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A significant number of patients with a peripheral neuropathy have IgM monoclonal gammopathy (IgM-MG). In this work, we encompassed the spectrum and outcome of IgM-related neuropathies (IgM-NP) in a large monocentric cohort of patients with IgM-MG.We retrospectively reviewed the neurological and hematological findings and the course of neuropathy in all patients with IgM-MG over a five-year period in our center (Henri Mondor hospital, Assistance Publique Hôpitaux de Paris (APHP), France).Among 550 patients with IgM-MG, 83 patients (15%) had IgM-NP (55 males, mean age 67 y.o.). The median serum level of IgM-MG was 3.4 g/L, mostly kappa light chain component. The hematological diagnosis was Monoclonal Gammopathy of Undetermined Significance (MGUS) in 62 patients. Anti-MAG antibodies were detected in 38 patients with heterogeneous clinical and neurophysiological features. Four patients had neurolymphomatosis presenting as a non-length dependent predominantly motor neuropathy, which occurred long after the finding of IgM-MG and was responsive to hematological treatment. Five patients had an AL amyloid neuropathy revealed by a small fiber neuropathy. Finally, 30 patients were classified as "Neuropathy of Uncertain Relationship with the IgM" (NURIM) with characteristics close to those of an anti-MAG-NP at the time of diagnosis, except for the neurophysiological features with a predominant axonal pattern.This study emphasizes the wide spectrum of IgM-NP associated with a variety of hematological diagnoses. In particular, the course and prognosis vary considerably. In this setting, further studies are needed to unravel the group of patients classified as NURIM.

Immunoglobulin M neuropathy associated with anti-myelin-associated glycoprotein antibody (IgM/anti-MAG) neuropathy typically presents with chronic, distal-dominant symmetrical sensory or sensorimotor deficits. Ultrasonographic studies of IgM/anti-MAG neuropathy are limited, and were all performed on Western populations. We aimed to characterize the nerve ultrasonographic features of IgM/anti-MAG neuropathy in the Japanese population and evaluate whether they differ from the findings of the common subtypes of chronic inflammatory demyelinating polyneuropathy (CIDP).In this cross-sectional study, we retrospectively reviewed medical records and extracted the cross-sectional areas (CSAs) of C5-C7 cervical nerve roots and median and ulnar nerves of 6 IgM/anti-MAG neuropathy patients, 10 typical CIDP (t-CIDP) patients, 5 multifocal CIDP (m-CIDP) patients, and 17 healthy controls (HCs).Cervical nerve root CSAs were significantly larger at every examined site on both sides in IgM/anti-MAG neuropathy than in m-CIDP and HCs but were comparable to those in t-CIDP. Peripheral nerve enlargements were greatest at common entrapment sites (ie, wrist and elbow) in IgM/anti-MAG neuropathy, a pattern shared with t-CIDP but not with m-CIDP. The degree of nerve enlargement at entrapment sites compared to non-entrapment sites was significantly higher in IgM/anti-MAG neuropathy than in t-CIDP.Our study delineated the ultrasonographic features of IgM/anti-MAG neuropathy in the Japanese population and observed similar characteristics to those of t-CIDP, with subtle differences. Further studies comparing results from various populations are required to optimize the use of nerve ultrasound worldwide.

Female Dark Agouti rats were immunized with increasing doses of myelin oligodendrocyte glycoprotein (MOG) to develop experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis. Typical EAE motor impairments were assessed daily and noninvasive visual evoked potentials (VEPs) were recorded at baseline and 5 weeks after immunization, with final histopathology of optic nerves (ONs). Immunized rats exhibited a relapsing-remitting clinical course. Both VEP and histological abnormalities were detected in a MOG dose-dependent gradient. Increasing MOG dosage augmented visual function impairment in EAE, which could be monitored with VEP recording to assess demyelination and axonal loss along ONs.

Introduction Autoimmune neuropathies have diverse presentations and underlying immune mechanisms. Demonstration of efficacy of therapeutic agents that inhibit the complement cascade would confirm the role of complement activation. D A review of the pathophysiology of the autoimmune neuropathies, to identify those that are likely to be complement mediated. Expert opinion Complement mediated mechanisms are implicated in the acute and chronic neuropathies associated with IgG or IgM antibodies that target the Myelin Associated Glycoprotein (MAG) or gangliosides in the peripheral nerves. Antibody and complement mechanisms are also suspected in the Guillain-Barre syndrome and chronic inflammatory demyelinating neuropathy, given the therapeutic response to plasmapheresis or intravenous immunoglobulins, even in the absence of an identifiable target antigen. Complement is unlikely to play a role in paraneoplastic sensory neuropathy associated with antibodies to HU/ANNA-1 given its intracellular localization. In chronic demyelinating neuropathy with anti-nodal/paranodal CNTN1, NFS-155, and CASPR1 antibodies, myotonia with anti-VGKC LGI1 or CASPR2 antibodies, or autoimmune autonomic neuropathy with anti-gAChR antibodies, the response to complement inhibitory agents would depend on the extent to which the antibodies exert their effects through complement dependent or independent mechanisms. Complement is also likely to play a role in Sjogren's, vasculitic, and cryoglobulinemic neuropathies.

Background: Combined central and peripheral demyelination (CCPD) is a disease of inflammatory demyelination that affects central and peripheral nerves simultaneously or temporally separated. Objectives: This study evaluated the clinical characteristics and the existence of antinodal/paranodal antibodies in patients with CCPD. Methods: We reviewed the clinical manifestations, laboratory tests, electrophysiological examinations, neuroimaging findings, treatment, and prognosis of 31 patients with CCPD. Using a live cell–based assay, we tested antinodal/paranodal antibodies. Results: The most common symptoms were motor weakness (83.3%), hyporeflexia (63.3%), and sphincter disturbance (58.1%). In total, 16.6% of patients had impaired vision symptoms, whereas 33.3% of patients had abnormal visual-evoked potentials (VEPs). A total of 21.1% (4/19) of patients were positive for anti-AQP4 (aquaporin 4) antibodies, 20.0% (2/10) of patients were positive for anti-NF155 (neurofascin-155) antibodies, and 10.0% (1/10) of patients were positive for anti-MAG (myelin-associated glycoprotein) antibodies. The effective rates of intravenous corticosteroids, intravenous immunoglobulins, and rituximab were 72.2%, 37.5%, and 100%, respectively. At the illness peak, 75% of patients with CCPD had an mRS (modified Rankin Scale) score of 4 or greater. In remission, 37.5% had an mRS score of 4 or greater. Conclusion: The clinical manifestations of patients with CCPD are highly heterogeneous. We recommend testing antinodal/paranodal antibodies for patients with CCPD.

PURPOSE OF REVIEW The diagnosis of Myelin-Associated Glycoprotein (MAG) neuropathy is based on the presence of elevated titers of IgM anti-MAG antibodies, which are typically associated with IgM monoclonal gammopathy, and a slowly progressive, distal demyelinating phenotype. The condition, however, can be under or over diagnosed in patients with mildly elevated antibody titers, absent monoclonal gammopathy, or an atypical presentation. The purpose of this paper is to examine recent advances in our understanding of the currently available anti-MAG antibody assays, their reliability, and their use in deciding treatment or monitoring the response to therapy. RECENT FINDINGS Higher titers of anti-MAG antibodies are more likely to be associated with the typical MAG phenotype or response to therapy. Mildly elevated antibody levels can occur in patients with chronic inflammatory demyelinating polyneuropathy. Testing for cross-reactivity with HNK1 can add to the specificity of the antibody assays. Patients with MAG neuropathy can present with an atypical phenotype and in the absence of a detectable monoclonal gammopathy. SUMMARY Assays for anti-MAG antibodies by Enzyme-Linked Immunosorbent Assay can be improved by testing for antibody binding at multiple serum dilutions, the inclusion of antigen-negative microwells as internal controls for each sample, testing for cross-reactivity with HNK1, and formal validation. The diagnosis needs to be considered in patients with demyelinating neuropathy, even in the absence of a monoclonal gammopathy or typical phenotype. The change in antibody levels needs to be considered in evaluating the response to therapy with B-cell depleting agents.

Myelin-associated glycoprotein (MAG) and Nogo inhibit neurite outgrowth by binding to receptors such as NgR1, PirB and LRP1, and they have also been shown to induce phosphorylation of Smad2, a key intermediate in the transforming growth factor β (TGFβ) signalling pathway. In this study, we determined that MAG and Nogo do not transactivate the TGFβ receptor through their canonical receptors or discoidin domain receptor 1, which we identified as a novel receptor for MAG and Nogo. Instead, MAG and Nogo promoted Smad2 phosphorylation by stimulating secretion of TGFβ. Proteomic analysis of the neuronal secretome revealed that MAG also regulated the secretion of proteins that affect central nervous system plasticity-inducing the secretion of S100A6, septin-7 and neurofascin 186, while inhibiting the secretion of frataxin, MAP6, syntenin-1 and GAP-43. This represents a novel function for MAG that has broad implications for the treatment for spinal cord injury.

Schizophrenia (SCZ) is a debilitating mental disorder with various causes involving complex interactions between genetic factors and environmental agents. The immune system plays a vital role in the pathology and function of the nervous system. Interleukin 35 (IL-35) is a regulatory and anti-inflammatory cytokine that can prevent autoimmune and inflammatory diseases. This study aimed to investigate the role of autoantibodies against some central nervous system (CNS) antigens and IL-35 serum levels in patients with Schizophrenia. This case-control study involved 80 participants. The serum levels of IL-35 were measured by enzyme-linked immunosorbent assay and the autoantibodies in the CNS by indirect immunofluorescence assay (IFA). The serum levels of IL-35 were decreased in patient groups compared to healthy subjects. Autoantibodies against N-methyl-D-aspartate receptor (NMDAR) and myelin-associated glycoprotein (MAG) were positive in 15% (6/40) and 7.5% (3/40), respectively; however, no antibodies against myelin, aquaporin-4 (AQP4), myelin oligodendrocyte glycoprotein (MOG), voltage-gated potassium channel (VGKC), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), γ-butyric acid receptor type B1 γ-butyric acid receptor type B1 (GABABR), antidipeptidyl peptidase-like protein-6 (DPPX), immunoglobulin-like cell adhesion molecule 5 (IgLON5), Glycine receptor (R) and acetylcholine receptor (Ach R) were detected (No statistics were computed). We found that decreased serum IL-35 levels and the existence autoantibodies against NMDAR antigen may contribute to the pathogenesis of SCZ.

OBJECTIVE Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown. METHODS We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients. RESULTS Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17-127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3-64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = -40 to -14%, p

In the nervous system, a myelin sheath that originates from oligodendrocytes or Schwann cells wraps around axons to facilitate electrical signal transduction. The interface between an axon and myelin is maintained by a number of biomolecular interactions. Among the interactions are those between GD1a and GT1b gangliosides on the axon and myelin-associated glycoprotein (MAG) on myelin. Interestingly, these interactions can also inhibit neuronal outgrowth. Ganglioside-MAG interactions are often studied in cellular or animal models where their relative concentrations are not easily controlled or in assays where the gangliosides and MAG are not presented as part of fluid lipid bilayers. Here, we present an approach to characterize MAG-ganglioside interactions in real time, where MAG, GD1a, and GT1b contents are controlled and they are in their in vivo orientation within fluid lipid bilayers. Using a quartz crystal microbalance with dissipation monitoring (QCM-D) biosensor functionalized with a supported lipid bilayer (SLB) and MAG, we detect vesicular GD1a and GT1b binding and determine the interaction kinetics as a function of vesicular ganglioside content. MAG-bound vesicles are deformed similarly, regardless of the ganglioside or its mole fraction. We further demonstrate how MAG-ganglioside interactions can be disrupted by antiganglioside antibodies that override MAG-based neuron growth inhibition.

Monoclonal gammopathy is encountered quite frequently in the general population. This type of hematologic abnormality may be mild, referred to as monoclonal gammopathy of undetermined significance or related to different types of hematologic malignancies. The association of a peripheral neuropathy with monoclonal gammopathy is also fairly common, and hemopathy may be discovered in an investigation of peripheral neuropathy. In such a situation, it is essential to determine the exact nature of the hematologic process in order not to miss a malignant disease and thus initiate the appropriate treatment (in conjunction with hematologists and oncologists). In this respect, nerve biopsy (discussed on a case-by-case basis) is of great value in the management of such patients. We therefore propose to present the objectives and main interests of nerve biopsy in this situation.

Typical distal symptoms in anti-myelin-associated glycoprotein (anti-MAG) neuropathy are believed to be due to the binding of immunoglobulin M to distal nerve terminals. We describe the case of a 56-year-old man diagnosed with immunoglobulin M anti-MAG neuropathy in the setting of Waldenström macroglobulinemia, which developed acute neurological worsening presenting as cauda equina syndrome. Lumbosacral magnetic resonance imaging revealed enlarged nerve roots with diffuse heterogeneous gadolinium enhancement. Treatment with steroids resulted in substantial clinical improvement. Increased recognition of atypical presentations may lead to improved characterization of anti-MAG neuropathy as a more widespread disease.

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow’s milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.

Similar to other immune-mediated diseases, IgG4-related disease (IgG4-RD) is the disease that develops in genetically susceptible individuals exposed to external or endogenous antigens. In the present study, it was confirmed that MAG (myelin-associated glycoprotein) antibodies (IgG, IgG4, and IgM) were detected by immunofluorescence (IFA) in serum of the patients with IgG4-RD. In vivo, the levels of prolactin and Th2 cytokines in CGRP+/- rats were higher than those in wild-type. Our findings indicate that the presence of CGRP-deficiency-mediated MAG antibodies is a probable molecular basis for the initial events which were triggered in IgG4-RD immune responses via prolactin upregulation.

Introduction The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. Methods Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. Results In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. Conclusions Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

Rap1 is a small GTPase that has been implicated in dendritic development and plasticity. In this study, we investigated the role of Rap1 in axonal growth and its activation in response to neurotrophins and myelin-associated inhibitors. We report that Rap1 is activated by brain-derived neurotrophic factor and that this activation can be blocked by myelin-associated glycoprotein (MAG) or central nervous system myelin, which also induced increases in Rap1GAP1 levels. In addition, we demonstrate that adenoviral overexpression of Rap1 enhances neurite outgrowth in the presence of MAG and myelin, while inhibition of Rap1 activity through overexpression of Rap1GAP1 blocks neurite outgrowth. These findings suggest that Rap1GAP1 negatively regulates neurite outgrowth, making it a potential therapeutic target to promote axonal regeneration.

Peptide-protein docking is challenging due to the considerable conformational freedom of the peptide. CAPRI rounds 38-45 included two peptide-protein interactions, both characterized by a peptide forming an additional beta strand of a beta sheet in the receptor. Using the Rosetta FlexPepDock peptide docking protocol we generated top-performing, high-accuracy models for targets 134 and 135, involving an interaction between a peptide derived from L-MAG with DLC8. In addition, we were able to generate the only medium-accuracy models for a particularly challenging target, T121. In contrast to the classical peptide-mediated interaction, in which receptor side chains contact both peptide backbone and side chains, beta-sheet complementation involves a major contribution to binding by hydrogen bonds between main chain atoms. To establish how binding affinity and specificity are established in this special class of peptide-protein interactions, we extracted PeptiDBeta, a benchmark of solved structures of different protein domains that are bound by peptides via beta-sheet complementation, and tested our protocol for global peptide-docking PIPER-FlexPepDock on this dataset. We find that the beta-strand part of the peptide is sufficient to generate approximate and even high resolution models of many interactions, but inclusion of adjacent motif residues often provides additional information necessary to achieve high resolution model quality.

Adrenomyeloneuropathy (AMN) is a late-onset axonopathy of spinal cord tracts caused by mutations of the ABCD1 gene that encodes adrenoleukodystrophy protein (ALDP), a peroxisomal transporter of very long-chain fatty acids (VLCFA). Disturbed metabolic interaction between oligodendrocytes (OL) and axons is suspected to play a major role in AMN axonopathy. To develop a vector targeting OL, the human ABCD1 gene driven by a short 0.3 kb part of the human myelin-associated glycoprotein (MAG) promoter was packaged into an adeno-associated viral serotype 9 (rAAV9). An intravenous injection of this vector on postnatal day 10 in Abcd1

In anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN.In this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström's Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN).NfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients.Our results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.

Accumulation of intermediate metabolites due to enzyme deficiencies and demyelination can provoke inflammation in genetic leukodystrophies. Thirty patients with genetic leukodystrophy and 48 healthy control sera were tested for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies by fixed and/or live cell-based assays. MOG-IgG was detected in two late infantile metachromatic leukodystrophy (MLD) cases, both of which were also weakly positive for IgG1, and one with IgG3 as the dominant anti-MOG IgG subclass. MOG-IgG was borderline positive in a vanishing white matter (VWM) disease patient. These results suggest that inherited metabolic or degenerative processes can have an autoimmune component, possibly as an epiphenomenon.

The inability of neural cells to regenerate themselves after an injury represents the major difference between neural cells and other cells of the body. Various factors are responsible for this, as the expression of myelin-derived inhibitors of axonal outgrowth such as neurite outgrowth inhibitor (Nogo), myelin-associated growth factor, and oligodendrocyte-myelin glycoprotein (OMgp) hinder the central nervous system (CNS) axons to recover properly and inhibit the neuron regeneration. The patient with spinal cord injury can even permanently lose their function due to the inability of axons to regenerate. However, their role in neural regeneration in vivo is not known completely. During the study, we found that once CNS gets injured, the axon growth inhibitor OMgp binds to the Nogo-66 Receptor 1 (NgR1) which in turn restricts the normal functioning of CNS. Considering the OMgp as the target protein, two flavonoid libraries (curcumin and piperine) were screened against it to get potential inhibitors. The effectiveness of the ligands was first screened by three-tier structure-based virtual screening by Glide, Schrodinger. Based on the docking score, the best-docked compounds were taken for absorption, distribution, metabolism, and excretion analysis and the top two complexes from each library were chosen for simulation studies. Flavonoid ligands showed a much better binding affinity when compared with already known inhibitors Riluzole and Minocycline. To date, no natural inhibitors are known for OMgp. Hence, this study can provide novel insight for upcoming research in this area. Communicated by Ramaswamy H. Sarma.

Studies have shown that myelin-associated glycoprotein (MAG) can inhibit axon regeneration after nerve injury. However, the effects of MAG on neuroma formation after peripheral nerve injury remain poorly understood. In this study, local injection of MAG combined with nerve cap made of chitin conduit was used to intervene with the formation of painful neuroma after sciatic nerve transfection in rats. After 8 weeks of combined treatment, the autotomy behaviors were reduced in rats subjected to sciatic nerve transfection, the mRNA expression of nerve growth factor, a pain marker, in the proximal nerve stump was decreased, the density of regenerated axons was decreased, the thickness of the myelin sheath was increased, and the ratio of unmyelinated to myelinated axons was reduced. Moereover, the percentage of collagen fiber area and the percentage of fibrosis marker alpha-smooth muscle actin positive staining area in the proximal nerve stump were decreased. The combined treatment exhibited superior effects in these measures to chitin conduit treatment alone. These findings suggest that MAG combined with chitin conduit synergistically inhibits the formation of painful neuroma after sciatic nerve transection and alleviates neuropathic pain. This study was approved by the Animal Ethics Committee of Peking University People’s Hospital (approval No. 2019PHE027) on December 5, 2019.

Compression neuropathies are common and debilitating conditions that result in variable functional recovery after surgical decompression. Recent drug repurposing studies have verified that clemastine promotes functional recovery through enhancement of myelin repair in demyelinating disease. We investigated the utility of clemastine as a treatment for compression neuropathy using a validated murine model of compression neuropathy encircling the compression tube around the sciatic nerve. Mice received PBS or clemastine solution for 6 weeks of compression phase. Mice taken surgical decompression received PBS or clemastine solution for 2 weeks of decompression phase. Electrodiagnostic, histomorphometric, and Western immunoblotting analyses were performed to verify the effects of clemastine. During the compression phase, mice treated with clemastine had significantly decreased latency and increased amplitude compared to untreated mice that received PBS. Histomorphometric analyses revealed that mice treated with clemastine had significantly higher proportions of myelinated axons, thicker myelin, and a lower G-ratio. The expression levels of myelin proteins, including myelin protein zero and myelin associated glycoprotein, were higher in mice treated with clemastine. However, the electrophysiologic and histomorphometric improvements were observed regardless of clemastine treatment in mice taken surgical decompression. Mice treated with clemastine during compression of the sciatic nerve demonstrated that clemastine treatment attenuated electrophysiologic and histomorphometric changes caused by compression through promoting myelin repair.

BACKGROUND AND PURPOSE Primary autoimmune cerebellar ataxia (PACA) in the absence of another triggering disease represents an emerging category of neurological illness. We report such a case whose ataxia was markedly responsive to plasma exchange. We analyzed patient serum for the presence of IgM or IgG anticerebellar neuronal antibodies. METHODS Case presentation: rat cerebellar slice cultures incubated with patient sera were studied for IgG and IgM antibody uptake, intracellular binding, and neuronal death. Patient serum was evaluated for anti-myelin associated glycoprotein (anti-MAG) and associated anti-glycolipid antibodies. RESULTS Antibodies were taken up by viable cerebellar neurons and bound to intracellular antigens. Uptake and predominantly nuclear binding of IgG were seen in granule cells whereas cytoplasmic binding of IgM was observed predominantly in Purkinje cells. Intracellular antibody accumulation was not accompanied by neuronal death, consistent with the patient's excellent clinical response to plasma exchange. Anti-MAG or other associated anti-glycolipid antibodies were not detected. CONCLUSIONS PACA may be associated with both IgG and IgM antibodies reactive with cerebellar neuronal antigens. Our patient's response to plasma exchange supports a role for antineuronal antibodies in disease pathogenesis and emphasizes the need for rapid diagnosis and treatment.

Introduction: This study assessed the morphological changes and diffusion tensor imaging (DTI)-derived parameters of the brachial plexus using magnetic resonance neurography (MRN) in patients with anti-myelin-associated glycoprotein (anti-MAG) neuropathy. Methods: Eight patients with anti-MAG neuropathy underwent MRN of the brachial plexus with 3-dimensional (3D) short tau inversion recovery (STIR) and DTI sequences. Two neuroradiologists and a neurologist qualitatively assessed nerve hypertrophy on 3D STIR MRN. The cross-sectional area (CSA) of the nerve roots was measured. Quantitative analyses of fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, and MD) were obtained after postprocessing on DTI and manual segmentation. Results: There was nerve hypertrophy in 37.5% of the patients with anti-MAG neuropathy. All patients with anti-MAG neuropathy with nerve hypertrophy were refractory to rituximab therapy. The CSA of the nerve roots was inversely correlated with FA and positively correlated with MD and RD. FA decreased in the nerve roots and inversely correlated with disease duration. Conclusions: Nerve hypertrophy appears in the proximal portion of peripheral nerves, such as the brachial plexus, in patients with anti-MAG neuropathy. Altered diffusion in the nerve roots might be associated with the loss of myelin integrity due to the demyelination process in anti-MAG neuropathy.

Several studies in the last decade demonstrated that progestogens play an important role in the biology of Schwann cells, the main neuroglial cells of the peripheral nervous system. Since a recent study showed that the S42 rat Schwann cell line expressed membrane progesterone receptors (mPRs), members of the PAQR family, in this study, we examined mPR expression in a more physiological model, primary rat Schwann cells. We demonstrated that primary rat Schwann cells show a different pattern of mPR expression compared to the previously studied model; mPRα (PAQR7) and β (PAQR8) isoforms were the major mPR members identified, with different sub-cellular localizations. Activation of the nuclear progesterone receptor (PR) with the specific agonist R5020 upregulated mPR expression, while activation of mPRs with the specific agonist Org OD 02-0 changed their sub-cellular localization. An in-depth analysis revealed additional effects of mPR activation, such as AKT activation, reduced expression of the myelin-associated glycoprotein (MAG), morphological changes, altered expression of several Schwann cell differentiation markers, and increased Schwann cell migration and proliferation. In conclusion, we identified mPRα and mPRβ in primary rat Schwann cells, and our findings suggest a putative role for mPRs in the regulation of Schwann cell migration, proliferation, and differentiation. Therefore, mPRs are a potential pharmacological target for Schwann cell-related disorders and neurodegenerative diseases, especially those in which Schwann cell-mediated axon remyelination is desirable.

Anti-MAG polyneuropathy (anti-MAG PN) is an immune-mediated peripheral sensorimotor neuropathy characterized by distal demyelination and ataxia. However, this disorder, unlike other immune-mediated neuropathies, is difficult to treat in most cases. We retrospectively collected all anti-MAG PN patients followed in two hospitals for a period of 12 years to determine prognostic factors, especially those that indicated a good response to the various therapeutic strategies used. Forty-seven patients were included in the study; of these, 61% had a classical ‘distal demyelinating pattern’, 34.2% had a ‘CIDP-like pattern’, and the others had an ‘axonal pattern’. The most commonly used treatments were intravenous immunoglobulin (IVIg) as the first-line treatment and rituximab as the second- or third-line treatment. No prognostic factor was identified for IVIg, but electrophysiological parameters at onset were better in patients with a good response to rituximab than in non-responder patients, even though mild or high disability was observed in nearly half the patients at last examination. Even though disability seems to progress in most cases despite the treatments used, our results suggest that an early electrophysiological reduction in sensory nerves could be considered a ‘red flag’ for the prompt initiation of rituximab to try to delay long-term disability.

IMPORTANCE: Aberrant synkinetic movement after facial nerve injury can lead to prominent facial asymmetry and resultant psychological distress. The current practices of neuroinhibition to promote greater facial symmetry are often temporary in nature and require repeated procedures. OBJECTIVE: To determine whether myelin-associated glycoprotein (MAG), a specific neuroinhibitor, can prevent neuroregeneration with efficacy comparable with that of vincristine, a well-established neurotoxin. DESIGN, SETTING, AND PARTICIPANTS: Rats transgenic for Thy-1 cell surface antigen–green fluorescent protein (Thy1-Gfp) were randomized into 3 groups. Each rat received bilateral crush axotomy injuries to the buccal and marginal mandibular branches of the facial nerves. The animals received intraneural injection of saline, MAG, or vincristine. MAIN OUTCOMES AND MEASURES: The animals were imaged via fluorescent microscopy at weeks 1, 3, 4, and 5 after surgery. Quantitative fluorescent data were generated as mean intensities of nerve segments proximal and distal to the axotomy site. Electrophysiological analysis, via measurement of compound muscle action potentials, was performed at weeks 0, 3, 4, and 5 after surgery. RESULTS: A total of 12 rats were included in the study. Administration of MAG significantly reduced fluorescent intensity of the distal nerve in comparison with the control group at week 3 (mean [SD], MAG group: 94 [11] intensity units vs control group: 130 [11] intensity units; P

In this study, we assessed the modifications over time of daily activities and quality of life (QoL) in 32 subjects with anti-myelin-glycoprotein (MAG) antibody neuropathy. A widespread panel including clinical scores and patient-reported questionnaires, in compliance of the terms by the International Classification of Functioning, Disability, and Health (ICF) of the World Health Organization (WHO), was employed at enrollment (T0) and at follow-up evaluation (T1) after a mean interval of 15.4 ± 5.7 months. The Sensory Modality Sum score (SMS) at four limbs showed a significant worsening over time (mean score 27.2 ± 3.9 at T0 vs 25.7 ± 3 at T1 at upper limbs, P = .03; 20.5 ± 4.8 at T0 vs 18.6 ± 5.9 at T1 at lower limbs, P = .04). The Visual Analogue Scale (VAS) for pain significantly worsened at upper limbs at T1 (mean values 0.84 ± 1.95 at T0 vs 1.78 ± 2.6 at T1, P = .03). All the other tests did not show significant differences between T0 and T1. In the subgroup who underwent rituximab (15/32 treated before T0, 3/32 patients treated between T0 and T1 with median interval of 1 year), no significant differences were observed between T0 and T1. Despite the quite long follow-up, statistical significance was not achieved either for the limited number of patients or for the lack of sensitive outcome measures. In our cohort, the significant worsening of the SMS and VAS after a median of 14 months can be considered as a reliable expression of the natural history of the disease, and suggest that these scales might represent possible outcome measures in anti-MAG antibody neuropathy.

Dysimmune neuropathies are heterogeneous group of acquired immune-mediated diseases, accompanied by damage to the peripheral nervous system. As a standard therapy, prednisolone and intravenous immunoglobulins are used. Also encouraging efficacy is demonstrated by the use of a genetically engineered chimeric monoclonal antibody to the CD20 antigen found on the surface of normal and malignant B-cells – rituximab. Rituximab shows encouraging results. We reviewed the use of rituximab for dysimmune polyneuropathies and described our experience in administration of Lewis–Sumner syndrome and myelin-associated glycoprotein related neuropathy with rituximab.

In peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG), an IgM monoclonal gammopathy recognizes a specific epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several components of the peripheral nerve myelin. Recently an ELISA test has been developed to detect antibodies against HNK1 epitope. Objectives were to determine the usefulness of this assay in the management of anti-MAG neuropathy. Anti-HNK1 antibodies were assessed with the GanglioCombi™ MAG ELISA test (Buhlmann) in 41 anti-MAG neuropathies and in 118 controls: 34 chronic inflammatory demyelinating polyradiculoneuropathies, 3 Miller Fisher syndromes, 12 sensory neuronopathies, 63 length-dependent axonal sensory polyneuropathies, 6 healthy controls. Anti-HNK1 antibody was tested before and 1 year after rituximab therapy in seven patients with anti-MAG neuropathy. Anti-HNK1 antibodies were positive in 40/41 anti-MAG neuropathies, and in 1/118 controls (sensitivity 98%, specificity 99%). Only considering controls with IgM paraprotein, specificity was 96% (23/24). In anti-MAG neuropathies, anti-HNK1 titre was correlated with sensory deficiency evaluated with the INCAT sensory sum score (r = 0.4, p = 0.01) and with disability evaluated with the Rasch-built Overall Disability Scale (r = $$-$$ 0.4, p = 0.01) and Overall Neuropathy Limitation Scale (r = 0.4, p = 0.02). Anti-HNK1 titres were not related to age, disease duration, atypical clinical features and anti-MAG antibodies titres. Anti-MAG titres were not associated with disease severity. Anti-HNK1 titres were decreased by 18% 1 year after rituximab treatment. Anti-HNK1 antibodies have good sensitivity and specificity for the diagnosis of anti-MAG neuropathy. Interestingly, anti-HNK1 titres are related to the disease severity and decrease after rituximab infusions.

The role played by progestogens in modulating Schwann cell pathophysiology is well established. Progestogens exert their effects in these cells through both classical genomic and non-genomic mechanisms, the latter mediated by the GABA-A receptor. However, there is evidence that other receptors may be involved. Membrane progesterone receptors (mPRs) are novel 7-transmembrane receptors coupled to G proteins that have been characterized in different tissues and cells, including the central nervous system (CNS). The mPRs were shown to mediate some of progestogens’ neuroprotective effects in the CNS, and to be upregulated in glial cells after traumatic brain injury. Based on this evidence, this paper investigated the possible involvement of mPRs in mediating progestogen actions in S42 Schwann cells. All five mPR isoforms and progesterone receptor membrane component 1 (PGRMC1) were detected in Schwann cells, and were present on the cell membrane. Progesterone and the mPR-specific agonist, Org-OD-02-0 (02) bound to these membranes, indicating the presence of functional mPRs. The mPR agonist 02 rapidly increased cell migration in an in vitro assay, suggesting a putative role of mPRs in the nerve regeneration process. Treatment with pertussis toxin and 8-Br-cAMP blocked 02-induced cell migration, suggesting this progestogen action is mediated by activation of an inhibitory G protein, leading to a decrease in intracellular cAMP levels. In contrast, long-term mPR activation led to increased expression levels of myelin associated glycoprotein (MAG). Taken together, these findings show that mPRs are present and active in Schwann cells and have a role in modulating their physiological processes.

Brain injuries in multiple sclerosis (MS) involve immunopathological, structural and metabolic defects on myelin sheath, oligodendrocytes (OLs), axons and neurons suggesting that different cellular mechanisms ultimately result in the formation of MS plaques, demyelination, inflammation and brain damage. Bioenergetics, oxygen and ion metabolism dominate the metabolic and biochemical pathways that maintain neuronal viability and impulse transmission which directly or indirectly point to mitochondrial integrity and adenosine triphosphate (ATP) availability indicating the involvement of mitochondria in the pathogenesis of MS. Loss of myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoproetin (MOG), 2, 3,-cyclic nucleotide phosphodiestarase (CNPase); microglia and microphage activation, oligodendrocyte apoptosis as well as expression of inducible nitric oxide synthase (i-NOS) and myeloperoxidase activities have been implicated in a subset of Balo's type and relapsing remitting MS (RRMS) lesions indicating the involvement of metabolic defects and oxidative stress in MS. Here, we provide an insighting review of defects in cellular metabolism including energy, oxygen and metal metabolism in MS as well as the relevance of animal models of MS in understanding the molecular, biochemical and cellular mechanisms of MS pathogenesis. Additionally, we also discussed the potential for mitochondrial targets and antioxidant protection for therapeutic benefits in MS.

Introduction Polyneuropathy with immunoglobulin M monoclonal gammopathy (IgM-PNP) is associated with the presence of IgM antibodies against nerve constituents such as myelin associated glycoprotein (MAG) and gangliosides. Methods To test whether B-cell-stimulating cytokines are increased in IgM-PNP, we measured serum concentrations of 11 cytokines in 81 patients with IgM-PNP and 113 controls. Results Median interleukin (IL)-6 concentrations were higher in patients with IgM-PNP, and median IL-10 concentrations were higher in the subgroup with anti-MAG IgM antibodies. These serum concentrations were not increased in 110 patients with multifocal motor neuropathy. Discussion Median IL-6 and IL-10 serum concentrations differ between patients with anti-MAG neuropathy and other patients with IgM-PNP compared with healthy and neuropathy controls. These differences may indicate differences in immune-mediated disease mechanisms. Muscle Nerve 59:694-698, 2019.

Adult, circuit-integrated neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions. ispartof: CURRENT OPINION IN NEUROBIOLOGY vol:53 pages:162-173 ispartof: location:England status: published

Regeneration is bungled following CNS injuries, including spinal cord injury (SCI). Inherent decay of permissive conditions restricts the regrowth of the mature CNS after an injury. Hypertrophic scarring, insignificant intrinsic axon-growth activity, and axon-growth inhibitory molecules such as myelin inhibitors and scar inhibitors constitute a significant hindrance to spinal cord repair. Besides these molecules, a combined absence of various mechanisms responsible for axonal regeneration is the main reason behind the dereliction of the adult CNS to regenerate. The neutralization of specific inhibitors/proteins by stymieing antibodies or encouraging enzymatic degradation results in improved axon regeneration. Previous efforts to induce regeneration after SCI have stimulated axonal development in or near lesion sites, but not beyond them. Several pathways are responsible for the axonal growth obstruction after a CNS injury, including SCI. Herein, we summarize the axonal, glial, and intrinsic factor which impedes the regeneration. We have also discussed the methods to stabilize microtubules and through this to maintain the proper cytoskeletal dynamics of growth cone as disorganized microtubules lead to the failure of axonal regeneration. Moreover, we primarily focus on diverse inhibitors of axonal growth and molecular approaches to counteract them and their downstream intracellular signaling through the RhoA/ROCK pathway.

Multifocal motor neuropathy with conduction block (MMN) and anti-myelin-associated glycoprotein (MAG) neuropathy are rare chronic acquired demyelinating neuropathies with distinct clinical and electrophysiological characteristics. These neuropathies are generally not known to coexist. This report describes a patient with long-standing MMN who subsequently developed clinical features of anti-MAG neuropathy. This suggests that subtypes of chronic inflammatory neuropathies may not be sharply defined. In addition, a presentation of MMN with anti-MAG titers may be a prognostic indicator of poor response to standard MMN treatment.

Myelin oligodendrocyte glycoprotein is a transmembrane protein found on the outer lamella of the myelin sheath. The autoimmune attack on the MOG leads to demyelination which differs from normal multiple sclerosis. MOG has three epitope regions MOG1–22, MOG35–55, and MOG92–106 in the extracellular region, and the crucial MOG35–55 epitope and Human Leukocyte Antigen (HLA) interaction is the initial step for autoantibody generation. To study the effective role of glycosylation in MOG-HLA interaction, we performed molecular dynamics simulations of the complex where HLA interacts with three MOG epitopes both in the absence and presence of glycan. The results projected that the epitope MOG1–22 is decisive for the HLA interaction in the absence of glycan and HLA interacts with the epitope MOG35–55 irrespective of glycan existence. The residues Arg9, Arg46, and Arg66 were found to interact strongly with HLA even in the presence of glycan. The glycan increased the flexibility of hMOG and enhanced the interaction of MOG with water molecules. Communicated by Ramaswamy H. Sarma

Taking into account the possibility of myelin-associated proteins having a role in brain tumour development, the study aimed to evaluate the diagnostic usefulness of myelin-associated proteins (Nogo-A, MAG, OMgp) released into extracellular space in patients with brain tumours. Protein concentration in primary brain tumour (n = 49) and non-tumoural subjects (n = 24) was measured in cerebrospinal fluid (CSF) and serum by means of ELISA. Immunohistochemistry for IDH1-R132H was done on 5-μm thick formalin-fixed, paraffin-embedded tumour sections with the use of an antibody specific for the mutant IDH1-R132H protein. The receiver operator characteristic curve analysis showed that CSF Nogo-A and serum MAG were useful in differentiating patients with primary brain tumour from non-tumoural individuals. This was also true in the case of the separate analysis of the astrocytic tumour versus non-tumoural groups and the meningeal tumour versus non-tumoural groups. Neither Nogo-A nor MAG or OMgp concentrations were significantly different, in serum or CSF, between IDH1 wild-type astrocytic brain tumour patients compared to IDH1 mutant patients. Our results indicated the potential usefulness of CSF Nogo-A and serum MAG evaluation as circulating biomarkers of primary brain tumours. Because blood is relatively easy to obtain, future research should be conducted to explicitly indicate the value of serum MAG concentration evaluation as a brain tumour biomarker.Key messagesMyelin-associated proteins may be circulating brain tumour biomarkers.Nogo-A and MAG proteins seem to be the most useful in brain tumour diagnosis.Decreased CSF Nogo-A concentration is an adverse prognostic factor for patients’ survival. Myelin-associated proteins may be circulating brain tumour biomarkers. Nogo-A and MAG proteins seem to be the most useful in brain tumour diagnosis. Decreased CSF Nogo-A concentration is an adverse prognostic factor for patients’ survival.

To emphasize physio-pathological, clinical and prognosis differences between conditions causing serious and sometimes very similar clinical manifestations: anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies related diseases, and seronegative NMOSD (neuromyelitis optica spectrum disorders).Based on Wingerchuk et al. (Neurology 85:177-189, 2015) criteria for NMOSD and on those more recently proposed by Jarius et al. (J Neuroinflammation 15:134, 2018) for MOGAD (MOG associated disorders), we retrospectively surveyed 10 AQP4-NMOSD, 8 MOGAD and 2 seronegative NMOSD, followed at the specialized neuroimmunology unit of the CHU Liège.Female predominance was only observed in AQP4 group. Age at onset was 37.8 and 27.7 years old for AQP4-NMOSD and MOGAD respectively. In both groups, the first clinical event most often consisted of optic neuritis (ON), followed by isolated myelitis. Fifteen of our 20 patients encountered a relapsing course with 90% relapses in AQP4-NMOSD, 62.5% in MOGAD and 50% in seronegative group, and a mean period between first and second clinical event of 7.1 and 4.8 months for AQP4-NMOSD and MOGAD, respectively. In total we counted 54 ON, with more ON per patient in MOGAD. MOG-associated ON mainly affected the anterior part of the optic nerve with a papilledema in 79.2% of cases. Despite a fairly good visual outcome after MOG-associated ON, retinal nerve fibre layer (RNFL) thickness decreased, suggesting a fragility of the optic nerve toward further attacks.As observed in larger cohorts, our MOGAD and AQP4-NMOSD cases differ by clinical and prognostic features. A better understanding of these diseases should encourage prompt biological screening and hasten proper diagnosis and treatment.

BackgroundCerebrospinal fluid (CSF) albumincytologic dissociation represents a supportive diagnostic criterion of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).Few studies have investigated possible systemic or intrathecal humoral immune response activation in CIDP.Aim of our study was to investigate whether the search of oligoclonal IgG bands (OCBs) might provide additional data helpful in CIDP diagnostic work-up.MethodsForty-eight consecutive patients with CIDP (34 men, mean age 59.4, range 16–83) were recruited. CSF analysis included nephelometric measurement of albumin and IgG concentrations, calculation of QALB, QAlbLIM and intrathecal IgG synthesis, and OCBs detection with isoelectric focusing. Data were compared with those from CSF and serum of 32 patients with Guillain-Barré syndrome (GBS), 18 patients with anti-myelin associated glycoprotein (MAG) antibody neuropathy, 4 patients with multifocal motor neuropathy and 32 patients with non-inflammatory neuropathies (NINPs).ResultsPatients with CIDP and anti-MAG antibody neuropathy had significantly higher CSF albumin concentrations and QALB values than NINPs (p=0.0003 and p=0.0095, respectively). A total of 9 (19%) patients with CIDP presented identical serum and CSF OCBs (‘mirror pattern’) versus 3 patients (16.6%) with anti-MAG antibody neuropathy, 13 patients (40.6%) with GBS and 12.5% patients with NINPs. Only one patient with CIDP showed unique-to-CSF OCBs. First-line therapy was effective in 80.4% of patients with CIDP, irrespective of CSF findings.ConclusionsCompared with NINP, CIDP, GBS and anti-MAG antibody neuropathies had a significantly increased CSF protein and blood–spinal nerve root barrier damage. Intrathecal humoral immune response is rare in our patients with CIDP. Systemic oligoclonal activation is more frequent, but not significantly different from what was detected in the control groups.

Myelin-associated glycoprotein (MAG) is a key molecule involved in the nurturing effect of myelin on ensheathed axons. MAG also inhibits axon outgrowth after injury. In preclinical stroke models, administration of a function-blocking anti-MAG monoclonal antibody (mAb) aimed to improve axon regeneration demonstrated reduced lesion volumes and a rapid clinical improvement, suggesting a mechanism of immediate neuroprotection rather than enhanced axon regeneration. In addition, it has been reported that antibody-mediated crosslinking of MAG can protect oligodendrocytes (OLs) against glutamate (Glu) overload by unknown mechanisms.To unravel the molecular mechanisms underlying the protective effect of anti-MAG therapy with a focus on neuroprotection against Glu toxicity.MAG activation (via antibody crosslinking) triggered the clearance of extracellular Glu by its uptake into OLs via high affinity excitatory amino acid transporters. This resulted not only in protection of OLs but also nearby neurons. MAG activation led to a PKC-dependent activation of factor Nrf2 (nuclear-erythroid related factor-2) leading to antioxidant responses including increased mRNA expression of metabolic enzymes from the glutathione biosynthetic pathway and the regulatory chain of cystine/Glu antiporter system xcMAG activation triggers Glu uptake into OLs under conditions of Glu overload and induces a robust protective antioxidant response.

Background and purpose Polyneuropathies associated with monoclonal gammopathy of undetermined significance (MGUS) encompass a group of phenotypically and immunologically heterogeneous neuropathies. While the best characterized is that associated with anti-myelin glycoprotein (MAG) antibodies, there are phenotypical and immunological neuropathy variants that still lack a clear classification. We analyzed a significant number of patients, in order to better evaluate the distribution of neuropathy phenotypes and to look for some common characteristics. Methods Clinical, neurophysiological, and laboratory data from 87 consecutive MGUS patients with peripheral neuropathy were analyzed and compared among patient groups with different MGUS classes and autoantibody reactivity. Results Anti-MAG neuropathy cases account for the most homogeneous group with regard to clinical and neurophysiological findings. Patients with anti-gangliosides or sulfatide (GS) antibodies, despite a marked phenotype heterogeneity, still share several common features, including a younger age at diagnosis, a more severe disease, and a prompt and sustained response to both immunoglobulin and rituximab therapies, mostly requiring chronic administration of immune treatment. Conclusions Although heterogeneous, MGUS-associated, anti-GS antibody positive neuropathies have important similar features possibly resulting from a similar biological background.

Introduction A distal-predominant demyelinating symmetric pattern is most frequent in patients with neuropathy associated with anti-myelin-associated glycoprotein (MAG) antibodies. The literature however lacks longitudinal data to describe whether this is consistent over time. Methods From the Ottawa Neuromuscular Center database, we identified 23 patients with both IgM gammopathy and anti-MAG antibodies. For median, ulnar and fibular motor conduction studies, we analyzed distal latency and amplitude, negative peak duration, terminal latency index and conduction velocity. For median, ulnar, sural and superficial fibular sensory conduction studies we analyzed distal latency and amplitude. Results were compared for the earliest and the latest data sets. Results The mean time interval between the two assessment points was 6.5 years. Median and ulnar motor nerve conduction studies did not show a significant change for any of the parameters tested. There was disproportionate prolongation of median distal motor latency and reduction in terminal latency index, compared to the ulnar nerve. Deep fibular motor conduction studies showed a marked reduction in amplitudes over time. Sensory potentials were recordable in the upper limb in less than 50% at the first study and less than 25% on the most recent study. There was an even larger attrition of recordable sural and superficial fibular sensory potentials. Discussion Our results highlight the stability of median and ulnar motor conduction study results over a mean observation period of 6.5 years. In contrast, lower limb motor and all sensory potentials show a marked trend towards becoming unrecordable.

BACKGROUND: Long-term alcohol consumption has been linked to structural and functional brain abnormalities. Furthermore, with persistent exposure to ethanol (EtOH), nutrient deficiencies often develop. Thiamine deficiency is a key contributor to alcohol-related brain damage and is suspected to contribute to white matter pathology. The expression of genes encoding myelin proteins in several cortical brain regions is altered with EtOH exposure. However, there is limited research regarding the impact of thiamine deficiency on myelin dysfunction. METHODS: A rat model was used to assess the impact of moderate chronic EtOH exposure (CET; 20% EtOH in drinking water for one or six months), pyrithiamine-induced thiamine deficiency treatment (PTD), both conditions combined (CET-PTD), or CET with thiamine injections (CET+T) on myelin-related gene expression (Olig1, Olig2, MBP, MAG, and MOG) in the frontal and parietal cortices and the cerebellum. RESULTS: The CET-PTD treatments caused the greatest suppression in myelin-related genes in the cortex. Specifically, the parietal cortex was the region that was most susceptible cortical to PTD-CET-induced alterations in myelin-related genes. In addition, PTD treatment, with and without CET, caused minor fluctuations in the expression of several myelin-related genes in the frontal cortex. In contrast, CET alone and PTD alone suppressed several myelin-related genes in the cerebellum. Regardless of the region, there was significant recovery of myelin-related genes with extended abstinence and/or thiamine restoration. CONCLUSION: Moderate chronic EtOH alone had a minor effect on the suppression of myelin-related genes in the cortex; however, when combined with thiamine deficiency, the reduction was amplified. There was a suppression of myelin-related genes following long-term EtOH and thiamine deficiency in the cerebellum. However, the suppression in the myelin-related genes mostly occurred 24-h after EtOH removal or following thiamine restoration; within three weeks of abstinence or thiamine recovery, gene expression rebounded.