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Background and purpose: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross‐sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. Methods: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3‐T MRI to assess global and compartmental normalized brain volumes, T2‐lesion load, and cortical mean thickness. Follow‐up data and serum samples were available in 144 pwMS (median follow‐up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age‐corrected sNfL z‐scores from a normative database of healthy controls were used for sensitivity analyses. Results: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient βj = −0.352, p < 0.001), white matter (βj = −0.229, p = 0.007), thalamus (βj = −0.372, p = 0.004), and putamen (βj = −1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow‐up had a greater risk of EDSS worsening (p = 0.007). Conclusions: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short‐term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG)‐antibody (Ab)–associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse‐onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021;90:976–982 [ABSTRACT FROM AUTHOR]

The authors' differential diagnosis included MOGAD, but myelin oligodendrocyte glycoprotein-IgG (MOG-IgG) was negative (tested in 2/3), however, crucial information regarding the timepoint and method are lacking. Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: international MOGAD panel proposed criteria. With great interest, we read the article by Money et al. reporting 3 cases of monkeypox virus disease (MPXV) associated central nervous system (CNS) disease which raised the question if this reflects a para-infectious injury or a viral invasion of the CNS.[1] The reported cases strikingly resemble antibody-mediated CNS myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) in many aspects[2]: (1) patients presented with typical phenotypes, including prodromal phases with fever and myalgia followed by acute disseminated encephalomyelitis (ADEM), longitudinally extensive transverse myelitis (LETM), or encephalopathy with seizures, (2) cerebrospinal fluid (CSF) pleocytosis, (3) prompt treatment response to plasma exchange only, and (4) almost complete clinical and radiographic recovery. [Extracted from the article]

We agree that further studies in larger and immunotherapy-naïve cohorts of patients are clearly needed to better assess complement activation profiles in patients with NMOSD. These control groups included demographically matched and immunotherapy-naïve patients with relapse-onset multiple sclerosis, demographically matched and immunotherapy-naïve pediatric patients, demographically matched healthy controls, and an additional smaller group of patients with aquaporin 4 (AQP4)-immunoglobulin G (IgG)-seropositive neuromyelitis optica spectrum disorder (NMOSD). For the latter, we used samples available at our institution that were predominantly derived from patients after initiation of immunotherapy (3/13 patients were immunotherapy-naïve, 10/13 patients received rituximab or cyclophosphamide). [Extracted from the article]

Objective: To report the clinical, radiological, and immunological association of demyelinating disorders with anti–Nmethyl- D-aspartate receptor (NMDAR) encephalitis.Methods: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays.Results: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011).Interpretation: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis. [ABSTRACT FROM AUTHOR]

Background: Friedreich ataxia is an autosomal recessive disorder caused by mutations in the frataxin gene, leading to reduced levels of the mitochondrial protein frataxin. Assays to quantitatively measure frataxin in peripheral blood have been established. To determine the validity of frataxin as a biomarker for clinical trials, we assessed frataxin in clinically affected tissue. Methods: In 7 patients with Friedreich ataxia, frataxin content was measured in blood and skeletal muscle before and after treatment with recombinant human erythropoietin, applying the electrochemiluminescence immunoassay. Results: We found frataxin content to be correlated in peripheral blood mononuclear cells and skeletal muscle in drug-naive patients with Friedreich ataxia. The correlation of frataxin content in both compartments remained significant after 8 weeks of treatment. Skeletal-muscle frataxin values correlated with ataxia using the Scale for the Assessment and Rating of Ataxia score. Conclusions: Our results endorse frataxin measurements in peripheral blood cells as a valid biomarker in Friedreich ataxia. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective Severe inflammation and astrocyte loss with profound demyelination in spinal cord and optic nerves are typical pathological features of neuromyelitis optica (NMO). A diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin-4 (AQP-4) on astrocytes. Methods We induced acute T-cell-mediated experimental autoimmune encephalomyelitis in Lewis rats and confronted the animals with an additional application of immunoglobulins from AQP-4 antibody-positive and -negative NMO patients, multiple sclerosis patients, and control subjects. Results The immunoglobulins from AQP-4 antibody-positive NMO patients are pathogenic. When they reach serum titers in experimental animals comparable with those seen in NMO patients, they augment clinical disease and induce lesions in the central nervous system that are similar in structure and distribution to those seen in NMO patients, consisting of AQP-4 and astrocyte loss, granulocytic infiltrates, T cells and activated macrophages/microglia cells, and an extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans. AQP-4 antibody containing NMO immunoglobulin injected into naïve rats, young rats with leaky blood-brain barrier, or after transfer of a nonencephalitogenic T-cell line did not induce disease or neuropathological alterations in the central nervous system. Absorption of NMO immunoglobulins with AQP-4-transfected cells, but not with mock-transfected control cells, reduced the AQP-4 antibody titers and was associated with a reduction of astrocyte pathology after transfer. Interpretation Human anti-AQP-4 antibodies are not only important in the diagnosis of NMO but also augment disease and induce NMO-like lesions in animals with T-cell-mediated brain inflammation. Ann Neurol 2009;66:630-643 [ABSTRACT FROM AUTHOR]

The role of microglial activation in multiple system atrophy (MSA) was investigated in a transgenic mouse model featuring oligodendroglial alpha-synuclein inclusions and loss of midbrain dopaminergic neurons by means of histopathology and morphometric analysis. Our findings demonstrate early progressive microglial activation in substantia nigra pars compacta (SNc) associated with increased expression of iNOS and correlating with dopaminergic neuronal loss. Suppression of microglial activation by early long-term minocycline treatment protected dopaminergic SNc neurons. The results suggest that oligodendroglial overexpression of alpha-synuclein may induce neuroinflammation related to nitrosive stress which is likely to contribute to neurodegeneration in MSA. Further, we detected increased toll-like receptor 4 immunoreactivity in both transgenic mice and MSA brains indicating a possible signaling pathway in MSA which needs to be further studied as a candidate target for neuroprotective interventions. [ABSTRACT FROM AUTHOR]

The Parkinson variant of multiple system atrophy (MSA-P) is a distinct atypical parkinsonian disorder with a loss of dopaminergic neurons comparable to that found in Parkinson's disease (PD). The additional loss of striatopallidal projections is thought to account for levodopa unresponsiveness in MSA-P. Whereas histological features of MSA-P have been successfully reproduced in the double lesion rat model, loss of levodopa responsiveness has so far not been demonstrated. In the current study, 6-hydroxydopamine (6-OHDA) induced unilateral lesions of the substantia nigra produced a marked contralateral forelimb stepping deficit, which improved significantly after challenge with levodopa (P < 0.001). This response was abolished by the subsequent striatal quinolinic acid (QA) lesion. In the cylinder test, the marked asymmetry observed after 6-OHDA lesioning was reversed by levodopa to baseline levels. After QA, cylinder test performance under levodopa failed to reach baseline (P = 0.001) or 6-OHDA + levodopa (P = 0.002) levels. Nigral cell loss (90% +/- 5%) correlated with both stepping test (r = 0.608; P = 0.008) and cylinder test results (r = 0.656; P = 0.005). Lesion extent of the dorsal striatum correlated significantly with the loss of levodopa response (r = 0.593; P = 0.01) in the stepping test. These findings contribute further to the behavioral characterization of the double lesion rat model of MSA, improving its value in the evaluation of future neurorestorative strategies. [ABSTRACT FROM AUTHOR]

α-Synuclein represents the major constituent of oligodendroglial cytoplasmic inclusions, the hallmark lesion of multiple system atrophy (MSA), a progressive disorder that is associated with selective degenerative cell loss in basal ganglia, cerebellum, brainstem, and spinal cord. The role of abnormal α-synuclein aggregation in oligodendroglial cells is still obscure, in particular, whether α-synuclein might impair oligodendroglial and, secondarily, neuronal integrity of those cells in the diseased brain. In an attempt to answer some of these questions, we have developed an 'in vitro model of MSA' by expressing the wild-type or C-terminally truncated form of α-synuclein in glial cell cultures. With this simplified system, we have demonstrated that α-synuclein significantly affects the survival of glia and its vulnerability to environmental stress, which might represent a major step in the pathogenesis of MSA. © 2005 Movement Disorder Society [ABSTRACT FROM AUTHOR]

We studied 38 patients with malaria tropica over a period of 5 days during antiparasitic therapy. Serum or plasma levels of interleukin (IL) 1β, IL-6, IL-10, tumour necrosis factor-α (TNF-α), the soluble vascular adhesion molecule (sVCAM) and the soluble intracellular adhesion molecule (sICAM) were determined by enzyme-linked immunosorbent assay. Protein C and antithrombin III activity were analysed by chromogenic tests and protein S activity by a clotting test. Antithrombin III, protein C and protein S activity was significantly lower in patients with severe malaria and displayed a highly significant increase in activity over the time of evaluation. Levels of sVCAM and sICAM were increased for the whole study period, but no significant differences were found between severe and mild malaria cases. Serum IL-1β, IL-6 and IL-10 levels were significantly higher in patients with severe malaria, whereas no significant differences were found for TNF-α. IL-6 and IL-10 decreased significantly over 5 days during schizontocidal therapy. Our data show an impairment of the coagulation system which correlates with pro-inflammatory cytokines and therefore with the severity of the disease. [ABSTRACT FROM AUTHOR]

Using an antiserum of a patient with cutaneous manifestations of Lyme borreliosis we have isolated the germ encoding a 27 kDa protein antigen (P27) of Borrelia burgdorferi B29 from a λ-gt11 expression library. Nucleotide sequence analysis revealed that it is a basic protein of 248 amino acids with a typical prokaryotic leader sequence of 17 amino acid residues at the N-terminus of the proposed translation product. Biochemical investigations showed that P27 is a surface-exposed lipoprotein. From pulsed-field gel electrophoresis and subsequent Southern blot analysis it is evident that the p27 gene is located on a linear plasmid of a size of approximately 55 kb. It was over-expressed in Escherichia coli and the purified recombinant protein was used for biochemical and serological studies. Northern and Western blot analysis demonstrated that p27 is expressed in the European B. burgdorferi strain B29, but not in the American strain B31. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses research into the anti-αB-crystallin immunoreactivity in Guillain-Barré syndrome.

This commentary is on the original article by Hacohen et al. on pages 836–841 of this issue. [ABSTRACT FROM AUTHOR]