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International Journal of Molecular... Jan 2019The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central... (Review)
Review
The exact cause of multiple sclerosis (MS) remains elusive. Various factors, however, have been identified that increase an individual's risk of developing this central nervous system (CNS) demyelinating disease and are associated with an acceleration in disease severity. Besides genetic determinants, environmental factors are now established that influence MS, which is of enormous interest, as some of these contributing factors are relatively easy to change. In this regard, a low vitamin D status is associated with an elevated relapse frequency and worsened disease course in patients with MS. The most important question, however, is whether this association is causal or related. That supplementing vitamin D in MS is of direct therapeutic benefit, is still a matter of debate. In this manuscript, we first review the potentially immune modulating mechanisms of vitamin D, followed by a summary of current and ongoing clinical trials intended to assess whether vitamin D supplementation positively influences the outcome of MS. Furthermore, we provide emerging evidence that excessive vitamin D treatment via the T cell-stimulating effect of secondary hypercalcemia, could have negative effects in CNS demyelinating disease. This jointly merges into the balancing concept of a therapeutic window of vitamin D in MS.
Topics: Animals; Central Nervous System Diseases; Demyelinating Diseases; Dietary Supplements; Humans; Hypercalcemia; Vitamin D
PubMed: 30626090
DOI: 10.3390/ijms20010218 -
Neurologia Mar 2023The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the...
INTRODUCTION
The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes.
METHODS
Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease.
RESULTS
The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P = .001). TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs 31.6 ± 10.7; P = .0001).
CONCLUSIONS
The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
Topics: Female; Humans; Age of Onset; ATP Binding Cassette Transporter, Subfamily B, Member 1; Demyelinating Diseases; Genotype; Risk Factors
PubMed: 35256320
DOI: 10.1016/j.nrleng.2020.05.021 -
Progress in Brain Research 2017Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years,...
Diseases of glia, including astrocytes and oligodendrocytes, are among the most prevalent and disabling, yet least appreciated, conditions in neurology. In recent years, it has become clear that besides the overtly glial disorders of oligodendrocyte loss and myelin failure, such as the leukodystrophies and inflammatory demyelinations, a number of neurodegenerative and psychiatric disorders may also be causally linked to glial dysfunction and derive from astrocytic as well as oligodendrocytic pathology. The relative contribution of glial dysfunction to many of these disorders may be so great as to allow their treatment by the delivery of allogeneic glial progenitor cells, the precursors to both astroglia and myelin-producing oligodendrocytes. Given the development of new methods for producing and isolating these cells from pluripotent stem cells, both the myelin disorders and appropriate glial-based neurodegenerative conditions may now be compelling targets for cell-based therapy. As such, glial cell-based therapies may offer potential benefit to a broader range of diseases than ever before contemplated, including disorders such as Huntington's disease and the motor neuron degeneration of amyotrophic lateral sclerosis, which have traditionally been considered neuronal in nature.
Topics: Demyelinating Diseases; Humans; Myelin Sheath; Neuroglia; Oligodendroglia; Pluripotent Stem Cells
PubMed: 28554396
DOI: 10.1016/bs.pbr.2017.02.010 -
Frontiers in Immunology 2023Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating... (Review)
Review
Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections in the central nervous system and induces chronic inflammatory demyelinating disease in susceptible mice. TMEV infects dendritic cells, macrophages, B cells, and glial cells. The state of TLR activation in the host plays a critical role in initial viral replication and persistence. The further activation of TLRs enhances viral replication and persistence, leading to the pathogenicity of TMEV-induced demyelinating disease. Various cytokines are produced via TLRs, and MDA-5 signals linked with NF-κB activation following TMEV infection. In turn, these signals further amplify TMEV replication and the persistence of virus-infected cells. The signals further elevate cytokine production, promoting the development of Th17 responses and preventing cellular apoptosis, which enables viral persistence. Excessive levels of cytokines, particularly IL-6 and IL-1β, facilitate the generation of pathogenic Th17 immune responses to viral antigens and autoantigens, leading to TMEV-induced demyelinating disease. These cytokines, together with TLR2 may prematurely generate functionally deficient CD25-FoxP3+ CD4 T cells, which are subsequently converted to Th17 cells. Furthermore, IL-6 and IL-17 synergistically inhibit the apoptosis of virus-infected cells and the cytolytic function of CD8+ T lymphocytes, prolonging the survival of virus-infected cells. The inhibition of apoptosis leads to the persistent activation of NF-κB and TLRs, which continuously provides an environment of excessive cytokines and consequently promotes autoimmune responses. Persistent or repeated infections of other viruses such as COVID-19 may result in similar continuous TLR activation and cytokine production, leading to autoimmune diseases.
Topics: Mice; Animals; Theilovirus; Interleukin-6; Demyelinating Diseases; NF-kappa B; Virulence; COVID-19; Cytokines; Virus Replication
PubMed: 37153539
DOI: 10.3389/fimmu.2023.1167972 -
Neurobiology of Disease Jan 2023Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination...
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.
Topics: Animals; Mice; Brain; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Microbiota; Microglia; Multiple Sclerosis; Vagus Nerve
PubMed: 36493975
DOI: 10.1016/j.nbd.2022.105951 -
NeuroImage Nov 2018MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T and quantitative magnetization transfer measures...
MRI is a valuable tool to assess myelin during development and demyelinating disease processes. While multiexponential T and quantitative magnetization transfer measures correlate with myelin content, neither provides the total myelin volume fraction. In many cases correlative measures are adequate; but to assess microstructure of myelin, (e.g. calculate the g-ratio using MRI), an accurate measure of myelin volume fraction is imperative. Using a volumetric model of white matter, we relate MRI measures of myelin to absolute measures of myelin volume fraction and compare them to quantitative histology. We assess our approach in control mice along with two models of hypomyelination and one model of hypermyelination and find strong agreement between MRI and histology amongst models. This work investigates the sensitivities of MRI myelin measures to changes in axon geometry and displays promise for estimating g-ratio from MRI.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Magnetic Resonance Imaging; Mice; Mice, Knockout; Models, Theoretical; Myelin Sheath; Neuroimaging; Sensitivity and Specificity; White Matter
PubMed: 28025129
DOI: 10.1016/j.neuroimage.2016.12.067 -
Revue Neurologique Dec 2016Animal models are fundamental to advance knowledge of disease pathogenesis and to test/develop new therapeutic strategies. Most of the current knowledge about the... (Review)
Review
Animal models are fundamental to advance knowledge of disease pathogenesis and to test/develop new therapeutic strategies. Most of the current knowledge about the pathogenic mechanisms underpinning autoimmune demyelination processes implicating autoantigens has been obtained using the Experimental Autoimmune Neuritis (EAN) animal model. The most widely used EAN model is obtained by active immunization of Lewis rats using a peptide, P0 (180-199), issuing from the major peripheral nervous system myelin protein. But this model mimics only the classical monophasic acute form of demyelinating polyradiculoneuropathy, i.e. Guillain-Barré syndrome (GBS). We developed a new model by immunizing Lewis rats using the same immunodominant neuritogenic peptide P0 (180-199) but this time with its S-palmitoyl derivative, S-palm P0 (180-199). All of the animals immunized with the S-palm P0 (180-199) peptide developed a chronic relapsing-remitting form of the disease corresponding to the electrophysiological criteria of demyelination (slow sensory nerve conduction velocity, prolonged motor nerve latency, partial motor nerve conduction blocks) with axon degeneration. These findings were confirmed by immunohistopathology study and thus, appear to mimic human chronic inflammatory demyelinating polyradiculopathy (CIDP). This new model opens up new avenues of research for testing new anti-inflammatory and neuroprotective therapeutic strategies.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Immunohistochemistry; Motor Neurons; Neural Conduction; Neuritis, Autoimmune, Experimental; Palmitic Acid; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Rats; Rats, Inbred Lew
PubMed: 27838091
DOI: 10.1016/j.neurol.2016.05.006 -
Journal of the Neurological Sciences Oct 2017Tumefactive demyelinating lesions (TDLs) are large inflammatory lesions that can mimic tumors or other space-occupying lesions. Differential diagnosis and management of... (Review)
Review
BACKGROUND AND OBJECTIVE
Tumefactive demyelinating lesions (TDLs) are large inflammatory lesions that can mimic tumors or other space-occupying lesions. Differential diagnosis and management of these lesions remain challenging for neurologists. We aim to review the clinico-radiological features of patients with TDLs, as well as their management.
METHODS
We performed a retrospective review of cases of TDLs treated in our center from January 2010 to February 2017. We reviewed the literature.
RESULTS
Out of 711 patients, we found 15 with TDLs (12 women and 3 men), with a mean age of TDL onset of 36years. Out of the 15 patients, 9 had TDLs as a first demyelinating event and 44% (4/15) of these converted to MS by McDonald 2010 criteria in a mean time of 8months (SD 3.10). Clinical presentation was polysymptomatic and the most common radiological findings included solitary lesions (66.66%), located primarily in the frontal (40%) or parietal (33%) lobes, showing mostly an infiltrative morphological pattern (50%) and an open-ring enhancement (43%). Multiple Sclerosis was the most common diagnosis (67%, 10/15). Acute treatment included steroids, plasmapheresis, rituximab and cyclophosphamide.
CONCLUSIONS
Prevalence of tumefactive demyelination in MS was higher than expected in MS patients, according to literature. Time to conversion to MS was significantly shorter than other published series. Clinical presentation was polysymptomatic and the most common radiological findings were isolated frontal lesions with an open-ring enhancement.
Topics: Adult; Brain; Demyelinating Diseases; Diagnosis, Differential; Disease Management; Female; Humans; Male; Middle Aged; Neuroimaging; Retrospective Studies; Young Adult
PubMed: 28991707
DOI: 10.1016/j.jns.2017.08.005 -
Multiple Sclerosis and Related Disorders May 2024To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). (Meta-Analysis)
Meta-Analysis Comparative Study Review
Efficacy and comparison of corticosteroids only and corticosteroids with plasmapheresis or intravenous immunoglobulin for the treatment of optic neuritis in demyelinating disease: A systematic review and network meta-analysis.
PURPOSE
To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG).
DESIGN
After an episode of ON, although visual recovery is usually good, some patients may have significant visual sequelae. While the efficacy of first-line CTC is now indisputable, there is no consensus on the nature of second-line treatment. To date, no systematic review has compared the efficacy of treatment of ON with CTC alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). A meta-analysis is needed to compare the efficacy of PLP and IVIG in steroid-resistant ON.
METHODS
This systematic review included all studies comparing at least two of the three treatments for steroid-resistant ON (CTC alone, CTC+PLP, and CTC+IVIG). From all articles published on PubMed between January 2000 and June 2022, two independent ophthalmologists selected studies of interest using the PRISMA method. Methodology, patient characteristics, and outcomes were identified. A network metaanalysis was then performed to compare the efficacy of the three treatments.
RESULTS
Six comparative studies were included, representing 209 patients. The percentage of significant visual recovery after CTC alone, CTC+PLP, and CTC+IVIG in the acute treatment of steroid-resistant ON was 30 %, 45 %, and 77 %, respectively. Comparison of CTC+IVIG vs CTC alone, CTC+PLP vs CTC only, and CTC+PLP vs CTC+IVIG yielded odds ratios of 12.81, 2.47, and 0.19 respectively.
CONCLUSION
Treatment of steroid-resistant ON with CTC+PLP or CTC+IVIG is more effective than treatment with CTC alone. Although no study has directly compared the two treatments, IVIG may be more effective than PLP.
Topics: Optic Neuritis; Humans; Immunoglobulins, Intravenous; Adrenal Cortex Hormones; Plasmapheresis; Network Meta-Analysis; Combined Modality Therapy; Immunologic Factors; Demyelinating Diseases
PubMed: 38457882
DOI: 10.1016/j.msard.2024.105521 -
Multiple Sclerosis and Related Disorders Dec 2022Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs)...
BACKGROUND
Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs) following vaccination.
METHODS
We prospectively collected cases of new-onset CNS-IDDs with a temporal relationship between disease onset and COVID-19 vaccination and investigated their proportion among newly registered cases of CNS-IDD over the past year.
RESULTS
Among 117 cases, 10 (8.5%) had their first disease manifestation within one month following COVID-19 vaccination: 2 multiple sclerosis, 2 neuromyelitis optica spectrum disorder, 3 MOG antibody-associated disease, and 3 unclassified CNS-IDDs.
CONCLUSION
This observation suggests that COVID-19 vaccination may trigger the onset of various CNS-IDDs in susceptible individuals.
Topics: Humans; Autoantibodies; Central Nervous System; Central Nervous System Diseases; COVID-19; COVID-19 Vaccines; Demyelinating Autoimmune Diseases, CNS; Neuromyelitis Optica
PubMed: 36037757
DOI: 10.1016/j.msard.2022.104141