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Objective: Aquaporin-4-antibody-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder (MOGAD) are relapsing neuroinflammatory diseases, frequently leading to chronic pain. In both diseases, the spinal cord (SC) is often affected by myelitis attacks. We hypothesized that regional SC volumes differ between AQP4-IgG + NMOSD and MOGAD and that pain intensity is associated with lower SC volumes. To evaluate changes in the SC white matter (WM), gray matter (GM), and pain intensity in patients with recent relapses (myelitis or optic neuritis), we further profiled phenotypes in a case series with longitudinal imaging and clinical data. Methods: Cross-sectional data from 36 participants were analyzed in this retrospective study, including 20 AQP4-IgG + NMOSD and 16 MOGAD patients. Pain assessment was performed in all patients by the Brief Pain Inventory and painDETECT questionnaires. Segmentation of SC WM, GM, cervical cord volumes (combined volume of WM + GM) was performed at the C2/C3 cervical level. WM% and GM% were calculated using the cervical cord volume as a whole per patient. The presence of pain, pain severity, and clinical disability was evaluated and tested for associations with SC segmentations. Additionally, longitudinal data were deeply profiled in a case series of four patients with attacks between two MRI visits within one year. Results: In AQP4-IgG + NMOSD, cervical cord volume was associated with mean pain severity within 24 h (ß = -0.62, p = 0.009) and with daily life pain interference (ß = -0.56, p = 0.010). Cross-sectional analysis showed no statistically significant SC volume differences between AQP4-IgG + NMOSD and MOGAD. However, in AQP4-IgG + NMOSD, SC WM% tended to be lower with increasing time from the last attack (ß = -0.41, p = 0.096). This tendency was not observed in MOGAD. Our case series including two AQP4-IgG + NMOSD patients revealed SC GM% increased by roughly 2% with either a myelitis or optic neuritis attack between visits. Meanwhile, GM% decreased by 1-2% in two MOGAD patients with a myelitis attack between MRI visits. Conclusion: In AQP4-IgG + NMOSD, lower cervical cord volume was associated with increased pain. Furthermore, cord GM changes were detected between MRI visits in patients with disease-related attacks in both groups. Regional SC MRI measures are pertinent for monitoring disease-related cord pathology in AQP4-IgG + NMOSD and MOGAD.
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Susac syndrome (SuS) is an orphan microangiopathic disease characterized by a triad of encephalopathy, visual disturbances due to branch retinal artery occlusions, and sensorineuronal hearing loss. Our previous systematic review on all cases of SuS reported until 2012 allowed for a better understanding of clinical presentation and diagnostic findings. Based on these data, we suggested diagnostic criteria in 2016 to allow early diagnosis and treatment of SuS. In view of the accumulation of new SuS cases reported in the last 10 years and improved diagnostic tools, we here aimed at updating the demographic and clinical features of SuS and to review the updated ancillary tests being used for SuS diagnosis. Therefore, based on the 2016 criteria, we systematically collected and evaluated data on SuS published from January 2013 to March 2022.
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Síndrome de Susac , Síndrome de Susac/diagnóstico , HumanosRESUMO
Antiphospholipid syndrome (APS) affects the brain by both hypercoagulation and immunological mechanisms. APS is characterized by several autoantibodies binding to a thrombolytic complex including beta-2-glycoprotein I (ß2-GPI) and annexin A2 (ANXA2). Teriflunomide, an oral drug for the treatment of multiple sclerosis (MS), has a cytostatic effect on B cells and is therefore a potential antibody-targeting treatment for APS. In this study, we assessed the effect of teriflunomide in two APS mouse models by inducing autoantibody formation against ß2-GPI and ANXA2 in female BALB/c mice. The ANXA2 model displayed a behavioral change suggesting an anti-anxiety effect in open field and forced swim tests, early in the course of the disease. This effect was normalized following teriflunomide treatment. Conversely, behavioral tests done later during the study demonstrated depression-like behavior in the ANXA2 model. No behavioral changes were seen in the ß2-GPI model. Total brain IgG levels were significantly elevated in the ANXA2 model but not in the teriflunomide treated group. No such change was noted in the brains of the ß2-GPI model. High levels of serum autoantibodies were induced in both models, and their levels were not lowered by teriflunomide treatment. Teriflunomide ameliorated behavioral changes in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with the effect of teriflunomide on neuroinflammation.Teriflunomide ameliorated behavioral and brain IgG levels in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with an effect of teriflunomide on the IgG permeability to the brain and neuroinflammation.
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Ansiolíticos , Síndrome Antifosfolipídica , Lúpus Eritematoso Sistêmico , Animais , Anexinas , Síndrome Antifosfolipídica/complicações , Autoanticorpos , Crotonatos , Modelos Animais de Doenças , Feminino , Humanos , Hidroxibutiratos , Imunoglobulina G , Lúpus Eritematoso Sistêmico/complicações , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas , Toluidinas , beta 2-Glicoproteína IRESUMO
INTRODUCTION: Antiphospholipid syndrome (APS) is an autoimmune disorder manifested by thromboembolic events, recurrent spontaneous abortions and elevated titers of circulating antiphospholipid antibodies. In addition, the presence of antiphospholipid antibodies seems to confer a fivefold higher risk for stroke or transient ischemic attack. Although the major antigen of APS is ß2 glycoprotein I, it is now well established that antiphospholipid antibodies are heterogeneous and bind to various targets. Recently, antibodies to Annexin A2 (ANXA2) have been reported in APS. This is of special interest since data indicated ANXA2 as a key player in fibrinolysis. Therefore, in the present study we assessed whether anti-ANXA2 antibodies play a pathological role in thrombosis associated disease. MATERIALS AND METHODS: Mice were induced to produce anti-ANXA2 antibodies by immunization with ANXA2 (iANXA2) and control mice were immunized with adjuvant only. A middle cerebral artery occlusion stroke model was applied to the mice. The outcome of stroke severity was assessed and compared between the two groups. RESULTS: Our results indicate that antibodies to ANXA2 lead to a more severe stroke as demonstrated by a significant larger stroke infarct volume (iANXA2 133.9 ± 3.3 mm3 and control 113.7 ± 7.4 mm3; p = 0.017) and a more severe neurological outcome (iANXA2 2.2 ± 0.2, and control 1.5 ± 0.18; p = 0.03). CONCLUSIONS: This study supports the hypothesis that auto-antibodies to ANXA2 are an independent risk factor for cerebral thrombosis. Consequently, we propose screening for anti-ANXA2 antibodies should be more widely used and patients that exhibit the manifestations of APS should be closely monitored by physicians.
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Anexina A2/imunologia , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/imunologia , Trombose Intracraniana/metabolismo , Adulto , Animais , Anexina A2/administração & dosagem , Anexina A2/metabolismo , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/metabolismo , Autoanticorpos/metabolismo , Autoimunidade/imunologia , Modelos Animais de Doenças , Feminino , Fibrinólise/imunologia , Humanos , Infarto da Artéria Cerebral Média/imunologia , Infarto da Artéria Cerebral Média/fisiopatologia , Injeções Subcutâneas , Trombose Intracraniana/etiologia , Ataque Isquêmico Transitório/imunologia , Camundongos , Camundongos Endogâmicos BALB C/imunologia , Pessoa de Meia-Idade , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/imunologia , beta 2-Glicoproteína I/metabolismoRESUMO
Alemtuzumab is a monoclonal anti-CD52 antibody prescribed to treat relapsing-remitting multiple sclerosis (RRMS). Alemtuzumab affects the balance of the immune system by depleting circulating lymphocytes, leading to the formation of a new immune repertoire less likely to induce autoimmune attack against CNS myelin. We collected real-world data of RRMS patients treated with alemtuzumab. We assessed relapse rate, disability progression, and MRI-related disease activity over a 24 month period. Our study included 35 RRMS patients (19 female and 16 male) with a mean age of 37.3 years (SD = 10.5). The patient cohort had a mean disease duration of 10.4 years, median previous disease modifying treatments (DMTs) of 3.0, and a median expanded disability status scale (EDSS) score of 4.0 (IQR 2.5-6.0). Neurological disability remained stable during treatment and there was no statistically significant change in EDSS score. Prior to treatment, the median relapse rate was 2.0 (IQR 1.0-3.0); after treatment the median relapse rate was 0.0. This 2.0 decrease in relapse rate is statistically significant (p < 0.0001). Moreover, the treated patients exhibited a statistically significant decrease in gadolinium (GD) enhancing lesions on MRI [both in number (p < 0.005) and volume (p < 0.005)]. Thirty-three percent of patients reached NEDA-3 (no evidence of disease activity) status by the end of treatment. In a real-world setting, alemtuzumab treatment significantly decreased relapse rate and GD-enhancing lesions while preventing disability progression. Tolerability of treatment was high, with patients experiencing only minor adverse events.
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Alemtuzumab/uso terapêutico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Adulto , Alemtuzumab/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Urticária/induzido quimicamenteRESUMO
Neuroaxonal injury and loss result in the release of cytoskeleton components, including neurofilaments, into the cerebrospinal fluid and peripheral blood. Once released, neurofilaments are highly immunogenic, inducing a specific antibody response. Anti-neurofilament antibody levels correlate with the progression of diverse neurological diseases; however, their role both in the pathogenesis of disease and as a tool for monitoring disease progression is not well understood. This study reviews the current literature on anti-neurofilament antibodies. We suggest the testing of anti-neurofilament antibodies be further developed for diagnosis and targeted for treatment.
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Autoanticorpos/sangue , Doenças Neurodegenerativas/sangue , Proteínas de Neurofilamentos/sangue , Animais , Autoanticorpos/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Humanos , Filamentos Intermediários/imunologia , Filamentos Intermediários/metabolismo , Doenças Neurodegenerativas/imunologia , Proteínas de Neurofilamentos/imunologiaRESUMO
OBJECTIVE: Mutations in the glucocerebrosidase (GBA) gene are divided into mild and severe (mGBA, sGBA) based on their contribution to the phenotype of Gaucher disease (GD) among homozygotes. We conducted a longitudinal analysis of Parkinson's disease (PD) patients carrying mutations in the GBA gene to better characterize genotype-phenotype correlations. METHODS: Patients underwent a comprehensive assessment of medical, neurological, cognitive and non-motor functions. Data from these patients was explored to evaluate differences in disease phenotype based on genotype. RESULTS: A total of 355 PD patients participated in this study; 152 idiopathic PD patients, 139â¯mGBA, 48 sGBA and 16 GD-PD. Groups were similar in age, sex, years of education and age of onset. Both sGBA and GD-PD had higher Unified Parkinson Disease Rating Scale (UPDRS) scores (pâ¯=â¯0.041), higher frequencies of REM sleep behavior disorder (RBD) (pâ¯=â¯0.022) and hallucinations (pâ¯<â¯0.0001) compared to the other groups of patients. sGBA experienced more non-motor symptoms (pâ¯<â¯0.0001), depression (pâ¯<â¯0.001) and worse hyposmia (pâ¯=â¯0.010). Trail making test was significantly longer in GD-PD followed by sGBA, mGBA and iPD (pâ¯=â¯0.005). DISCUSSION: Motor, cognitive, olfactory and psychiatric symptoms are more severe in sGBA and GD-PD compared to mGBA and iPD, reinforcing the notion that the severity of the PD phenotype is related to the severity of the mutation in the GBA gene.
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Doença de Gaucher/complicações , Glucosilceramidase/genética , Mutação/genética , Doença de Parkinson/complicações , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Doença de Gaucher/genética , Estudos de Associação Genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/etiologia , Transtornos do Olfato/genética , Fenótipo , Transtorno do Comportamento do Sono REM/etiologia , Índice de Gravidade de DoençaRESUMO
Autophagy, a cellular degradation system, promotes both cell death and survival. The interaction between Bcl-2 family proteins and Beclin 1, a Bcl-2 interacting protein that promotes autophagy, can mediate crosstalk between autophagy and apoptosis. We investigated the interaction between anti-and pro-apoptotic Bcl-2 proteins with Beclin 1. Our results show that Beclin 1 directly interacts with Bcl-2, Bcl-x(L), Bcl-w and to a lesser extent with Mcl-1. Beclin 1 does not bind the pro-apoptotic Bcl-2 proteins. The interaction between Beclin 1 and the anti-apoptotic protein Bcl-x(L) was inhibited by BH3-only proteins, but not by multi-domain proteins. Sequence alignment and structural modeling suggest that Beclin 1 contains a putative BH3-like domain which may interact with the hydrophobic grove of Bcl-x(L). Mutation of the Beclin 1 amino acids predicted to mediate this interaction inhibited the association of Beclin 1 with Bcl-x(L). Our results suggest that BH3 only proapoptotic Bcl-2 proteins may modulate the interactions between Bcl-x(L) and Beclin 1.