma-associated herpesvirus infection", "Human immunodeficiency virus one infection", "Lipid and atherosclerosis", and "Amphetamine addiction". Even though the function of these ceRNA axes needs to be investigated further, this study provides research targets for studying ceRNA-mediated molecular mechanisms related to periplaque demyelination in MS.

A novel cell-free intrathecal approach with PRP for the treatment of spinal cord multiple sclerosis in cats

BackgroundMultiple sclerosis (MS) is a progressive autoimmune demyelinating disease of the central nervous system. To date, there is no effective therapy for it. Our study aimed to determine the potential role of platelet-rich plasma (PRP) in the treatment of MS in cats.MethodsThe current study was conducted on 15 adult Persian cats that were divided into three groups: control negative, control positive (ethidium bromide (EB)-treated group), and PRP co-treated group (EB-treated group intrathecally injected with PRP on day 14 post-spinal cord injury). PRP was obtained by centrifuging blood on anticoagulant citrate dextrose and activating it with red and green laser diodes. The Basso–Beattie–Bresnahan (BBB) scores were used to assess the motor function recovery on days 1, 3, 7, 14, 20, and 28 following 14 days from EB injection. Moreover, magnetic resonance imaging (MRI) analysis, histopathological investigations, transmission electron microscopy (TEM) studies, and immunohistochemical analysis were conducted, and the gene expressions of nerve growth factors (NGFs), brain-derived neurotrophic factors (BDNF), and stromal cell-derived factors (SDF) were evaluated.ResultsOur results indicated that PRP had a significant ameliorative effect on the motor function of the hindlimbs as early as day 20 and so on. MRI revealed that the size and intensity of the lesion were significantly reduced in the PRP co-treated group. The histopathological and TEM investigations demonstrated that the PRP co-treated group had a significant improvement in the structure and organization of the white matter, as well as a high remyelination capacity. Furthermore, a significant increase in myelin basic protein and Olig2 immunoreactivity as well as a reduction in Bax and glial fibrillar acidic protein immune markers was observed. NGFs were found to be upregulated by gene expression.ConclusionAs a result, we concluded that the intrathecal injection of PRP was an effective, safe, and promising method for the treatment of MS.

Trans-Spinal Direct Current Stimulation in Spasticity: A Literature Mini-Review

Spasticity is common after a stroke and has a negative impact on functional and quality-of-life measures. There is an unmet medical need to provide safe and effective treatment using non-pharmacological approaches. Trans-spinal direct current stimulation (tsDCS) is an emerging modality for non-invasive neuromodulation that induces reduction of spinal excitability leading to a decrease in spasticity. We describe current treatment options for spasticity, including a literature review about the use of tsDCS in patients with spasticity. We found four clinical studies that used tsDCS to treat spasticity for different neurological conditions including hereditary spastic paraplegia, upper extremity spasticity following stroke, multiple sclerosis, and incomplete chronic spinal cord injury. Spasticity was the primary outcome in three of the studies and a secondary outcome in the final study. The three studies that addressed spasticity as the primary outcome found that active tsDCS decreased spasticity compared to sham. These studies suggest that tsDCS can modulate spinal motor and sensory spinal pathways through the use of specific electrode montages and stimulation parameters. This therapy can improve motor functions and may represent a viable treatment option for spasticity.

Improving cervical spinal cord lesion detection in multiple sclerosis using filtered fused proton density-T2 weighted images

BackgroundMagnetic Resonance Imaging (MRI) is considered a vital in depicting multiple sclerosis (MS) lesions. Current studies demonstrate that proton density (PD) weighted images (WI) are superior to T2 WI in detecting MS lesions (plaques) in the spinal cord.PurposeTo evaluate the diagnostic value of filtered fused PD/T2 weighted images in detecting cervical spinal cord MS lesions.Material and MethodsIn this retrospective study, we selected a sample size of 50 MS patients. Using contrast limited adaptive histogram equalization (CLAHE), a digital image processing filter was used on the (PD/T2) fused images. The produced images were inspected and compared to the original PD images by two experienced neuroradiologists using interobserver and intraobserver. An ROI analysis was also performed on the processed and original PD images.ResultsThe repeatability measurement of the match between the two examinations was highly consistent for both neuroradiologists. The repeatability for both neuroradiologists was 96.05%, and the error measurement was 3.95%. The reproducibility measurement of the neuroradiologist’s evaluation shows that the processed images could help to identify lesions better [excellent (84.87%)] than PD images [good (61.19%)]. ROIs analysis was performed on 113 MS lesions and normal areas in different images within the sample size. It revealed an enhanced ratio of 2.2 between MS lesions and normal spinal cord tissue in processed fused images compared to 1.34 in PD images.ConclusionThe processed images of the fused images (PD/T2) have superior diagnostic sensitivity for MS lesions in the cervical spine than PD images alone.

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions.

PurposeValidation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord.MethodsFour fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent‐driven equilibrium single‐pulse observation of T1 and T2 protocol to produce apparent proton density, T1, T2, myelin water, intracellular water, and free‐water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps.ResultsExcellent correspondence was found between high‐resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining.ConclusionHigh‐resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord.

Detection of multiple sclerosis lesions in the cervical cord: which of the MAGNIMS 'mandatory' non-gadolinium enhanced sagittal sequences is optimal at 3T?

The magnetic resonance imaging in multiple sclerosis consensus guidelines currently mandate three sagittal non-contrast enhanced sequences of T2-weighted fast spin echo, proton density-weighted fast spin echo and short tau inversion recovery; however, these particular three sequences have not previously been compared at 3T. This study compared T2-weighted fast spin echo, proton density-weighted fast spin echo, short tau inversion recovery as well as the double inversion recovery sequence for the sagittal detection of multiple sclerosis lesions in the cervical spinal cord at 3T. Nineteen multiple sclerosis patients underwent magnetic resonance imaging with 3T sagittal T2-weighted fast spin echo, proton density-weighted fast spin echo, short tau inversion recovery and double inversion recovery between November 2012 and April 2013. Two neuroradiologists independently reviewed the images, and the number of lesions detected on each sequence was recorded. Lesion conspicuity was quantitatively assessed with the lesion-to-cord-contrast ratio and lesion contrast-to-noise ratio. The Wilcoxon signed rank test was performed for statistical analysis. Proton density-weighted fast spin echo and short tau inversion recovery detected 32% more lesions compared to T2-weighted fast spin echo, and 37% more lesions compared to double inversion recovery. The lesion-to-cord-contrast ratio was highest in short tau inversion recovery, while the lesion contrast-to-noise ratio was highest for proton density-weighted fast spin echo. This study provides the necessary evidentiary support at 3T for the magnetic resonance imaging in multiple sclerosis spinal magnetic resonance imaging protocol consensus guidelines. At 3T sagittal proton density-weighted fast spin echo and short tau inversion recovery sequences allowed improved detection of cervical spinal cord multiple sclerosis lesions, compared to T2-weighted fast spin echo and three-dimensional double inversion recovery magnetic resonance imaging. Utilising T2-weighted fast spin echo alone at 3T is insufficient for lesion detection.

Imaging of the Spinal Cord in Multiple Sclerosis: Past, Present, Future.

Spinal cord imaging in multiple sclerosis (MS) plays a significant role in diagnosing and tracking disease progression. The spinal cord is one of four key areas of the central nervous system where documenting the dissemination in space in the McDonald criteria for diagnosing MS. Spinal cord lesion load and the severity of cord atrophy are believed to be more relevant to disability than white matter lesions in the brain in different phenotypes of MS. Axonal loss contributes to spinal cord atrophy in MS and its degree correlates with disease severity and prognosis. Therefore, measures of axonal loss are often reliable biomarkers for monitoring disease progression. With recent technical advances, more and more qualitative and quantitative MRI techniques have been investigated in an attempt to provide objective and reliable diagnostic and monitoring biomarkers in MS. In this article, we discuss the role of spinal cord imaging in the diagnosis and prognosis of MS and, additionally, we review various techniques that may improve our understanding of the disease.

Synaptic Loss in Multiple Sclerosis Spinal Cord.

Disability in multiple sclerosis (MS) is considered primarily a result of axonal loss. However, correlation with spinal cord cross-sectional area-a predictor of disability-is poor, questioning the unique role of axonal loss. We investigated the degree of synaptic loss in postmortem spinal cords (18 chronic MS, 8 healthy controls) using immunohistochemistry for synaptophysin and synapsin. Substantial (58-96%) loss of synapses throughout the spinal cord was detected, along with moderate (47%) loss of anterior horn neurons, notably in demyelinating MS lesions. We conclude that synaptic loss is significant in chronic MS, likely contributing to disability accrual. ANN NEUROL 2020;88:619-625.

Editorial for: “Sodium in the Relapsing–Remitting Multiple Sclerosis Spinal Cord: Increased Concentrations and Associations With Microstructural Tissue Anisotropy”

Editorial for: “Sodium in the Relapsing–Remitting Multiple Sclerosis Spinal Cord: Increased Concentrations and Associations With Microstructural Tissue Anisotropy”

The impact of regional astrocyte interferon-\u03b3 signaling during chronic autoimmunity: a novel role for the immunoproteasome

BackgroundIn early autoimmune neuroinflammation, interferon (IFN)γ and its upregulation of the immunoproteasome (iP) is pathologic. However, during chronic multiple sclerosis (MS), IFNγ has protective properties. Although dysregulation of the iP has been implicated in neurodegeneration, its function remains to be fully elucidated. Here, we demonstrate that IFNγ signaling in regional astrocytes induces the iP and promotes protection of the CNS during chronic autoimmunity.MethodsIn a multiple sclerosis (MS) brain, we evaluated mRNA expression and labeled postmortem MS brainstem and spinal cord for iP subunits and indicators of oxidative stress. Primary regional human astrocytes were analyzed for iP regulation and function by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, OxyBlot, and reactive oxygen species and caspase activity detection assays. Following immunization with myelin oligodendrocyte glycoprotein (MOG)35-55, the role of IFNγ signaling and the iP during chronic experimental autoimmune encephalomyelitis (EAE) were assessed using pharmacologic inhibition of the iP and genetic interruption of IFNγ signaling specifically in astrocytes. Central nervous system (CNS) tissues were analyzed by immunohistochemistry (IHC) and immunofluorescence, and cell-specific colocalization was quantified.ResultsIn MS tissue, iP expression was enhanced in the spinal cord compared to brainstem lesions, which correlated with a decrease in oxidative stress. In vitro, IFNγ stimulation enhanced iP expression, reduced reactive oxygen species burden, and decreased oxidatively damaged and poly-ubiquitinated protein accumulation preferentially in human spinal cord astrocytes, which was abrogated with the use of the iP inhibitor, ONX 0914. During the chronic phase of an MS animal model, EAE, ONX 0914 treatment exacerbated the disease and led to increased oxidative stress and poly-ubiquitinated protein buildup. Finally, mice with astrocyte-specific loss of the IFNγ receptor exhibited worsened chronic EAE associated with reduced iP expression, enhanced lesion size and oxidative stress, and poly-ubiquitinated protein accumulation in astrocytes.ConclusionsTaken together, our data reveal a protective role for IFNγ in chronic neuroinflammation and identify a novel function of the iP in astrocytes during CNS autoimmunity.

Sodium in the Relapsing–Remitting Multiple Sclerosis Spinal Cord: Increased Concentrations and Associations With Microstructural Tissue Anisotropy

Associations between brain total sodium concentration, disability, and disease progression have recently been reported in multiple sclerosis. However, such measures in spinal cord have not been reported. To measure total sodium concentration (TSC) alterations in the cervical spinal cord of people with relapsing-remitting multiple sclerosis (RRMS) and a control cohort using sodium MR spectroscopy (MRS). Retrospective cohort. Nineteen people with RRMS and 21 healthy controls. 3 T sodium MRS, diffusion tensor imaging, and 3D gradient echo. Quantification of total sodium concentration in the cervical cord using a reference phantom. Measures of spinal cord cross-sectional area, fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity from 1 H MRI. Clinical assessments of 9-Hole Peg Test, 25-Foot Timed walk test, Paced Auditory Serial Addition Test with 3-second intervals, grip strength, vibration sensitivity, and posturography were performed on the RRMS cohort as well as reporting lesions in the C2/3 area. Multiple linear regression models were run between sodium and clinical scores, cross-sectional area, and diffusion metrics to establish any correlations. A significant increase in spinal cord total sodium concentration was found in people with RRMS relative to healthy controls (57.6 ± 18 mmol and 38.0 ± 8.6 mmol, respectively, P < 0.001). Increased TSC correlated with reduced fractional anisotropy (P = 0.034) and clinically with decreased mediolateral stability assessed with posturography (P = 0.045). Total sodium concentration in the cervical spinal cord is elevated in RRMS. This alteration is associated with reduced fractional anisotropy, which may be due to changes in tissue microstructure and, hence, in the integrity of spinal cord tissue. 1 TECHNICAL EFFICACY STAGE: 2.

B cells and multiple sclerosis spinal cord pathology.

B cells and multiple sclerosis spinal cord pathology.

TGFB1-Mediated Gliosis in Multiple Sclerosis Spinal Cords Is Favored by the Regionalized Expression of HOXA5 and the Age-Dependent Decline in Androgen Receptor Ligands.

In multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord (SC) functions slowly deteriorate beyond age 40. We previously showed that in the SC of these patients, large areas of incomplete demyelination extend distance away from plaque borders and are characterized by a unique progliotic TGFB1 (Transforming Growth Factor Beta 1) genomic signature. Here, we attempted to determine whether region- and age-specific physiological parameters could promote the progression of SC periplaques in MS patients beyond age 40. An analysis of transcriptomics databases showed that, under physiological conditions, a set of 10 homeobox (HOX) genes are highly significantly overexpressed in the human SC as compared to distinct brain regions. Among these HOX genes, a survey of the human proteome showed that only HOXA5 encodes a protein which interacts with a member of the TGF-beta signaling pathway, namely SMAD1 (SMAD family member 1). Moreover, HOXA5 was previously found to promote the TGF-beta pathway. Interestingly, SMAD1 is also a protein partner of the androgen receptor (AR) and an unsupervised analysis of gene ontology terms indicates that the AR pathway antagonizes the TGF-beta/SMAD pathway. Retrieval of promoter analysis data further confirmed that AR negatively regulates the transcription of several members of the TGF-beta/SMAD pathway. On this basis, we propose that in progressive MS patients, the physiological SC overexpression of HOXA5 combined with the age-dependent decline in AR ligands may favor the slow progression of TGFB1-mediated gliosis. Potential therapeutic implications are discussed.