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Experimental Neurology Sep 2016There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic... (Review)
Review
There is an increasing number of neurologic disorders found to be associated with loss and/or dysfunction of the CNS myelin sheath, ranging from the classic demyelinating disease, multiple sclerosis, through CNS injury, to neuropsychiatric diseases. The disabling burden of these diseases has sparked a growing interest in gaining a better understanding of the molecular mechanisms regulating the differentiation of the myelinating cells of the CNS, oligodendrocytes (OLGs), and the process of (re)myelination. In this context, the importance of the extracellular milieu is becoming increasingly recognized. Under pathological conditions, changes in inhibitory as well as permissive/promotional cues are thought to lead to an overall extracellular environment that is obstructive for the regeneration of the myelin sheath. Given the general view that remyelination is, even though limited in human, a natural response to demyelination, targeting pathologically 'dysregulated' extracellular cues and their downstream pathways is regarded as a promising approach toward the enhancement of remyelination by endogenous (or if necessary transplanted) OLG progenitor cells. In this review, we will introduce the extracellular cues that have been implicated in the modulation of (re)myelination. These cues can be soluble, part of the extracellular matrix (ECM) or mediators of cell-cell interactions. Their inhibitory and permissive/promotional roles with regard to remyelination as well as their potential for therapeutic intervention will be discussed.
Topics: Animals; Cell Differentiation; Demyelinating Diseases; Extracellular Matrix; Humans; Nerve Regeneration; Oligodendroglia; Stem Cells
PubMed: 27016069
DOI: 10.1016/j.expneurol.2016.03.019 -
Genes Jun 2023Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous... (Review)
Review
Demyelinating diseases alter myelin or the coating surrounding most nerve fibers in the central and peripheral nervous systems. The grouping of human central nervous system demyelinating disorders today includes multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) as distinct disease categories. Each disease is caused by a complex combination of genetic and environmental variables, many involving an autoimmune response. Even though these conditions are fundamentally similar, research into genetic factors, their unique clinical manifestations, and lesion pathology has helped with differential diagnosis and disease pathogenesis knowledge. This review aims to synthesize the genetic approaches that explain the differential susceptibility between these diseases, explore the overlapping clinical features, and pathological findings, discuss existing and emerging hypotheses on the etiology of demyelination, and assess recent pathogenicity studies and their implications for human demyelination. This review presents critical information from previous studies on the disease, which asks several questions to understand the gaps in research in this field.
Topics: Humans; Multiple Sclerosis; Neuromyelitis Optica; Central Nervous System; Myelin Sheath; Diagnosis, Differential
PubMed: 37510224
DOI: 10.3390/genes14071319 -
Acta Neuropathologica Communications Nov 2018Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. Active... (Review)
Review
Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. Active MS lesions mainly consist of macrophages and microglia containing abundant intracellular myelin remnants. Initial studies showed that these foamy phagocytes primarily promote MS disease progression by internalizing myelin debris, presenting brain-derived autoantigens, and adopting an inflammatory phenotype. However, more recent studies indicate that phagocytes can also adopt a beneficial phenotype upon myelin internalization. In this review, we summarize and discuss the current knowledge on the spatiotemporal physiology of foamy phagocytes in MS lesions, and elaborate on extrinsic and intrinsic factors regulating their behavior. In addition, we discuss and link the physiology of myelin-containing phagocytes to that of foamy macrophages in other disorders such atherosclerosis.
Topics: Animals; Demyelinating Diseases; Humans; Macrophages; Microglia; Multiple Sclerosis; Myelin Sheath; Phagocytes
PubMed: 30454040
DOI: 10.1186/s40478-018-0628-8 -
Neurotherapeutics : the Journal of the... Jan 2016Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute... (Review)
Review
Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination.
Topics: Child; Encephalomyelitis, Acute Disseminated; Humans; Immunologic Factors; Immunotherapy; Multiple Sclerosis
PubMed: 26496907
DOI: 10.1007/s13311-015-0396-0 -
Molecular Genetics and Metabolism Apr 2015Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have...
Leukodystrophies are a heterogeneous, often progressive group of disorders manifesting a wide range of symptoms and complications. Most of these disorders have historically had no etiologic or disease specific therapeutic approaches. Recently, a greater understanding of the pathologic mechanisms associated with leukodystrophies has allowed clinicians and researchers to prioritize treatment strategies and advance research in therapies for specific disorders, some of which are on the verge of pilot or Phase I/II clinical trials. This shifts the care of leukodystrophy patients from the management of the complex array of symptoms and sequelae alone to targeted therapeutics. The unmet needs of leukodystrophy patients still remain an overwhelming burden. While the overwhelming consensus is that these disorders collectively are symptomatically treatable, leukodystrophy patients are in need of advanced therapies and if possible, a cure.
Topics: Brain Diseases; Demyelinating Diseases; Hereditary Central Nervous System Demyelinating Diseases; Humans; Leukodystrophy, Metachromatic; Leukoencephalopathies
PubMed: 25684057
DOI: 10.1016/j.ymgme.2015.01.014 -
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 -
Journal of Interferon & Cytokine... Aug 2014There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to... (Review)
Review
There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination.
Topics: Animals; B-Lymphocytes; Central Nervous System; Cytokines; Demyelinating Diseases; Humans; Immune Tolerance; Immunity, Mucosal; Intestines; Lymphocyte Activation; Microbiota; Symbiosis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory
PubMed: 25084177
DOI: 10.1089/jir.2013.0134 -
Immunological Reviews Jul 2012Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive... (Review)
Review
Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases.
Topics: Adaptive Immunity; Animals; Astrocytes; B-Lymphocytes; Blood-Brain Barrier; Demyelinating Diseases; Humans; Immunity, Innate; Killer Cells, Natural; Mast Cells; Mononuclear Phagocyte System; T-Lymphocyte Subsets
PubMed: 22725961
DOI: 10.1111/j.1600-065X.2012.01135.x -
Brain Pathology (Zurich, Switzerland) Jul 1996Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub-acute... (Review)
Review
Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy and Pelizaeus-Merzbacher disease. While demyelination is a pathological end-point that is common to all of these diseases, the cellular and molecular mechanisms responsible for this pathology are very different . These range from genetic defects that affect lipid metabolism in the leukodystrophies, cytopathic effects of viral infection in SSPE to the action of immunological effector mechanisms in MS and the viral encephalopathies. Irrespective of the initial cause of myelin degradation, many of these disorders are associated with some degree of CNS inflammation, as indicated by the local activation of microglia, recruitment of macrophages or the intrathecal synthesis of immunoglobulin. Many of these phenomena are now being duplicated in animal models, providing not only new insights into the pathogenesis of human demyelinating diseases , but also unexpected interrelationships between the immune response in the CNS and the pathogenesis of diseases such as Alzheimers disease and HIV encephalopathy. Autoimmune mediated models of inflammatory demyelinating CNS disease have proved particularly valuable in this respect as they allow the effects of defined immune effector mechanisms to be studied in the absence of CNS infection.
Topics: Animals; Demyelinating Diseases; Disease Models, Animal; Humans
PubMed: 8864286
DOI: 10.1111/j.1750-3639.1996.tb00857.x -
Tidsskrift For Den Norske Laegeforening... May 2013Evoked potentials are used to detect conduction disturbances in the central nervous system. This paper provides an overview of the areas in which evoked potentials are... (Review)
Review
BACKGROUND
Evoked potentials are used to detect conduction disturbances in the central nervous system. This paper provides an overview of the areas in which evoked potentials are used in clinical neurophysiological diagnostics, with the emphasis on coma and demyelinating disease.
METHOD
The article is based on a literature search in PubMed and the authors' long experience of neurological and neurophysiological diagnostics.
RESULTS
Somatosensory evoked potential (SEP) can be a reliable predictor of failure to regain consciousness as early as 24 hours after anoxic coma has occurred. If coma is caused by a brain trauma, cerebrovascular episode or other neurological disease, information about which sensory brainstem pathways are damaged can be obtained from somatosensory evoked potentials and brainstem auditory evoked potentials (BAEP), which can also be useful for planning rehabilitation. Normal SEP and BAEP findings in cases of coma caused by trauma are associated with a favourable prognosis. Visually evoked potential (VEP) can often reveal signs of a history of optic neuritis. SEP and BAEP can also reveal subclinical lesions in the central nervous system and be a supplementary diagnostic test for multiple sclerosis.
INTERPRETATION
The clinical value of SEP and BAEP is high in coma cases. Evoked potentials are also important in intraoperative monitoring. The clinical value of VEP is high when a history of optic neuritis is a deciding factor for a multiple sclerosis diagnosis. Some selected patients who are being assessed for demyelinating disease will benefit from a full EP study.
Topics: Coma; Demyelinating Diseases; Evoked Potentials; Humans; Monitoring, Intraoperative; Optic Neuritis
PubMed: 23652144
DOI: 10.4045/tidsskr.12.1176