Axonal damage in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in a C57BL/6 mouse model may be not secondary to inflammatory demyelination

The present study established a chronic experimental autoimmune encephalomyelitis model in C57BL/6 mice induced by myelin oligodendrocyte glycoprotein peptides and complete Freund＇s adjuvant. Onset latency was 12 days, with an incidence rate of 100%. Neuropathological characteristics included perivascular inflammatory cell infiltration, demyelination, neuronal degeneration, and axonal damage within cerebral and myelic white matter. Electron microscopy revealed swollen mitochondria, complete organ disappearance, and fused or broken myelin sheath structure, which were accompanied by myelin sheath reconstruction. Moreover, axonal damage was not consistent with demyelination distribution, and severity of axonal damage did not correlate with demyelination. Results suggested that axonal damage in an experimental autoimmune encephalomyelitis model is not secondary to inflammatory demyelination.

Overlapping syndrome of recurrent anti-N-methyl-D-aspartate receptor encephalitis and anti-myelin oligodendrocyte glycoprotein demyelinating diseases:A case report

BACKGROUND Anti-N-methyl-D-aspartate receptor encephalitis(NMDARe)is capable of presenting a relapsing course and coexisting with myelin oligodendrocyte glycoprotein antibody disease,whereas it has been relatively rare.We describe a man with no history of tumor who successively developed anti-NMDARe and anti-myelin oligodendrocyte glycoprotein antibody disease.CASE SUMMARY A 29-year-old man was initially admitted with headache,fever,intermittent abnormal behavior,decreased intelligence,limb twitching and loss of consciousness on July 16,2018.On admission,examination reported no abnormality.During his presentation,he experienced aggravated symptoms,and the reexamination of cranial magnetic resonance imaging(MRI)indicated punctate abnormal signals in the left parietal lobe.External examination of cerebrospinal fluid and serum results revealed serum NMDAR antibody(Ab)(-),cerebrospinal fluid NMDAR-Ab(+)1:10 and Epstein-Barr virus capsid antigen antibody Ig G(+).Due to the imaging findings,anti-NMDARe was our primary consideration.The patient was treated with methylprednisolone and gamma globulin pulse therapy,mannitol injection dehydration to reduce intracranial pressure,sodium valproate sustained-release tablets for anti-epilepsy and olanzapine and risperidone to mitigate psychiatric symptoms.The patient was admitted to the hospital for the second time for“abnormal mental behavior and increased limb movements”on December 14,2018.Re-examination of electroencephalography and cranial MRI showed no abnormality.The results of autoimmune encephalitis antibody revealed that serum NMDAR-Ab was weakly positive and cerebrospinal fluid NMDAR-Ab was positive.Considering comprehensive recurrent anti-NMDARe,the patient was treated with propylene-hormone pulse combined with immunosuppressive agents(mycophenolate mofetil),and the symptoms were relieved.The patient was admitted for“hoarseness and double vision”for the third time on August 23,2019.Re-examination of cranial MRI showed abnormal signals in the medulla oblongata and right frontal lobe,and synoptophore examination indicated concomitant esotropia.The patient’s visual acuity further decreased,and the reexamination of cranial MRI+enhancement reported multiple scattered speckled and patchy abnormal signals in the medulla oblongata,left pons arm,left cerebellum and right midbrain,thalamus.The patient was diagnosed with an accompanying demyelinating disease.Serum antimyelin oligodendrocyte glycoprotein 1:10 and NMDAR antibody 1:10 were both positive.The patient was diagnosed with myelin oligodendrocyte glycoprotein antibody-related inflammatory demyelinating disease of the central nervous system complicated with anti-NMDARe overlap syndrome.The patient was successfully treated with methylprednisolone,gamma globulin pulse therapy and rituximab treatment.The patient remained asymptomatic and follow-up MRI scan 6 mo later showed complete removal of the lesion.CONCLUSION We emphasize the rarity of this antibody combination and suggest that these patients may require longer follow-up due to the risk of recurrence of two autoimmune disorders.

Neuromyelitis optica and myelin oligodendrocyte glycoprotein

Neuromyelitis optica(NMO)refers to an antibody mediated,inflammatory disorder of the central nervous system(CNS)characterized by recurrent or monophasic attacks of optic neuritis and myelitis.Most patients with NMO possess a specific serum immunoglobin,NMO-IgG,which can serve as a biomarker for NMO.The autoantibodies target aquaporin-4(AQP4),the main water channel protein found in the CNS including the brain,spinal cord,and optic nerve.The remaining 10-25%of patients are seronegative for NMO-IgG despite meeting the diagnostic criteria for NMO.Recent studies have shown that a subset of these patients is seropositive for antibodies against myelin oligodendrocyte glycoprotein(MOG).This paper will provide an overview of the current English scientific literature published regarding the history,epidemiology,AQP4 biomarker,MOG biomarker,diagnosis,clinical features,related diseases in NMO spectrum disorder(NMOSD),and treatments of NMO.

Serum antibodies to 25 myelin oligodendrocyte glycoprotein epitopes in multiple sclerosis and neuromyelitis optica： clinical value for diagnosis and disease activity

Background Whether antibody to myelin oligodendrocyte glycoprotein （MOG） can be a diagnostic marker for multiple sclerosis （MS） is still controversial. Recent studies suggested that serum specific anti-MOG epitope antibody might be an MS specific marker. However, these studies did not include neuromyelitis optica （NMO） which might be proven to also have anti-MOG antibody. Hence, the present study was undertaken to investigate the clinical value of serum antibodies to 25 MOG epitopes in conventional MS （CMS） and NMO. Methods Serum anti-MOG epitope IgG was detected in 61 CMS patients, 54 NMO patients, and 77 healthy controls, using enzyme-linked immunosorbent assay （ELISA）. Results Anti-MOG27-38 IgG levels in both CMS and NMO patients were significantly higher than that in healthy controls （optical density （OD）： 0.64±0.38, 0.48±0.23 vs. 0.19±0.09; P=0.000）. CMS and NMO patients in relapse stage had significantly higher anti-MOG27-38 IgG level than patients in remission stage （OD： 0.55±0.14 vs. 0.24±0.09, P=0.027）. Conclusion Although serum anti-MOG epitope IgG could not differentiate MS from NMO, it may be a useful marker for monitoring disease activity.

Biomarkers for neuromyelitis optica:a visual analysis of emerging research trends

Neuromyelitis optica is an inflammatory demyelinating disease of the central nervous system that differs from multiple sclerosis.Over the past 20 years,the search for biomarke rs for neuromyelitis optica has been ongoing.Here,we used a bibliometric approach to analyze the main research focus in the field of biomarkers for neuromyelitis optica.Research in this area is consistently increasing,with China and the United States leading the way on the number of studies conducted.The Mayo Clinic is a highly reputable institution in the United States,and was identified as the most authoritative institution in this field.Furthermore,Professor Wingerchuk from the Mayo Clinic was the most authoritative expe rt in this field.Keyword analysis revealed that the terms "neuro myelitis optica"(261 times), "multiple sclerosis"(220 times), "neuromyelitis optica spectrum disorder"(132 times), "aquaporin4"(99 times),and "optical neuritis"(87 times) were the most frequently used keywords in literature related to this field.Comprehensive analysis of the classical literature showed that the majority of publications provide conclusive research evidence supporting the use of aquaporin-4-IgG and neuromyelitis optica-IgG to effectively diagnose and differentiate neuromyelitis optica from multiple sclerosis.Furthermore,aquaporin-4-IgG has emerged as a highly specific diagnostic biomarker for neuromyelitis optica spectrum disorder.Myelin oligodendrocyte glycoprotein-IgG is a diagnostic biomarke r for myelin oligodendrocyte glycoprotein antibody-associated disease.Recent biomarkers for neuromyelitis optica in clude cerebrospinal fluid immunological biomarkers such as glial fibrillary acidic protein,serum astrocyte damage biomarkers like FAM19A5,serum albumin,and gammaaminobutyric acid.The latest prospective clinical trials are exploring the potential of these biomarkers.Preliminary results indicate that glial fibrillary acidic protein is emerging as a promising candidate biomarker for neuromyelitis optica spectrum disorder.The ultimate goal of future research is to identify non-invasive biomarkers with high sensitivity,specificity,and safety for the accurate diagnosis of neuro myelitis optica.

Comparison of macular changes according to the etiology of optic neuritis:a cross-sectional study

AIM:To compare the macular structure including foveal thickness among patients with optic neuritis(ON)according to the etiology and to investigate the possible correlation between structural and visual outcomes METHODS:In this retrospective cross-sectional study,the clinical data of patients with aquaporin-4 immunoglobulin G-related ON(AQP4 group,40 eyes),myelin oligodendrocyte glycoprotein IgG-related ON(MOG group,31 eyes),and multiple sclerosis-related ON(MS group,24 eyes)were obtained.The retinal thickness of the foveal,parafoveal and perifoveal regions were measured.Visual acuity(VA),visual field index and mean deviation were measured as visual outcomes.RESULTS:The AQP4 group showed a significantly thinner fovea(226.4±13.4μm)relative to the MOG(236.8±14.0μm,P=0.015)and MS(238.9±14.3μm,P=0.007)groups.The thickness in the parafoveal area also was thinner in the AQP4 group,though the difference in perifoveal retinal thickness was not significant.Foveal thickness was correlated with VA in the AQP4 group(coefficientρ=-0.418,P=0.014),but not in the MOG and MS groups(P=0.218 and P=0.138,respectively).There was no significant correlation between foveal thickness and visual field test in all three groups.CONCLUSION:The significant thinning in the fovea and parafoveal areas in the AQP4 group compared to the MOG and MS groups are found.Additionally,macular changes in AQP4-ON show a significant correlation with VA.The results provide the possibility that retinal structural damage could reflect functional damage in AQP4-ON,distinct from MOGON and MS-ON.

Optical coherence tomography in central nervous system demyelinating diseases related optic neuritis

AIM：To compare the thickness of the peripapillary retinal nerve fiber layer（RNFL）and ganglion cell-inner plexiform layer（GCIPL）among patients with various forms of optic neuritis（ON）and to identify whether any particular parameters or their thinning pattern can be used to distinguish the type of ON.METHODS：This prospective study was conducted at the Department of Ophthalmology,Faculty of Medicine,Siriraj Hospital,Thailand,between January,2015 and December,2016.We enlisted patients over 18 years of age with history of ON and categorized patients into 4 groups：1）aquaporin 4 antibodies（AQP4-IgG）positive;2）multiple sclerosis（MS）;3）myelin oligodendrocyte glycoprotein antibodies（MOG-IgG）positive;4）idiopathic-ON patients.Healthy controls were also included during the same study period.All patients underwent complete ophthalmological examination and spectral domain optical coherence tomography（OCT）imaging to analyze RNFL and GCIPL thickness after at least 3mo since the last episode of acute ON.The generalized estimating equation（GEE）models were used to compare the data amongst ON groups. RESULTS： Among 87 previous ON eyes from 57 patients（43 AQP4-IgG＋ON,17 MS-ON,8 MOG-IgG＋ON,and 19idiopathic-ON）,mean logMAR visual acuity of AQP4-IgG＋ON,MS-ON,MOG-IgG＋ON,and idiopathic-ON groups was 0.76±0.88,0.12±0.25,0.39±0.31,and 0.75±1.08,respectively.Average,superior,and inferior RNFL were significantly reduced in AQP4-IgG＋ON,MOG-IgG＋ON and idiopathic-ON eyes,relative to those of MS-ON.Differences were not statistically significant for RNFL or GCIPL between the AQP4-IgG＋ON and MOG-IgG＋ON groups,whereas visual acuity in MOG-IgG＋ON was slightly,but not significantly,better（0.39 vs 0.76）.Although RNFL thickness in MOG-IgG＋ON was significantly reduced as compared to MS-ON,mean visual acuity and GCIPL were not different.CONCLUSION：Thinning of superior and inferior quadrants of RNFL are more commonly seen in MOG-IgG＋ON and AQP4-IgG＋ON.Long term visual acuity in MOG-IgG＋ON is often better than AQP4-IgG＋ON,whereas the structural change from OCT is comparable.

Inhibitory effect of icariin on expression of myelin inhibitory factors in the central nervous system of rats with focal cerebral ischemia

Icariin, the major active component of Chinese medicinal herb epimedium brevicornum maxim, is used widely in traditional Chinese medicine for the treatment of neurological diseases. However, the effects of icariin on myelin inhibitory factors are as yet unclear. In the present study, administration of icariin at 20 mg/kg showed a marked reduction in neurological deficit of middle cerebral artery occlusion rats. Icariin exhibited better inhibitory effects on myelin inhibitory factors： Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein in ischemia regions of middle cerebral artery occlusion rats compared with monosialotetrahexosylganglioside. These results indicate that icariin exhibits potent inhibitory effects on expression of myelin inhibitors after middle cerebral artery occlusion-induced focal cerebral ischemia in vivo. This effect may be mediated, at least in part, by the inhibition of both Nogo-A, myelin-associated glycopretein and oligodendrocyte myelin glycoprotein activation, followed by the enhancement of axonal sprouting and regeneration, resulting in neurological functional recovery.

Axonal growth inhibitors and their receptors in spinal cord injury:from biology to clinical translation

Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.

Neurofilament light chain in demyelinating conditions of the central nervous system: a promising biomarker

Neurofilaments are the major structural proteins of the neuronal cytoskeleton and are classified according to molecular weight into heavy,intermediate,and light chains.They are released into the interstitial fluid and cerebrospinal fluid(CSF)as a consequence of axonal damage.In particular,the light chain(NfL)represents the most abundant and soluble subunit and has been demonstrated to be increased in the CSF of patients with inflammatory,degenerative,vascular,or traumatic injuries in correlation with clinical and radiological activity.Similar results have been obtained measuring serum NfL with high-sensitivity single-molecule array,which enables reliable and repeatable measurement of the low NfL concentrations in serum.In particular,CSF and serum NfL values are strongly correlated in patients with multiple sclerosis(MS)and have been demonstrated to be increased in patients with MS and clinically isolated syndromes(CIS)in accordance with clinical and radiological activity.NfL levels increase in patients with a recent relapse and seem to predict cognitive impairment,long-term outcome,and conversion of CIS to MS.The few available data on patients with other demyelinating diseases suggest that NfL levels are also increased in neuromyelitis optica spectrum disorders and related conditions in correlation with attack severity,suggesting that axonal damage may occur in these disorders.We herein report and discuss published data on the role of NfL as a possible predictor of disease activity,clinical outcome and treatment response in patients with demyelinating conditions of the central nervous system.

Clinical Features of Patients with Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

Background： Neuromyelitis optica spectrum disorder （NMOSD） was long believed to be an aggressive form of multiple sclerosis （MS）. This study aimed to describe the clinical features of patients with MS and NMOSD to assist in differential diagnoses in clinical practice. Methods： Data including the patients＇ serum and cerebrospinal fluid （CSF） tests, image findings, and clinical information from 175 patients with MS or NMOSD at Xuanwu Hospital, Capital Medical University from November 2012 to May 2014 were collected and analyzed retrospectively. An enzyme-linked immunosorbent assay was performed to detect the myelin oligodendrocyte glycoprotein （MOG） autoantibodies in CSF and serum. Cell-based assays were used to detect aquaporin-4-antibody （AQP4-Ab）. The Chi-square test was used to compare the categorical variables. Wilcoxon rank sum test was peribrmed to analyze the continuous variables. Results： Totally 85 MS patients （49%） and 90 NMOSD patients （51%） were enrolled, including 124 （71%） women and 51 （29%） men. Fewer MS patients （6%） had autoinamune diseases compared to NMOSD （19%） （x2= 6.9, P 〈 0.01 ）. Patients with NMOSD had higher Expanded Disability Status Scale scores （3.5 [3]） than MS group （2 [2]） （x2= -3.69, P 〈 0.01）. The CSF levels of white cell count and protein in both two groups were slightly elevated titan the normal range, without significant difference between each other. Positivity of serum AQP4-Ab in NMOSD patients was higher than that in MS patients （MS： 0, NMOSD： 67%; x2= 63.9, P 〈 0.01 ）. Oligoclonal bands in CSF among NMOSD patients were remarkably lower than that among MS （MS： 59%, NMOSD： 20%; x2= 25.7, P 〈 0.01）. No significant difference of MOG autoantibodies was found between the two groups. Conclusion： The different CSF features combined with clinical, magnetic resonance imaging, and serum characteristics between Chinese patients with MS and NMOSD could assist in the differential diagnosis.

MiR-125a-5p Regulates Vitamin D Receptor Expression in a Mouse Model of Experimental Autoimmune Encephalomyelitis

Multiple sclerosis(MS)is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system.Although the symptoms of MS can be managed by vitamin D3 treatment alone,this condition cannot be completely eradicated.Thus,there might be unknown factors capable of regulating the vitamin D receptor(VDR).Genome-wide analysis showed that miRNAs were associated with VDRs.We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS,mice with experimental autoimmune encephalomyelitis(EAE),which was induced by myelin oligodendrocyte glycoprotein 35–55 peptides.EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice.And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice.In addition,VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice.Importantly,activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice.Interestingly,VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn.More importantly,inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice.These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.