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Current Opinion in Pharmacology Jun 2022The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially... (Review)
Review
The key pathology of multiple sclerosis (MS) comprises demyelination, axonal damage, and neuronal loss, and when MS develops into the progressive phase it is essentially untreatable. Identifying new targets in both axons and oligodendrocyte progenitor cells (OPCs) and rejuvenating the aged OPCs holds promise for this unmet medical need. We summarize here the recent evidence showing that mitochondria in both axons and OPCs are impaired, and lipid metabolism of OPCs within demyelinated lesion and in the aged CNS is disturbed. Given that emerging evidence shows that rewiring cellular metabolism regulates stem cell aging, to protect axons from degeneration and promote differentiation of OPCs, we propose that restoring the impaired metabolism of both OPCs and axons in the aged CNS in a synergistic way could be a promising strategy to enhance remyelination in the aged CNS, leading to novel drug-based approaches to treat the progressive phase of MS.
Topics: Aged; Axons; Cell Differentiation; Demyelinating Diseases; Humans; Multiple Sclerosis; Oligodendrocyte Precursor Cells; Oligodendroglia; Stem Cells
PubMed: 35344763
DOI: 10.1016/j.coph.2022.102205 -
Revista de NeurologiaEpidemiological data indicate that environmental factors, possibly infections, are associated with the development of multiple sclerosis. Different viruses are known to... (Review)
Review
INTRODUCTION
Epidemiological data indicate that environmental factors, possibly infections, are associated with the development of multiple sclerosis. Different viruses are known to produce demyelination in natural and experimental animal infections. In humans some virus cause acute or chronic diseases that course with central nervous system demyelination. A series of virus have been claimed to be etiological agents of multiple sclerosis, although a causal role for any of them has so far been demonstrated.
METHOD
The mechanisms of viral demyelination are diverse,ranging from direct destruction of infected oligodendrocytes to triggering autoimmune responses without virus multiplication in target cells. The potential indirect mechanisms of viral demyelination and the heterogeneous histopathology shown in multiple sclerosis patients, suggesting an heterogeneus etiology, might explain why not a single virus has been as yet identified as the cause of this disease.
CONCLUSIONS
Viral infections that cause demyelination in animals and humans are briefly reviewed, focusing on the potential myelin destruction mechanisms and obstacles to the identifying viruses that might cause multiple sclerosis.
Topics: Animals; Demyelinating Diseases; Humans; Multiple Sclerosis; Virus Diseases
PubMed: 12436401
DOI: No ID Found -
Scientific Reports May 2023To describe the clinical spectrum and prognosis of atypical tumefactive demyelinating lesions (TDLs), which were confirmed by pathology. A total of 11 patients were...
To describe the clinical spectrum and prognosis of atypical tumefactive demyelinating lesions (TDLs), which were confirmed by pathology. A total of 11 patients were diagnosed with atypical TDLs confirmed by brain biopsy and surgery between January 2006 and December 2017. The clinical spectrum and prognosis in these patients were analyzed. The patients' ages ranged from 29 to 62 years, with a mean age of 48.9 years; 72.7% were males. The Expanded Disability Status Scale (EDSS) of the patients with first onset was 2.36. Most of the patients started with limb numbness and weakness (45.5%) or alalia (27.2%). The mean time from symptom onset to biopsy or surgery was 12.9 days (3-30 days). Most of the patients had solitary lesions (72.7%), supratentorial lesions (90.9%, particularly predominant in the frontal, temporal, and parietal lobes), moderate edema (63.6%), mild mass effect (54.5%), and patchy lesions (54.5%). Among them, three patients were positive for myelin basic protein (MBP) and one patient was positive for myelin oligodendrocyte glycoprotein (MOG). The patients were followed up for an average of 6.9 years (2-14 years), and recurrent TDLs were observed in 2 patients. Except for the 2 patients who relapsed, only 1 of the 9 patients died; the other 8 patients improved or maintained the status quo (the EDSS scores were lower or unchanged). The patients did not have any serious nervous system injury at onset, and the main presentation included extremity weakness, headache or dizziness, and alalia. The most common form was patchy on MRI enhancement. Cerebrospinal fluid and demyelination test can be an indicator of TDLs, and seizures may be a poor prognostic indicator. Most atypical TDLs have monophasic courses and good outcomes. The effect of neurosurgery alone was good in our group, and the effect of surgery on atypical TDLs can be further studied.
Topics: Male; Female; Humans; Demyelinating Diseases; Magnetic Resonance Imaging; Prognosis; Myelin-Oligodendrocyte Glycoprotein; Diagnosis, Differential
PubMed: 37179394
DOI: 10.1038/s41598-023-34420-4 -
Hearing Research Apr 2018Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor... (Comparative Study)
Comparative Study
Since cochlear implant function involves direct depolarization of spiral ganglion neurons (SGNs) by applied current, SGN physiological health must be an important factor in cochlear implant (CI) outcomes. This expected relationship has, however, been difficult to confirm in implant recipients. Suggestively, animal studies have demonstrated both acute and progressive SGN ultrastructural changes (notably axon demyelination), even in the absence of soma death, and corresponding altered physiology following sensorineural deafening. Whether such demyelination occurs in humans and how such changes might impact CI function remains unknown. To approach this problem, we incorporated SGN demyelination into a biophysical model of extracellular stimulation of SGN fibers. Our approach enabled exploration of the entire parameter space corresponding to simulated myelin diameter and extent of fiber affected. All simulated fibers were stimulated distally with anodic monophasic, cathodic monophasic, anode-phase-first (AF) biphasic, and cathode-phase-first (CF) biphasic pulses from an extracellular disc electrode and monitored for spikes centrally. Not surprisingly, axon sensitivity generally decreased with demyelination, resulting in elevated thresholds, however, this effect was strongly non-uniform. Fibers with severe demyelination affecting only the most peripheral nodes responded nearly identically to normally myelinated fibers. Additionally, partial demyelination (<50%) yielded only minimal increases in threshold even when the entire fiber was impacted. The temporal effects of demyelination were more unexpected. Both latency and jitter of responses demonstrated resilience to modest changes but exhibited strongly non-monotonic and stimulus-dependent relationships to more profound demyelination. Normal, and modestly demyelinated fibers, were more sensitive to cathodic than anodic monophasic pulses and to CF than AF biphasic pulses, however, when demyelination was more severe these relative sensitivities were reversed. Comparison of threshold crossing between nodal segments demonstrated stimulus-dependent shifts in action potential initiation with different fiber demyelination states. For some demyelination scenarios, both phases of biphasic pulses could initiate action potentials at threshold resulting in bimodal latency and initiation site distributions and dramatically increased jitter. In summary, simulated demyelination leads to complex changes in fiber sensitivity and spike timing, mediated by alterations in action potential initiation site and slowed action potential conduction due to non-uniformities in the electrical properties of axons. Such demyelination-induced changes, if present in implantees, would have profound implications for the detection of fine temporal cues but not disrupt cues on the time scale of speech envelopes. These simulation results highlight the importance of exploring the SGN ultrastructural changes caused by a given etiology of hearing loss to more accurately predict cochlear implantation outcomes.
Topics: Auditory Pathways; Axons; Computer Simulation; Demyelinating Diseases; Electric Stimulation; Evoked Potentials, Auditory; Humans; Models, Neurological; Myelin Sheath; Reaction Time; Spiral Ganglion; Time Factors
PubMed: 29496363
DOI: 10.1016/j.heares.2018.01.014 -
Journal of Neurovirology Apr 2002Most murine hepatitis virus (MHV) strains, as their name suggests, infect the liver. However, several murine strains are tropic for the central nervous system (CNS) and... (Review)
Review
Most murine hepatitis virus (MHV) strains, as their name suggests, infect the liver. However, several murine strains are tropic for the central nervous system (CNS) and cause encephalitis with subsequent CNS demyelination. The CNS demyelination shares pathological similarities with human CNS demyelinating diseases such as multiple sclerosis (MS). These viruses are, therefore, used to study the role of the immune system in viral clearance from the CNS, in CNS demyelination, and in remyelination. Nevertheless, it is still unclear exactly how MHV induces demyelination and to what extent the immune system plays a role in this pathology. Here we review this field in the context of the immune response to MHV in the liver and the CNS focusing on studies that have been published in the past 5 years.
Topics: Animals; Coronavirus Infections; Demyelinating Diseases; Disease Models, Animal; Mice; Murine hepatitis virus
PubMed: 11935460
DOI: 10.1080/13550280290049534 -
The Malaysian Journal of Pathology Aug 2020Multiple sclerosis (MS) has variable clinical presentations, prognoses, pathogeneses, and pathological patterns. We conducted a pathological review of acute...
INTRODUCTION
Multiple sclerosis (MS) has variable clinical presentations, prognoses, pathogeneses, and pathological patterns. We conducted a pathological review of acute MS-associated lesions that focused on the degree of axonal injury, myelin loss, and glial reaction to determine whether the observed demyelination was of the primary or secondary type.
MATERIALS AND METHODS
After searching the records for a 15-year period at the London Health Sciences Centre Pathology Department, we identified 8 cases of surgical acute lesion biopsies in which clinical MS diagnoses were made before or after the biopsy.
RESULTS
The white matter pathologies in these cases could be sorted into 3 morphological patterns. The first pattern, which represents typical demyelinated plaques, was observed in 4 cases and was characterised by nearly complete demyelination accompanied by variable degrees of axon preservation and axonal swelling. The second pattern was observed in 3 cases and was characterised by demyelinating lesions containing variable numbers of myelinated axons mixed with a few demyelinated axons and variable numbers of axonal swellings. The myelinated axons ranged from scattered fibres to bands of variable thickness, and the demyelination was a mixture of primary and secondary demyelination. The third pattern was observed in 1 case and was characterised by well-demarcated areas of reduced myelin staining and numerous apoptotic nuclei. Axonal staining revealed many fragmented axons with reduced myelin staining but no definitely demyelinated axons.
CONCLUSIONS
This report shows that the predominant pathology underlying acute MS-related lesions is not limited to demyelination but can include axonal degeneration alone or in combination with primary demyelination which reflect different pathogenesis for these acute lesions.
Topics: Adult; Axons; Biopsy; Brain; Demyelinating Diseases; Female; Humans; Male; Middle Aged; Multiple Sclerosis; Retrospective Studies; White Matter
PubMed: 32860370
DOI: No ID Found -
Advances in Virus Research 1993Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) and progressive multifocal... (Review)
Review
Demyelination is a component of several viral diseases of humans. The best known of these are subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML). There are a number of naturally occurring virus infections of animals that involve demyelination and many of these serve as instructive models for human demyelinating diseases. In addition to the naturally occurring diseases, many viruses have been shown to be capable of producing demyelination in experimental situations. In discussing virus-associated demyelinating disease, the chapter reviews the architecture and functional organization of the CNS and considers what is known of the interaction of viruses with CNS cells. It also discusses the immunology of the CNS that differs in several important aspects from that of the rest of the body. Experimental models of viral-induced demyelination have also been considered. Viruses capable of producing demyelinating disease have no common taxonomic features; they include both DNA and RNA viruses, enveloped and nonenveloped viruses. The chapter attempts to summarize the important factors influencing viral demyelination, their common features, and possible mechanisms.
Topics: Animals; Central Nervous System; Demyelinating Diseases; Disease Models, Animal; Humans; Virus Diseases
PubMed: 8430521
DOI: 10.1016/s0065-3527(08)60087-1 -
Brain : a Journal of Neurology Oct 2000In this review we summarize the essential findings about the function of tumour necrosis factor (TNF) and its cognate receptors TNFR1 and TNFR2, and lymphotoxin alpha... (Review)
Review
In this review we summarize the essential findings about the function of tumour necrosis factor (TNF) and its cognate receptors TNFR1 and TNFR2, and lymphotoxin alpha (LT-alpha) ligands in immune-mediated CNS inflammation and demyelination. The advent of homologous recombination technology in rodents provides a new method which has been used during the last 5 years and has led to insights into the pathophysiology of experimental autoimmune encephalomyelitis (EAE) in an unprecedented way. Studies with knockout mice in which genes of the TNF ligand/receptor superfamily are not expressed and studies with transgenic mice overexpressing TNF and TNFR reveal the critical role of the TNFR1 signalling pathway in the control of CNS demyelination and inflammation. These studies provide novel findings and at the same time shed light on the complex pathophysiology of EAE. Together, these findings may contribute to better understanding of EAE and open new avenues in experimental therapies for multiple sclerosis.
Topics: Animals; Antigens, CD; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Signal Transduction; T-Lymphocytes
PubMed: 11004118
DOI: 10.1093/brain/123.10.2005 -
Cells Oct 2019Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal...
Inflammatory demyelination, which is a characteristic of multiple sclerosis lesions, leads to acute functional deficits and, in the long term, to progressive axonal degeneration. While remyelination is believed to protect axons, the endogenous-regenerative processes are often incomplete or even completely fail in many multiple sclerosis patients. Although it is currently unknown why remyelination fails, recurrent demyelination of previously demyelinated white matter areas is one contributing factor. In this study, we investigated whether laquinimod, which has demonstrated protective effects in active multiple sclerosis patients, protects against recurrent demyelination. To address this, male mice were intoxicated with cuprizone for up to eight weeks and treated with either a vehicle solution or laquinimod at the beginning of week 5, where remyelination was ongoing. The brains were harvested and analyzed by immunohistochemistry. At the time-point of laquinimod treatment initiation, oligodendrocyte progenitor cells proliferated and maturated despite ongoing demyelination activity. In the following weeks, myelination recovered in the laquinimod- but not vehicle-treated mice, despite continued cuprizone intoxication. Myelin recovery was paralleled by less severe microgliosis and acute axonal injury. In this study, we were able to demonstrate that laquinimod, which has previously been shown to protect against cuprizone-induced oligodendrocyte degeneration, exerts protective effects during oligodendrocyte progenitor differentiation as well. By this mechanism, laquinimod allows remyelination in non-supportive environments. These results should encourage further clinical studies in progressive multiple sclerosis patients.
Topics: Animals; Brain; Cell Differentiation; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Sheath; Oligodendrocyte Transcription Factor 2; Oligodendroglia; Quinolones; Remyelination
PubMed: 31683658
DOI: 10.3390/cells8111363 -
AJNR. American Journal of Neuroradiology Dec 2013The complex interplay between hypernatremic osmotic disturbances and cerebral lesions is yet to be clarified. In this review, we discuss, on the basis of the reported... (Comparative Study)
Comparative Study Review
The complex interplay between hypernatremic osmotic disturbances and cerebral lesions is yet to be clarified. In this review, we discuss, on the basis of the reported data of hypernatremic CNS challenge in the adult population, the clinical and radiologic features of the condition. Our search captured 20 case studies and 1 case series with 30 patients in total who acquired acute hypernatremia due to different etiologies and developed CNS lesions. We explored the associations between premorbid conditions, clinical presentation, hypernatremic state, correction rate, and radiologic appearance, including the localization of brain lesions and the outcomes. The results revealed that altered mental status was the most commonly reported symptom and osmotic demyelination syndrome in the form of extrapontine myelinolysis was the prevailing radiologic pattern. Finally, we contrasted, when appropriate, clinical and experimental data related to hypernatremic and hyponatremic osmotic insults to aid the understanding of the pathophysiology of CNS osmotic brain injury.
Topics: Adult; Brain Diseases; Demyelinating Diseases; Female; Humans; Hypernatremia; Male; Neuroradiography; Statistics as Topic; Symptom Assessment; Syndrome; Young Adult
PubMed: 23413245
DOI: 10.3174/ajnr.A3392