Focal Areas Of Demyelination Research Articles

Brain macrophages acquire distinct transcriptomes in multiple sclerosis lesions and normal appearing white matter

Multiple sclerosis (MS) is a disease of the central nervous system that is characterized by inflammation and focal areas of demyelination, ultimately resulting in axonal degradation and neuronal loss. Several lines of evidence point towards a role for microglia and other brain macrophages in disease initiation and progression, but exactly how lesion formation is triggered is currently unknown. Here, we characterized early changes in MS brain tissue through transcriptomic analysis of normal appearing white matter (NAWM). We found that NAWM was characterized by enriched expression of genes associated with inflammation and cellular stress derived from brain macrophages. Single cell RNA sequencing confirmed a stress response in brain macrophages in NAWM and identified specific microglia and macrophage subsets at different stages of demyelinating lesions. We identified both phagocytic/activated microglia and CAM clusters that were associated with various MS lesion types. These overall changes in microglia and macrophages associated with lesion development in MS brain tissue may provide therapeutic targets to limit lesion progression and demyelination.

The Effectiveness of MRI Techniques in Evaluating Multiple Sclerosis Patients

Background and objective: Multiple sclerosis (MS) is the most common neurodegenerative disease characterized by multiple focal areas of demyelination called plaques or lesions. The main aim of the study is to evaluate patients with multiple sclerosis disease using MRI technology and to emphasis the effectiveness of this technology in diagnosis of the disease. Methods: This study was conducted in order to better recognition and understanding of MS disorder using radiologic MRI techniques and the main problem is the increase prevalence among public population . The database registry was limited to hospitalized patients whom diagnosed with multiple sclerosis using MRI techniques and the population of the study was 80 participants their age elder than 16 years old in period from April to November 2020 .Normal condition or other neurological disorders were excluded. Results: The most important results obtained in this study is that it is possible to diagnose Multiple sclerosis patients in an accurate manner using magnetic resonance imaging technology. The outcome of variable detected prevalence of 80 samples 52.5% of them were male, and 47.5% were female and the big distribution group was 53% aged between 30-39 years. The obtained data also showed that the most affected brain region was periventricular matter with 30%, followed by the frontal lobe with 27.5%. clinical etiology big distribution data were achieved for vision Problems with percentage of 22.5 % followed by Dizziness & vertigo sensation with percentage of 18.7% The MRI techniques showed two appearance of MS lesions and plaques, the most distribution achieved for foci appearance with percentage of 75% and patchy appearance with 25% present. Conclusion: Although for many years there was awareness of the morbidity and mortality associated with Multiple sclerosis however real progress only comes with the ability to early diagnosis using MRI technology.

Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis.

The central nervous system (CNS) is vulnerable to several viral infections including herpes viruses, arboviruses and HIV to name a few. While a rapid and effective immune response is essential to limit viral spread and mortality, this anti-viral response needs to be tightly regulated in order to limit immune mediated tissue damage. This balance between effective virus control with limited pathology is especially important due to the highly specialized functions and limited regenerative capacity of neurons, which can be targets of direct virus cytolysis or bystander damage. CNS infection with the neurotropic strain of mouse hepatitis virus (MHV) induces an acute encephalomyelitis associated with focal areas of demyelination, which is sustained during viral persistence. Both innate and adaptive immune cells work in coordination to control virus replication. While type I interferons are essential to limit virus spread associated with early mortality, perforin, and interferon-γ promote further virus clearance in astrocytes/microglia and oligodendrocytes, respectively. Effective control of virus replication is nonetheless associated with tissue damage, characterized by demyelinating lesions. Interestingly, the anti-inflammatory cytokine IL-10 limits expansion of tissue lesions during chronic infection without affecting viral persistence. Thus, effective coordination of pro- and anti-inflammatory cytokines is essential during MHV induced encephalomyelitis in order to protect the host against viral infection at a limited cost.

6. Trigeminal neuralgia typical and atypical. A disease or two?

Trigeminal Neuralgia (TN) is a clinical condition characterized by a sudden, usually unilateral, brief, stabbing, recurrent pain with a distribution consistent with one or more divisions of the fifth cranial nerve. In the classical form, the genesis of paroxysmal pain has been attributed to areas of focal demyelination due to vascular compression on the nerve. The 20–50% of patients with TN have an atypical form characterized by the presence of constant pain, often described as burning continuous or sub-continuous, as well as paroxysmal pain. We hypothesize an axonal damage underlying the constant pain component. We enrolled 55 patients with typical (n = 36) and atypical (n = 19) TN according to the criteria of the 3rd edition of the International Classification of Headache Disorders (ICHD-3). Each patient underwent magnetic resonance imaging (MRI), laser evoked potentials (LEPs) and trigeminal reflexes. The comparison between the duration of disease between the two groups showed no significant differences. We found a greater asymmetry of amplitude (healthy side vs affected side) of N2-P2 component from thermal stimulation in the group with atypical TN (p The atypical form has an axonal damage and is not a time-bound phenomenon. The involvement of C-fibers could be the mechanism behind continuous pain.

Diminished Myelin-Specific T Cell Activation Associated with Increase in CTLA4 and Fas Molecules in Multiple Sclerosis Patients Treated with IFN-β

Multiple sclerosis (MS) is a chronic inflammatory disease of the white matter of the central nervous system (CNS) characterized by focal areas of demyelination. Interferon-beta (IFN-beta) provides an effective treatment that lessens the frequency and severity of exacerbations in relapsing-remitting multiple sclerosis (RRMS), but the mechanisms by which IFN-beta is efficient remain uncertain. The data presented here demonstrate that IFN-beta impairs the proliferative response to myelin basic protein (MBP) and myelin, as well as increasing the expression of the CTLA4 intracellular molecule. Moreover, this treatment increases the expression of surface Fas molecules and of the soluble form of these molecules. Our hypothesis is that the increase in Fas and CTLA4 molecules in MS patients may lead to lymphocyte apoptosis, which suggests possible mechanisms underlying the therapeutic response to IFN-beta.

Superparamagnetic Iron Oxide-Labeled Schwann Cells and Olfactory Ensheathing Cells Can Be TracedIn Vivoby Magnetic Resonance Imaging and Retain Functional Properties after Transplantation into the CNS

Schwann cell (SC) and olfactory ensheathing cell (OEC) transplantation has been shown experimentally to promote CNS axonal regeneration and remyelination. To advance this technique into a clinical setting it is important to be able to follow the fates of transplanted cells by noninvasive imaging. Previous studies, using complex modification processes to enable uptake of contrast agents, have shown that cells labeled in vitro with paramagnetic contrast agents transplanted into rodent CNS can be visualized using magnetic resonance imaging (MRI). Here we show that SCs and OECs efficiently internalize dextran-coated superparamagnetic iron oxide (SPIO) from the culture medium by fluid phase pinocytosis. After transplantation into focal areas of demyelination in adult rat spinal cord both transplanted SPIO-labeled SCs and OECs produce a signal reduction using T(2)-weighted MRI in anesthetized rats that persists for up to 4 weeks. Although signal reduction was discernable after transplantation of unlabelled cells, this is nevertheless distinguishable from that produced by transplanted labeled cells. The region of signal reduction in SPIO-labeled cell recipients correlates closely with areas of remyelination. Because the retention of functional integrity by labeled cells is paramount, we also show that SPIO-labeled SCs and OECs are able to myelinate normally after transplantation into focal areas of demyelination. These studies demonstrate the feasibility of noninvasive imaging of transplanted SCs and OECs and represent a significant step toward the clinical application of promising experimental approaches.

Functional analysis of the CC chemokine receptor 5 (CCR5) on virus-specific CD8 + T cells following coronavirus infection of the central nervous system

Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). T cells participate in both defense and disease progression following MHV infection. Expression of chemokine receptors on activated T cells is important in allowing these cells to traffic into and accumulate within the central nervous system (CNS) of MHV-infected mice. The present study evaluated the contributions of CCR5 to the activation and trafficking of virus-specific CD8 + T cells into the MHV-infected CNS mice. Comparable numbers of virus-specific CD8 + T cells derived from immunized CCR5 +/+ or CCR5 −/− mice were present within the CNS of MHV-infected RAG1 −/− mice following adoptive transfer, indicating that CCR5 is not required for trafficking of these cells into the CNS. RAG1 −/− recipients of CCR5 −/−-derived CD8 + T cells exhibited a modest, yet significant ( P ≤ 0.05), reduction in viral burden within the brain which correlated with increased CTL activity and IFN-γ expression. Histological analysis of RAG1 −/− recipients of either CCR5 +/+or CCR5 −/−-derived CD8 + T cells revealed only focal areas of demyelination with no significant differences in white matter destruction. These data indicate that CCR5 signaling on CD8 + T cells modulates antiviral activities but is not essential for entry into the CNS.

Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy is a subacute demyelinating disease that occurs in patients with defects in cell-mediated immunity, including those with AIDS and lymphoproliferative disorders. It is caused by reactivation of JC virus (JCV), which infects 70% to 90% of the population by adulthood, but remains latent in normal hosts. Once reactivated, JCV infects oligodendrocytes and astrocytes, with resultant cell lysis, leading to focal areas of demyelination and necrosis in cerebral white matter causing focal neurologic deficits and characteristic findings on MRI. Polymerase chain reaction for the detection of JCV is a sensitive and specific test, replacing brain biopsy as the initial diagnostic test in the appropriate clinical setting. Historically, the prognosis of progressive multifocal leukoencephalopathy is poor, with most patients dying within 6 months of diagnosis. Antiviral medications targeted against JCV have shown little success. However, with the use of highly active antiretroviral therapy, survival of AIDS patients with progressive multifocal leukoencephalopathy has improved.

Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma

To evaluate the efficacy and toxicity of dendritic cell (DC) based therapy for intracerebral gliomas, we utilized a cell line derived from an astrocytoma that arose spontaneously in a VM/Dk mouse. This astrocytoma mirrors human gliomas phenotypically, morphologically and secretes transforming growth factor (TGF)-βs, immunosuppressive cytokines secreted by human gliomas. Systemic vaccination of mice with DCs pulsed with tumor homogenate followed by intracranial tumor challenge produced a >160% increase in median survival ( p=0.016) compared with mice vaccinated with PBS or unpulsed DCs ( p=0.083). Fifty percent of mice treated with pulsed DCs survived long-term. Immunologic memory was demonstrated by survival of mice rechallenged with tumor. Both cell-mediated and humoral immunity was induced. On histological examination only focal areas of demyelination at the tumor implantation site were present. There was no evidence that autoimmune encephalomyelitis was induced by DC vaccination. Therefore, in a murine model, vaccination with DCs pulsed with glioma tumor homogenate is a safe and effective therapy against a syngeneic glioma located in the immunologically privileged central nervous system (CNS).

Glial cell transplants: experimental therapies of myelin diseases.

Transplantation of cells into the CNS of human patients with neurodegenerative disorders offers a radical new approach to the treatment of previously incurable diseases. Considerable success has been achieved in Parkinson's disease following transplantation of human fetal dopaminergic neurons. Disorders of myelination of the brain, of either inherited or acquired origin, might also be treated by glial cell transplantation although there are additional challenges. Cells of the oligodendrocyte lineage have been found to be capable of myelinating axons on transplantation into numerous experimental pathological environments, including the CNS of myelin mutants and focal areas of demyelination in normal animals made by injection of myelinotoxic chemicals. In general, primary cells and progenitors are likely to have the greatest myelinating capacity. Cell lines can also be used, but those driven by oncogenes may produce little myelin, and tumor formation is likely. Schwann cells are also a potential source of cells, possibly as a homograft, and may be primed by treatment ex vivo with glial growth factors. The variable CNS milieu seen in human myelin disease will mean that transplanted cells must be able to migrate appropriately and myelinate axons in an adult, pathological environment, and this awaits experimental confirmation. Physiological analysis of transplants in such situations in adult animals will provide the functional data which may expedite clinical trials.

The virology of demyelinating diseases.

Infectious agents have been postulated as causes of multiple sclerosis for over a century. The possible role of a virus or viruses is supported by data that (1) a childhood exposure is involved and “viral” infections may precipitate exacerbations of disease, (2) experimental infections in animals and natural infections in humans can cause diseases with long incubation periods, remitting and relapsing courses, and demyelination, and (3) patients with multiple sclerosis have abnormal immune responses to viruses. The pathogenesis of three human demyelinating diseases of known viral etiology is discussed. In progressive multifocal leukoencephalopathy, a papovavirus selectively infects oligodendrocytes and causes focal areas of demyelination. In postmeasles encephalomyelitis, the virus is lymphotrophic and disrupts immune regulation that can result in an autoimmune perivenular demyelinating illness without evidence of infection of the central nervous system. In human immunodeficiency virus‐encephalopathy and myelopathy virus is present in macrophages and microglia and the myelin abnormalities apparently are caused by soluble factors such as viral proteins, cytokines, or neurotoxins. These findings may have implications on how, when, and where to seek viruses in multiple sclerosis.

Abnormal impulse generation in focally demyelinated trigeminal roots.

In 12 cats and two Macaca mulatta monkeys, areas of chronic focal injury were induced in the trigeminal root by implantation of a chromic suture in the nerve near its entry into the brain stem. Experimental lesions were examined histologically and electrophysiologically at 1 week, 3 weeks, and 6 weeks after surgery. At 3 weeks following implantation, lesioned nerves showed areas of focal inflammation surrounding implanted sutures with prominent demyelination of adjacent axons. A total of 497 trigeminal units were studied, 304 of which had associated demyelination of the root. In these 304 cells, two types of abnormal impulse generation from areas of focal demyelination were recorded. Reflected orthodromic action potentials and prolonged high-frequency after-discharges following short priming trains of orthodromic stimuli were observed in 23% and 4% of cells, respectively. Ectopic spike initiation from areas of focal demyelination was not dependent upon anatomical continuity of the nerve with the brain stem, was augmented by hyperventilation, and could be eliminated by the intravenous administration of diphenylhydantoin sodium. The relevance of these findings to the pathophysiological mechanisms of pain syndromes involving peripheral nerves in general and the trigeminal system in particular is discussed.

Ectopic impulse generation in focally demyelinated trigeminal nerve

In five cats, microgranulomas containing areas of focal demyelination were produced in the trigeminal nerve near the dorsal root entry zone. Two types of ectopic spike initiation were evoked: extra action potentials from orthodromic stimuli and prolonged high-frequency after discharges following short priming trains of antidromic or orthodromic stimuli.

Diaphragm pacing: Histopathological changes in the phrenic nerve following long-term electrical stimulation

Phrenic nerves were obtained at autopsy from 7 patients with chronic ventilatory insufficiency. One or both nerves had been subjected to electrical stimulation to pace the diaphragm for about 2 months to 4 years. Sections of the nerves made from above, at the level of, and below the site of application of the cuff electrode were studied microscopically. In most specimens, focal areas of demyelination were seen ranging from severity from swelling and fragmentation of isolated fibers to focal myelin destruction with phagocytic activity and total removal of myelin with fibrosis. Some axone loss was seen. The fact that the nerves from 2 patients, each stimulated for about 2 years, showed no changes suggests that injury to the nerve was not caused by the electrical stimuli but rather was secondary to the technique of application and fixation of the cuff electrode to the nerve.

CHRONIC PERIVASCULAR DEMYELINATION (HOMOPHASIC CEREBROSPINAL DEMYELINATING PERIANGIOSIS)

Focal areas of demyelination, with or without degeneration of axons, are a common observation in a variety of diseases of the central nervous system and in many experimentally produced conditions. There are the circumscribed cortical lesions of dementia paralytica; the lesions described in bacillary dysentery (Spielmeyer1) and those in encephalitis following measles (Walthard,2Ferraro and Scheffer3and Putnam4), varicella (van Bogaert5) and variola (Brouwer6). There are the pathologic changes resulting from burns (Globus and Bender7) and carbon monoxide poisoning (doubtful case reported by Hilpert8). It is obviously a mistake to conclude that every case in which there are disseminated circumscribed areas of demyelination must be an instance of multiple sclerosis. The pathologic diagnosis depends not only on the histologic picture of the individual lesion but on its position and total distribution. In other words, if one adds to the histotypical characteristics what