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Continuum (Minneapolis, Minn.) Aug 2013This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have... (Review)
Review
PURPOSE OF REVIEW
This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have yielded novel insights into potential mechanisms of demyelination.
RECENT FINDINGS
The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration. Active MS lesions show a profound pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups. Recent pathologic studies have suggested that the subarachnoid space and cortex may be initial sites and targets of the MS disease process, that inflammatory cortical demyelination is present early in MS, and that meningeal inflammation may drive cortical and white matter injury in some MS patients.
SUMMARY
MS is heterogeneous with respect to clinical, genetic, radiographic, and pathologic features; surrogate MRI, clinical, genetic, serologic, and/or CSF markers for each of the four immunopatterns need to be developed in order to recognize them in the general nonbiopsied MS population. Inflammatory cortical demyelination is an important early event in the pathogenesis of MS and may be driven by meningeal inflammation. These observations stress the importance of developing imaging techniques able to capture early inflammatory cortical demyelination in order to better understand the disease pathogenesis and to determine the impact of potential disease-modifying therapies on the cortex.
Topics: Adult; Cerebral Cortex; Chronic Disease; Demyelinating Diseases; Encephalomyelitis, Acute Disseminated; Fatal Outcome; Female; Humans; Leukoencephalitis, Acute Hemorrhagic; Leukoencephalopathies; Meningitis; Multiple Sclerosis; Neuromyelitis Optica; Young Adult
PubMed: 23917093
DOI: 10.1212/01.CON.0000433291.23091.65 -
Neurologic Clinics May 2013Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients... (Review)
Review
Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Symptoms usually include numbness, tingling, pain, and weakness. Dizziness with postural changes can be seen with autonomic neuropathy. Metabolic, vascular, and immune theories have been proposed for the pathogenesis of diabetic neuropathy. Axonal damage and segmental demyelination can be seen with diabetic neuropathies. Management of diabetic neuropathy should begin at the initial diagnosis of diabetes and mainly requires tight and stable glycemic control.
Topics: Demyelinating Diseases; Diabetic Neuropathies; Humans; Metabolic Diseases; Neuritis; Pain Management; Phenotype
PubMed: 23642717
DOI: 10.1016/j.ncl.2013.02.004 -
International Journal of Molecular... Nov 2022Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming...
Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.
Topics: Mice; Animals; Humans; Oligodendrocyte Precursor Cells; Demyelinating Diseases; Mice, Inbred C57BL; Remyelination; Cuprizone; Oligodendroglia; Myelin Sheath; Cell Differentiation; Microglia; Multiple Sclerosis; Disease Models, Animal
PubMed: 36499195
DOI: 10.3390/ijms232314868 -
NMR in Biomedicine Apr 2015Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS),... (Comparative Study)
Comparative Study
Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H-MRS metabolite spectra are different when comparing cuprizone-treated CX3 CR1(-/-) mice showing mild demyelination with cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions.
Topics: Animals; Aspartic Acid; Brain Chemistry; Choline; Creatine; Cuprizone; Demyelinating Diseases; Dipeptides; Disease Models, Animal; Female; Gliosis; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Neuroimaging; Oligodendroglia; Phosphocreatine; Proton Magnetic Resonance Spectroscopy
PubMed: 25802215
DOI: 10.1002/nbm.3277 -
Neuropharmacology Nov 2016Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged... (Review)
Review
Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
Topics: Animals; Biotin; Demyelinating Diseases; Disease Progression; Dose-Response Relationship, Drug; Humans; Hypoxia; Multiple Sclerosis; Vitamin B Complex
PubMed: 26327679
DOI: 10.1016/j.neuropharm.2015.08.028 -
Physiological Research 2011Over a century ago, hyperplasia and hypertrophy of astrocytes was noted as a histopathological hallmark of multiple sclerosis and was hypothesized to play an important... (Review)
Review
Over a century ago, hyperplasia and hypertrophy of astrocytes was noted as a histopathological hallmark of multiple sclerosis and was hypothesized to play an important role in the development and course of this disease. However until today, the factual contribution of astrocytes to multiple sclerosis is elusive. Astrocytes may play an active role during degeneration and demyelination by controlling local inflammation in the CNS, provoking damage of oligodendrocytes and axons, and glial scarring but might also be beneficial by creating a permissive environment for remyelination and oligodendrocyte precursor migration, proliferation, and differentiation. Recent findings from our lab suggest that brain lipid binding protein (FABP7) is implicated in the course of multiple sclerosis and the regulation of astrocyte function. The relevance of our findings and data from other groups are highlighted and discussed in this paper in the context of myelin repair.
Topics: Animals; Astrocytes; Carrier Proteins; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Humans; Multiple Sclerosis; Myelin Sheath; Nerve Tissue Proteins; Signal Transduction; Tumor Suppressor Proteins
PubMed: 21777034
DOI: 10.33549/physiolres.932168 -
NeuroImage. Clinical 2015Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures... (Review)
Review
Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis.
Topics: Child; Child, Preschool; Demyelinating Diseases; Humans; Neuroimaging; Pain; Spinal Cord
PubMed: 26509120
DOI: 10.1016/j.nicl.2015.08.019 -
Journal of Neurology, Neurosurgery, and... Dec 2014Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are... (Review)
Review
Trials of potential neuroreparative agents are becoming more important in the spectrum of multiple sclerosis research. Appropriate imaging outcomes are required that are feasible from a time and practicality point of view, as well as being sensitive and specific to myelin, while also being reproducible and clinically meaningful. Conventional MRI sequences have limited specificity for myelination. We evaluate the imaging modalities which are potentially more specific to myelin content in vivo, such as magnetisation transfer ratio (MTR), restricted proton fraction f (from quantitative magnetisation transfer measurements), myelin water fraction and diffusion tensor imaging (DTI) metrics, in addition to positron emission tomography (PET) imaging. Although most imaging applications to date have focused on the brain, we also consider measures with the potential to detect remyelination in the spinal cord and in the optic nerve. At present, MTR and DTI measures probably offer the most realistic and feasible outcome measures for such trials, especially in the brain. However, no one measure currently demonstrates sufficiently high sensitivity or specificity to myelin, or correlation with clinical features, and it should be useful to employ more than one outcome to maximise understanding and interpretation of findings with these sequences. PET may be less feasible for current and near-future trials, but is a promising technique because of its specificity. In the optic nerve, visual evoked potentials can indicate demyelination and should be correlated with an imaging outcome (such as optic nerve MTR), as well as clinical measures.
Topics: Clinical Trials as Topic; Demyelinating Diseases; Diffusion Tensor Imaging; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Neuroimaging; Positron-Emission Tomography; Treatment Outcome
PubMed: 24769473
DOI: 10.1136/jnnp-2014-307650 -
Journal of Neurochemistry Sep 2022Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human...
Microglia have been implicated in multiple sclerosis (MS) pathogenesis. The fractalkine receptor CX3CR1 limits the activation of pathogenic microglia and the human polymorphic CX3CR1 (hCX3CR1 ) variant increases disease progression in models of MS. However, the role of hCX3CR1 variant on microglial activation and central nervous system repair mechanisms remains unknown. Therefore, using transgenic mice expressing the hCX3CR1 variant, we aimed to determine the contribution of defective CX3CR1 signaling to neuroinflammation and remyelination in the cuprizone model of focal demyelination. Here, we report that mice expressing hCX3CR1 exhibit marked demyelination and microgliosis following acute cuprizone treatment. Nanostring gene expression analysis in demyelinated lesions showed that hCX3CR1 but not CX3CR1-deficient mice up-regulated the cuprizone-induced gene profile linked to inflammatory, oxidative stress, and phagocytic pathways. Although CX3CR1-deficient (CX3CR1-KO) and fractalkine-deficient (FKN-KO) mice displayed a comparable demyelination and microglial activation phenotype to hCX3CR1 mice, only CX3CR1-deficient and CX3CR1-WT mice showed significant myelin recovery 1 week from cuprizone withdrawal. Confocal microscopy showed that hCX3CR1 variant inhibits the generation of cells involved in myelin repair. Our results show that defective fractalkine signaling contributes to regional differences in demyelination, and suggest that the CX3CR1 pathway activity may be a key mechanism for limiting toxic gene responses in neuroinflammation. Cover Image for this issue: https://doi.org/10.1111/jnc.15416.
Topics: Animals; CX3C Chemokine Receptor 1; Chemokine CX3CL1; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Microglia; Myelin Sheath; Neuroinflammatory Diseases; Remyelination
PubMed: 35560167
DOI: 10.1111/jnc.15616 -
Journal of Neuroscience Research Dec 2018Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D... (Review)
Review
Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of unknown etiology. Both genetic-susceptibility and environment exposures, including vitamin D deficiency, Epstein-Barr viral and Herpesvirus (HHV-6) infections are strongly implicated in the activation of T cells and MS-pathogenesis. Despite precise knowledge of how these factors could be operating alone or in combination to facilitate and aggravate the disease progression, it is clear that prolonged induction of inflammatory molecules and recruitment of other immune cells by the activated T cells results in demyelination and axonal damage. It is imperative to understand the risk factors associated with MS progression and how these factors contribute to disease pathology. Understanding of the underlying mechanisms of what factors triggers activation of T cells to attack myelin antigen are important to strategize therapeutics and therapies against MS. Current review provides a detailed literature to understand the role of both pathogenic and non-pathogenic factors on the impact of MS.
Topics: Animals; Demyelinating Diseases; Genetic Predisposition to Disease; Models, Animal; Multiple Sclerosis; Signal Transduction
PubMed: 30204260
DOI: 10.1002/jnr.24322