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Abstract Background Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte–microglia interaction, which both contribute to evolution of NMOSD lesions. Main body Through transcriptomic and flow cytometry analyses, we found that Bruton’s tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes–microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. Conclusions Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.

Background Acute ischemic stroke is a major cause of mortality and disability worldwide, with approximately 7.4% to 7.7% recurrence within the first 3 months. This study aimed to identify potential biomarkers for predicting stroke recurrence. Methods and Results We conducted a nested case–control study using a hospital‐based cohort from the Third China National Stroke Registry selecting 214 age‐ and sex‐matched patients with ischemic stroke with hypertension and no history of diabetes or heart disease. Using data‐independent acquisition for discovery and multiple reaction monitoring for quantitative validation, we identified 26 differentially expressed proteins in large‐artery atherosclerosis (Causative Classification of Ischemic Stroke [CCS]1), 16 in small‐artery occlusion (CCS3), and 25 in undetermined causes (CCS5) among patients with recurrent stroke. In the CCS1 and CCS3 subgroups, differentially expressed proteins were associated with platelet aggregation, neuronal death/cerebroprotection, and immune response, whereas differentially expressed proteins in the CCS5 subgroup were linked to altered metabolic functions. Validated recurrence predictors included proteins associated with neutrophil activity and vascular inflammation (TAGLN2 [transgelin 2], ITGAM [integrin subunit α M]/TAGLN2 ratio, ITGAM/MYL9 [myosin light chain 9] ratio, TAGLN2/RSU1 [Ras suppressor protein 1] ratio) in the CCS3 subgroup and proteins associated with endothelial plasticity and blood–brain barrier integrity (ITGAM/MYL9 ratio and COL1A2 [collagen type I α 2 chain]/MYL9 ratio) in the CCS3 and CCS5 subgroups, respectively. Conclusions These findings provide a foundation for developing a blood‐based biomarker panel, using causative classifications, which may be used in routine clinical practice to predict stroke recurrence.

Abstract Background Plasma amyloid-β (Aβ) peptides and tau proteins are promising biomarkers of Alzheimer’s disease (AD), not only for predicting Aβ and tau pathology but also for differentiating AD from other neurodegenerative diseases. However, reference intervals for plasma biomarkers of AD in healthy elderly Chinese individuals have not yet been established. Methods Biomarkers of AD were measured using single-molecule array (Simoa) assays in plasma samples from 193 healthy, cognitively unimpaired Chinese individuals aged 50–89 years. The 95% reference intervals for plasma Aβ42, Aβ40, t-tau, p-tau181, and derived ratios were calculated by using log-transformed parametric methods. Results Plasma Aβ42, Aβ40, and p-tau181 levels were positively correlated with age, while the Aβ42/Aβ40 ratio was negatively correlated with age. The 95% reference intervals for plasma Aβ42 and Aβ40 were 2.72–11.09 pg/mL and 61.4–303.9 pg/mL, respectively, and the 95% reference intervals for plasma t-tau and p-tau181 were 0.20–3.12 pg/mL and 0.49–3.29 pg/mL, respectively. The 95% reference intervals for the Aβ42/Aβ40 ratio, p-tau181/t-tau ratio, and p-tau181/Aβ42 ratio were 0.022–0.064, 0.38–6.34, and 0.05–0.55, respectively. Conclusion Reference intervals for plasma biomarkers of AD may assist clinicians in making accurate clinical decisions.

Microglia are first responders to acute brain insults and initiate neuroinflammation to drive secondary tissue injury. Yet the key molecular switches in control of the inflammatory activity of microglia remain poorly understood. Intracerebral hemorrhage (ICH) is a devastating stroke subtype whereby a hematoma is formed within the brain parenchyma and associated with high mortality. Using a mouse model of ICH, we found upregulation of CD22 that predominantly occurred in microglia. Antibody blockade of CD22 led to a reduction in neurological deficits, brain lesion and hematoma volume. This was accompanied by reduced inflammatory activity, increased expression of alternative activation markers (CD206 and IL-10) and enhanced phagocytosis activity in microglia after ICH. CD22 blockade also led to an increase of phosphorylated SYK and AKT after ICH. Notably, the benefits of CD22 blockade were ablated in ICH mice subjected to microglial depletion with a colony-stimulating factor 1 receptor inhibitor PLX5622. Additionally, the protective effects of CD22 blockade was diminished in ICH mice receiving a SYK inhibitor R406. Together, our findings highlight CD22 as a key molecular switch to control the detrimental effects of microglia after acute brain injury, and provide a novel strategy to improve the outcome of ICH injury.

Summary: Background: Laboratory determination of autoantibodies against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) and other autoantigens have been integrated into the diagnosis of myasthenia gravis (MG). However, evidence supporting the selection of methodologies is lacking. Methods: In this prospective, multicentre cohort study, we recruited patients with suspected MG to evaluate the diagnostic accuracy of cell-based assay (CBA), radioimmunoprecipitation assay (RIPA) and enzyme-linked immunosorbent assay (ELISA) in detecting AChR and MuSK autoantibodies. This study is registered with www.clinicaltrials.gov, number NCT05219097. Findings: 2272 eligible participants were recruited, including 2043 MG, 229 non-MG subjects. AChR antibodies were detected in 1478, 1310, and 1280 out of a total of 2043 MG patients by CBA, RIPA, and ELISA, respectively; sensitivity, 72.3% (95% CI, 70.3–74.3), 64.1% (95% CI, 62.0–66.2), 62.7% (95% CI, 60.5–64.8); specificity, 97.8% (95% CI, 95.0–99.3), 97.8% (95% CI, 95.0–99.3), 94.8% (95% CI, 91.9–97.7). MuSK antibodies were found in 59, 50, and 54 from 2043 MG patients by CBA, RIPA and ELISA, respectively; sensitivity, 2.9% (95% CI, 2.2–3.7), 2.4% (95% CI, 1.8–3.2), 2.6% (95% CI, 2.0–3.4); specificity, 100% (95% CI, 98.4–100), 100% (95% CI, 98.4–100), and 99.1% (95% CI, 96.9–99.9). The area under the curve of AChR antibodies tested by CBA was 0.858, and there were statistical differences with RIPA (0.843; p = 0.03) and ELISA (0.809; p

Dimethyl fumarate (DMF) is a widely used oral disease-modifying therapy for multiple sclerosis (MS). Its efficacy and safety profiles are supported by over a decade of experience. Differences exist between Asia and Europe/United States in the prevalence and characteristics of MS; most data for DMF are derived from populations outside Asia. DMF was recently (2021) approved for use in China. The objectives of this review were to evaluate the evidence for DMF’s profile, to provide an update to healthcare providers on current knowledge surrounding its use and to assess the relevance of existing data to use in China. This study used a modified Delphi method based on the insights of a scientific Steering Committee (SC), with a structured literature review conducted to assess the data of DMF. The literature review covered all papers in English (from 01 January 2011 to 21 February 2022) that include ‘dimethyl fumarate’ and ‘multiple sclerosis’, and their MeSH terms, on PubMed, supplemented by EMBASE and Citeline searches. Papers were categorized by topic and assessed for relevance and quality, before being used to formulate statements summarizing the literature on each subject. SC members voted on/revised statements, requiring ⩾80% agreement and ⩽10% disagreement for inclusion. Statements not reaching this level were discussed further until agreement was reached or until there was agreement to remove the statement. A total of 1030 papers were retrieved and used to formulate the statements and evidence summaries considered by the SC members. A total of 45 statements were agreed by the SC members. The findings support the positive efficacy and safety profile of DMF in treating patients with MS. Limited Chinese patient data are an ongoing consideration; however, based on current evidence, the statements are considered applicable to both the global and Chinese populations. DMF is a valuable addition to address unmet MS treatment needs in China. Registration: Not applicable

Abstract Background Antibodies against myelin-oligodendrocyte-glycoprotein (MOG-Abs) associated disease (MOGAD) has been recognized as a disease entity. Optic neuritis (ON) is the most common symptom in MOGAD. To demonstrate the differences in retinal microvascular characteristics between patients with MOGAD-ON and aquaporin-4 antibody (AQP4-Ab) positive ON. Methods In a prospective study, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) were used to measure retinal and microvascular parameters. Results Twenty-six MOGAD-ON eyes, 40 AQP4-ON eyes, and 60 control eyes were included in the study. The thickness of RNFL and GCC in MOGAD-ON eyes was significantly lower than that of HC (p

Abstract Background Brain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke. Methods Using a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia. Results We observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice. Conclusions These findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.

Human brain bank is the foundation for neurology and neuroscience, which provides research materials for medical scientists to explore what happen in human brains. Through voluntary postmortem brain tissue donation, brain bank collects, classifies, stores and distributes brain tissue samples for researchers with appropriate research proposals, so as to facilitate researchers to conduct human brain research. History showed that the act of brain only autopsy distinguished neurology as a distinct discipline. The emerges of brain banking accompanied with the advances of neurology and neuroscience. It facilitates the development of neurology from neuropathological examination feedback about the clinical presentations of the brain donor, plays an important role in the definition of novel neurological diseases, and also makes an extraordinary contribution to the disease mechanisms and novel therapeutic discoveries. This manuscript elaborated the history, current situation, and the impacts of human brain banking on current neurology. Furthermore, we discussed about the opportunities and challenges of brain banking in China. DOI:10.3969/j.issn.1672⁃6731.2020.10.012

Summary: Background: Guillain-Barré syndrome (GBS) is the most prevalent acute autoimmune polyneuropathy, however, the incidence of GBS across China remains undetermined. We conducted the first nationwide study to extrapolate the incidence and mortality rates of GBS across all age groups at a national scale. Methods: This study analyzed patient metrics from the National Hospital Quality Monitoring System, a comprehensive administrative database of which incorporate all 1665 tertiary hospitals in mainland China. For all study patients the “Medical Record Homepage” encompasses 346 distinct variables such as demographic characteristics, diagnoses, procedures, expenses, etc., that are systematically recorded from these hospitals by standard protocol. All GBS diagnoses adhered to the National Institute of Neurologic and Communicative Disorders and Stroke (NINCDS) diagnostic criteria and were identified with ICD-10 code (G61•0). Findings: From 2016 to 2019, 75,548 hospital admissions for 38,861 GBS patients were identified. The age- and sex-adjusted incidence per 100,000 person-years is 0·698 (95% confidence interval [CI], 0·691-0·705), 0·233(0·225-0·242) in children and 0·829(0·820-0·837) in adults. The male-to-female ratio is 1·49. Peak disease onset was detected in the 70–74 years age group with an incidence of 1·806/100, 000 (95% CI, 1·741-1·870). Recognizable GBS distribution patterns were recognized in the southeastern coastal areas, where the cases of GBS were concentrated in the summer and autumn seasons. Prevalent comorbidities include hypertension (28·8%) and stroke (14·3%). The median length of hospitalization was 13·0 (8·0–18·0) days with a median hospitalization cost of $2371·60 ($1281·80–5463·60). Covering 69·9% of study patients, the Basic Medical Insurance was the most common payment mechanism. From 2016-2019, 426 adults and 13 children died in this study pool, with a hospital mortality rate of 11·2 per 1,000 person-years. Interpretation: For the first time, we obtained a national incidence for GBS at 0·233 in children and 0·829 in adults per 100,000 in China. A differential spatiotemporal incidence is presented most southeast coastal areas in the summer and autumn seasons. Funding: National Science Foundation of China (91949208, 91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing.

Background: Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood. Objective: To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD. Methods: pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab ( n = 29), rituximab ( n = 23), oral prednisone ( n = 16), and oral azathioprine or mycophenolate mofetil ( n = 4). Results: NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2–39.3) versus 11.5 (7.0–23.3) pg/mL; p = 0.001; pGFAP, 149.7 (88.6–406.5) versus 68.7 (59.4–80.8) pg/mL; p

Abstract The 5th International Porto Congress of Multiple Sclerosis took place between the 14th and 16th of February 2019 in Porto, Portugal. Its intensive programme covered a wide-range of themes—including many of the hot topics, challenges, pitfalls and yet unmet needs in the field of multiple sclerosis (MS)—led by a number of well-acknowledged world experts. This meeting review summarizes the talks that took place during the congress, which focussed on issues in MS as diverse as the development and challenges of progressive MS, epidemiology, differential diagnosis, medical management, molecular research and imaging tools.

Abstract Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice. Methods (NZB x NZW)F1 (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria. Results Vaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs). Conclusions The beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.

Abstract Background Interleukin 36 (IL-36) cytokines belong to the IL-1 family and play an important role in some autoimmune diseases. However, the relationship between IL-36 and neuromyelitis optica spectrum disorders (NMOSD) remains unclear. Methods We determined serum IL-36α, IL-36β and IL-36γ levels and assessed correlations with clinical characteristics in 50 NMOSD patients and 30 healthy controls (HC). Results The concentrations of serum IL-36β and IL-36γ were significantly higher in patients with NMOSD than in HCs and decreased during remission. Serum IL-36β levels were positively correlated with the annual relapse rate (ARR), spinal cord lesion length and Expanded Disability Status Scale (EDSS) scores. Conclusions Serum IL-36β and IL-36γ levels were related to disease activity in NMOSD patients and may be important biomarkers of NMOSD.

BackgroundInterleukin-6 receptor blockade is effective in reducing the risk of relapses in neuromyelitis optica spectrum disorder (NMOSD). However, its efficacy during acute attacks of NMOSD remains elusive.ObjectiveWe investigated the effects of tocilizumab on disability during acute attacks, as well as its maintenance, in patients with moderate-to-severe myelitis.MethodsNineteen patients with NMOSD received tocilizumab treatment as add-on to high-dose methylprednisolone (HDMP) in acute myelitis and twenty-two patients who only received HDMP were compared. Disease disability was assessed using a multi-level scaling system that included the expanded disability status scale (EDSS), Hauser ambulation index (HAI), modified Rankin scale (mRS), pain numerical rating scale (NRS), functional assessment of chronic illness therapy-fatigue scale (FACIT-F), activity of daily living (ADL), EuroQol five-dimensions-three-level questionnaire (EQ-5D-3L), and sensory function score and bowel and bladder function score in Kurtzke functional systems scores (FSS).ResultsImproved EDSS, HAI, and mRS, as well as increased ADL and EQ-5D-3L were significant in patients on tocilizumab compared with those on steroids as monotherapy at 3 months (p < 0.05). Both groups of patients showed improved pain, fatigue, sensory function, and autonomic function at follow-ups, compared with baseline respectively. The changes in NRS, FACIT-F, and sensory and autonomic FSS showed no significant differences between the two groups. Tocilizumab significantly lowered the risk of relapses (HR = 0.21, 95% CI 0.06–0.76, p = 0.017) and reduced the annualized relapse rate compared with those by steroids (0.1 ± 0.2 vs 0.5 ± 0.6, p = 0.013).ConclusionEarly initiation of tocilizumab provided a safe and effective add-on alternative during attacks, and its maintenance contributed to a significant reduction of relapse rate in NMOSD.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system and it is understandable that environmental and genetic factors underlie the etiology of NMOSD. However, the susceptibility genes and associated pathways of NMOSD patients who are AQP4-Ab positive and negative have not been elucidated.MethodsSecondary analysis from a NMOSD Genome-wide association study (GWAS) dataset originally published in 2018 (215 NMOSD cases and 1244 controls) was conducted to identify potential susceptibility genes and associated pathways in AQP4-positive and negative NMOSD patients, respectively (132 AQP4-positive and 83 AQP4-negative).ResultsIn AQP4-positive NMOSD cases, five shared risk genes were obtained at chromosome 6 in AQP4-positive NMOSD cases by using more stringent p-Values in both methods (p < 0.05/16,532), comprising CFB, EHMT2, HLA-DQA1, MSH5, and SLC44A4. Fifty potential susceptibility gene sets were determined and 12 significant KEGG pathways were identified. Sixty-seven biological process pathways, 32 cellular-component pathways, and 29 molecular-function pathways with a p-Value of

Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed its therapeutic efficacy on neuromyelitis optica spectrum disorder (NMOSD). To assess the immunological effects of this drug on B cells, follicular T helper (Tfh) cells, and peripheral T helper (Tph) cells in patients with NMOSD, peripheral B cell and Tfh cell phenotypes were evaluated in 26 patients with NMOSD before and after tocilizumab treatment by nine-color flow cytometry, as well as the expression of costimulatory and co-inhibitory molecules on B cells. Results showed that the frequency of CD27+IgD− switched memory B cells, CD27-IgD- double-negative B cells, and CD27highCD38high antibody-secreting cells was increased in patients with NMOSD. Tocilizumab treatment led to a significant shift of B cells to naïve B cells from memory B cells after 3 months. Three markers on B cells associated with T-cell activation (i.e., CD86 CD69, and HLA-DR) were downregulated after tocilizumab treatment. The frequencies of total Tfh and Tph cells were decreased, whereas that of follicular regulatory T cells tended to increase. Intrinsic increased PD-L1 and PD-L2 expression was characteristic of B cells in patients with NMOSD. Tocilizumab selectively restored PD-L1 on B-cell subsets. These results provided evidence that tocilizumab enhanced B- and T-cell homoeostasis by regulating B-cell differentiation and inhibiting lymphocyte activation in patients with NMOSD.

Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) often coexist with connective tissue disorders (CTD). The aim of this study was to investigate and compare the features of NMOSD with and without CTD. Methods NMOSD patients with (n = 18) and without CTD (n = 39) were enrolled, and the clinical, laboratory, and magnetic resonance imaging (MRI) features of the two groups were assessed. Results Most of the demographic and clinical features examined were similar between NMOSD patients with and without CTD. Serum immunoglobulin G (IgG), percentage of γ-globulin and seropositivity for several other autoantibodies were significantly elevated in NMOSD patients with CTD (P

Summary: Background: Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission, but the incidence of MG in China is unknown. We conducted the first nationwide study to determine the incidence and mortality rates of MG in all age groups at the national level in China. Methods: This national population-based registry study is based on the database of the Hospital Quality Monitoring System of National Health Commission, which covers 1665 hospitals providing myasthenia gravis care in 31 provinces and municipalities across China. 94,638 hospital admissions for 59,243 myasthenia gravis patients were identified from January 1st, 2016 to December 31st, 2018. Myasthenia gravis was identified by ICD-10 codes (G70). Incidence of myasthenia gravis was stratified by age, sex, and province. Findings: Of 59,243 patients, 30,503 individuals with myasthenia gravis were newly diagnosed. Age and sex adjusted incidence of myasthenia gravis was 0.68 per 100,000 person-years, with highest in the age group of 70–74 years. The incidence in females was 0.76 per 100,000 and 0.60 per 100,000 in males. The admission mortality rate was 14.69‰. Respiratory failure was the leading cause of death in patients with myasthenic crisis. There were 14,840 patients with thymomas, encompassing 14,636 (26.5%) adults and 204 (7.1%) juveniles. 9453 (63.7%) patients with thymomas underwent thymomectomy. The median length of hospital stay was 8 days (interquartile range (IQR) 4 to 15 days) with median hospitalization cost $1037 (IQR $493 to $2925). The Basic Medical Insurance was the most common payment method, covering 67.4% of patients. Interpretation: The age and sex adjusted incidence of MG was 0.68 per 100,000 person-years in China. The admission mortality rate was 14.69‰. Most cases of new onset MG occurred in the seventh decade of life. Funding: National Science Foundation of China (91642205, and 81830038); Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing

Background and purpose Data on the efficacy and safety of alteplase for acute ischaemic stroke (AIS) administered 3–4.5 hours after the onset of stroke symptoms in Chinese patients is limited. We sought to determine whether AIS patients would benefit from thrombolysis with alteplase between 3 and 4.5 hours after the onset of stroke symptoms in a prospective, multicentre, single-arm trial in China.Materials and methods Eligible AIS patients were given 0.9 mg/kg alteplase intravenously. The primary efficacy endpoint was a favourable outcome at 3 months, defined as a score of 0 or 1 on the modified Rankin Scale. Thresholds for the primary efficacy endpoint were determined to be 40% based on the literature review. The primary safety endpoint was symptomatic intracranial haemorrhage (sICH) according to the European Cooperative Acute Stroke Study III (ECASS III) trial definition. Post hoc analysis between this study and the ECASS III trial were compared using the propensity score matching (PSM) method.Results A total of 120 eligible AIS patients from 11 sites in China received thrombolysis therapy in this study. The median time from onset of symptoms to needle was 3 hours 54 min. The percentage of patients with a favourable outcome was 63.3% (95% CI 54.4 to 71.4), significantly higher than the predefined threshold (p

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory disease of the central nervous system with preferential involvement of the optic nerve and spinal cord. However, data on NMOSD incidences in China, a country encompassing 20% of the world's population and covering vast areas of Eastern Asia, are unknown. Methods: We conducted the first nationwide survey of NMOSD, based on the database of the National Hospital Quality Monitoring System (HQMS) of China, which covers all 1665 tertiary hospitals. The “Medical Record Homepage” of all patients were consistently collected via a standard protocol across each tertiary hospital. The primary outcome was the incidence of NMOSD, diagnosed according to the 2015 International Panel for Neuromyelitis Optica Diagnosis criteria and identified by ICD-10 code (G36•0). Burden of hospitalization, comorbidities, and death were also evaluated. Findings: We identified 33,489 hospital admissions for 17,416 NMOSD diagnosed patients from 2016 to 2018. 11,973 patients were newly diagnosed NMOSD. The age and sex adjusted incidence per 100,000 person years was 0•278 (95% confidence interval [CI], 0•273–0•283), with 0•075 (0•069–0•08) in child and 0•347 (0•34–0•353) in adult. The peak age of onset NMOSD is 45–65 years with an incidence 0•445/100,000 (95% CI, 0•433–0•457). The female to male ratio was 4•71 (p

Background: Multiple sclerosis (MS) is a leading cause of disability among young adults and effects considerable social and economic burdens. Data of MS incidence in China at the national level is lacking. We conducted the first nationwide hospital-based study to estimate the incidence and hospitalization burden of MS in China. Methods: This study is based on an administrative database of the National Hospital Quality Monitoring System, which covers all 1665 tertiary hospitals in mainland China. The “Medical Record Homepage” of all patients, including 346 variables including demographic characteristics, diagnoses, procedures, and expenses etc., were uniformly collected across each tertiary hospital via standard protocol. MS was defined by the 2010 International Panel criteria for MS and was identified by ICD-10 code (G35•0). Findings: We identified 27,336 hospital admissions for 15,060 MS patients from 2016 to 2018; amongst these patients, 9,879 were newly diagnosed. The age- and sex-adjusted incidence per 100,000 person-years is 0•235 (95% confidence interval [CI] 0•230–0•240), with 0•055 (0•050–0•060) in children and 0•288 (0•282–0•294) in adults, respectively. The female to male ratio is 2•02; the peak disease onset is age of 40–49 years. Residents in high-latitude and high-altitude areas are more likely to develop MS (F = 8•99; p

Background: In neuromyelitis optica spectrum disorders (NMOSDs), inflammation is not the sole driver of accumulation of disability; neurodegeneration is another important pathological process. We aim to explore different patterns of cortical atrophy and ventricular enlargement in NMOSD.Methods: We retrospectively analyzed a cohort of 230 subjects, comprising 55 healthy controls (HCs), 85 multiple sclerosis (MS), and 90 NMOSD patients from Tianjin Medical University General Hospital and Beijing Tiantan Hospital. Different compartments of the brain (total gray, cortex, subcortex gray, and ventricle volume) were evaluated with the FreeSurfer. Multiple linear regressions were adopted to explore associations between cortex volume and predict factors.Results: Compared with HCs, NMOSD, and MS displayed an enlarged lateral and third ventricle (p < 0.001), whereas expansion of the fourth ventricle was observed in MS rather than NMOSD (p = 0.321). MS and NMOSD patients exhibited cortical thinning in comparison with HCs. However, pronounced cortical atrophy were only significant in pre-cuneus, parahippocampal, and lateral occipital lobe between MS and NMOSD. Patients with NMOSD had decreased local gyrification index in orbitofrontal and pre-cuneus lobe, and reduced pial surface area. Linear regression analysis revealed cortex volume were predicated by advanced age (standardized β = −0.404, p = 0.001) as well as prolonged disease history (standardized β = −0.311, p = 0.006).Conclusion: NMOSD exhibited global cortex atrophy with enlarged lateral and third ventricles. Moreover, cortex volume is associated with age and disease duration.

Coagulopathy often develops soon after acute traumatic brain injury and its cause remains poorly understood. We have shown that injured brains release cellular microvesicles that disrupt the endothelial barrier and induce consumptive coagulopathy. Morphologically intact extracellular mitochondria accounted for 55.2% of these microvesicles, leading to the hypothesis that these extracellular mitochondria are metabolically active and serve as a source of oxidative stress that activates platelets and renders them procoagulant. In testing this hypothesis experimentally, we found that the extracellular mitochondria purified from brain trauma mice and those released from brains subjected to freeze-thaw injury remained metabolically active and produced reactive oxygen species. These extracellular mitochondria bound platelets through the phospholipid-CD36 interaction and induced α-granule secretion, microvesiculation, and procoagulant activity in an oxidant-dependent manner, but failed to induce aggregation. These results define an extracellular mitochondria-induced and redox-dependent intermediate phenotype of platelets that contribute to the pathogenesis of traumatic brain injury-induced coagulopathy and inflammation.

Adaptor for IL-17 receptors (Act1) is known to be crucial for IL-17-mediated immune responses. Here the authors show that Act1 also functions as a negative regulator of T and B cells by direct inhibition of STAT3.

Background: Stroke patients with diabetes suffer from higher mortality rate and worsened neurological outcome. However, the responses of immune system to cerebral ischemia in the setting of diabetes remain poorly understood.Methods: In this study, we investigated the temporal profile of leukocyte mobilization and brain infiltration following distal middle cerebral artery occlusion (dMCAO) in db/db mouse model of type 2 diabetes (T2D) and its db/+ normoglycemic controls.Results: We found a significant increase of brain-infiltrating CD4+ T cell at day 3 after dMCAO, and a delayed and dramatic increase of brain-infiltrating neutrophils, CD4+ T cells, CD8+ T cells, and B cells at day 7 after dMCAO in db/db mice vs. db/+ controls. Leukocyte subsets in the circulation and spleen were also measured, however, there is no significant difference between non-diabetic and diabetic groups. Furthermore, we identified an increased expression of activation marker CD69 in brain-infiltrating neutrophils, CD4+ T and CD8+ T cells, and IFN-γ in brain-infiltrating CD4+ T cells in db/db mice at day 7 after dMCAO.Conclusions: These findings for the first time demonstrate that cerebral ischemia induces a delayed and sustained augmentation of brain infiltration and activation of neutrophils and lymphocytes in type 2 diabetic mice and these altered immune responses might contribute to the severer brain tissue damage and worse neurological outcomes of diabetes stroke, which warrants further investigation.

Abstract Background Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear. Methods C57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-γ production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining. Results In mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-γ, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post-mortem brain sections from patients during the late stage of ischemic stroke. Conclusion Our results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke.

Objective We herein present a case involving a prevertebral abscess complicated by a spinal epidural abscess (SEA) secondary to intradiscal oxygen–ozone chemonucleolysis for treatment of a cervical disc herniation. Methods A 67-year-old woman with a history of intradiscal oxygen–ozone chemonucleolysis developed numbness and weakness in her right upper and bilateral lower extremities followed by urinary retention. Her symptoms did not respond to intravenous antibiotics alone. Magnetic resonance imaging of the cervical region revealed an extensive SEA anterior to the spinal cord, spinal cord myelopathy due to anterior compression by the lesion, and a prevertebral abscess extending from C2 to T1. She underwent surgical drainage and irrigation. Results The patient was successfully treated with surgical drainage and systemic antibiotic therapy without kyphosis. Streptococcus intermedius was detected within the abscess. All clinical symptoms except for the sensory deficit in the left leg were relieved. Conclusions The safety of intradiscal oxygen–ozone therapy requires further assessment. High-dose intravenous antibiotics should be initiated empirically at the earliest possible stage of prevertebral and epidural abscesses. Surgical drainage may be a rational treatment choice for patients with a prevertebral abscess complicated by an SEA and spinal cord myelopathy.

Distinguishing relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is clinically important because they differ in prognosis and treatment. This study aimed to identify perfusion abnormalities in RRMS and NMO and their correlations with gray matter volume (GMV) atrophy and clinical parameters. Structural and arterial spin labeling MRI scans were performed in 39 RRMS patients, 62 NMO patients, and 73 healthy controls. The gray matter cerebral blood flow (CBF) values were voxel-wisely compared among the three groups with and without GMV correction. The regional CBF changes were correlated with the Expanded Disability Status Scale scores in the corresponding patient groups. Although multiple brain regions showed CBF differences among the three groups without GMV correction, only three of these regions remained significant after GMV correction. Specifically, both the RRMS and NMO groups showed reduced CBF in the occipital cortex and increased CBF in the right putamen compared to the control group. The RRMS group had increased CBF only in the medial prefrontal cortex compared to the other two groups. The occipital CBF was negatively correlated with clinical disability in the NMO group; however, the CBF in the right putamen was positively correlated with clinical disability in both patient groups. These findings suggest that there are perfusion alterations independent of GMV atrophy in RRMS and NMO patients. The regional CBF in the occipital cortex and putamen could be used as imaging features to objectively assess clinical disability in these patients.

Astrocyte loss induced by neuromyelitis optica (NMO)-IgG and complement-dependent cytotoxicity (CDC) is the hallmark of NMO pathology. The survival of astrocytes is thought to reflect astrocyte exposure to environmental factors in the CNS and the response of astrocytes to these factors. However, still unclear are how astrocytes respond to NMO-IgG and CDC, and what CNS environmental factors may impact the survival of astrocytes. In a murine model of NMO induced by intracerebral injection of NMO-IgG and human complement, we found dramatic upregulation of IL-15 in astrocytes. To study the role of astrocytic IL-15 in NMO, we generated a transgenic mouse line with targeted expression of IL-15 in astrocytes (IL-15tg), in which the expression of IL-15 is controlled by a glial fibrillary acidic protein promoter. We showed that astrocyte-targeted expression of IL-15 attenuates astrocyte injury and the loss of aquaporin-4 in the brain. Reduced blood–brain barrier leakage and immune cell infiltration are also found in the lesion of IL-15tg mice subjected to NMO induction. IL-15tg astrocytes are less susceptible to NMO-IgG-mediated CDC than their wild-type counterparts. The enhanced resistance of IL-15tg astrocytes to cytotoxicity and cell death involves NF-κB signaling pathway. Our findings suggest that IL-15 reduces astrocyte loss and NMO pathology.

Previous studies have demonstrated immunosuppressive and anti-inflammatory effects of nicotine, including in the experimental autoimmune encephalomyelitis (EAE) model in mice of some forms of multiple sclerosis (MS). Other studies using knock-out (KO) mice have implicated nicotinic acetylcholine (ACh) receptors containing α7, α9, or β2 subunits (α7*-, α9*- or β2*-nAChR) in different, disease-exacerbating or disease-ameliorating processes. These outcomes are in harmony with gene expression analyses showing nAChR subunit mRNA in many classes of immune system cell types. Consistent with influences on disease status, predictable effects of nAChR subunit (and subtype) KO, or of nicotine exposure, are seen on immune cell numbers and distribution and on cytokine levels or other markers of immunity, inflammation, demyelination, and axonal degradation. Providing support for our hypotheses about distinctive roles for nAChR subtypes in EAE, here we have used direct and adoptive EAE induction and a nAChR subunit gene double knock-out (DKO) strategy. Immune cell expression of nAChR α9 subunits as protein is demonstrated by immunostaining of isolated CD4+, CD8+, CD11b+ and CD11c+ cells from wild-type (WT) mice, but not in cells from nAChR α9 subunit KO animals. Nicotine exposure is protective against directly-induced EAE in WT or α7/α9 DKO animals relative to effects seen in WT/vehicle-treated mice, but, remarkably, EAE is exacerbated in vehicle-treated α7/α9 DKO mice. Brain lesion volume and intra-cranial inflammatory activity similarly are higher in DKO/vehicle than in WT/vehicle-treated animals, although nicotine’s protective effects are seen in each instance. By contrast, in adoptive transfer studies, disease severity is attenuated and disease onset is delayed in recipients of splenocytes from WT animals treated with nicotine rather than with vehicle. Moreover, protection as seen in nicotine-treated WT animals is the same in recipients of splenocytes from nAChR α7/α9 DKO mice irrespective of their exposure to nicotine or vehicle. When combined with previous observations, these findings are consistent with disease exacerbation (or even induction) being mediated at least in part via α9*-nAChR in peripheral immune cells. They also suggest protective roles of central nervous system (CNS) α7*-nAChR. The results suggest that both α7*- and α9*-nAChR are potential targets of therapeutic ligands to modulate inflammation and autoimmunity.

Nature killer (NK) cells play an important role in anti-tumor immunotherapy. But it indicated that tumor cells impacted possibly on NK cell normal functions through some molecules mechanisms in tumor microenvironment.Our study analyzed the change about NK cells surface markers (NK cells receptors) through immunofluorescence, flow cytometry and real-time PCR, the killed function from mouse spleen NK cell and human high/low lung cancer cell line by co-culture. Furthermore we certificated the above result on the lung cancer model of SCID mouse.We showed that the infiltration of NK cells in tumor periphery was related with lung cancer patients' prognosis. And the number of NK cell infiltrating in lung cancer tissue is closely related to the pathological types, size of the primary cancer, smoking history and prognosis of the patients with lung cancer. The expression of NK cells inhibitor receptors increased remarkably in tumor micro-environment, in opposite, the expression of NK cells activated receptors decrease magnificently.The survival time of lung cancer patient was positively related to NK cell infiltration degree in lung cancer. Thus, the down-regulation of NKG2D, Ly49I and the up-regulation of NKG2A may indicate immune tolerance mechanism and facilitate metastasis in tumor environment. Our research will offer more theory for clinical strategy about tumor immunotherapy.

Cigarette smoke exposure markedly compromises the ability of the immune system to protect against invading pathogens and tumorigenesis. Nicotine is a psychoactive component of tobacco products that acts as does the natural neurotransmitter, acetylcholine, on nicotinic receptors (nAChRs). Here we demonstrate that natural killer (NK) cells strongly express nAChR β2. Nicotine exposure impairs the ability of NK cells to kill target cells and release cytokines, a process that is largely abrogated by nAChR β2 deficiency. Further, nicotinic suppression of NF-κB-induced transcriptional activity in NK cells is dependent on nAChR β2. This nAChR subtype also plays a large role in the NK cell-mediated control of melanoma lung metastasis, in a murine lung metastasis model exposed to nicotine. Our findings suggest nAChR β2 as a prominent pathway for nicotine induced impairment of NK cell functions which contributes to the occurrence of smoking-related pathologies.

A prominent clinical symptom in multiple sclerosis (MS), a progressive disorder of the central nervous system (CNS) due to heightened neuro-inflammation, is learning and memory dysfunction. Here, we investigated the effects of a ketogenic diet (KD) on memory impairment and CNS-inflammation in a murine model of experimental autoimmune encephalomyelitis (EAE), using electrophysiological, behavioral, biochemical and in vivo imaging approaches. Behavioral spatial learning deficits were associated with motor disability in EAE mice, and were observed concurrently with brain inflammation. The KD improved motor disability in the EAE model, as well as CA1 hippocampal synaptic plasticity (long-term potentiation) and spatial learning and memory (assessed with the Morris Water Maze). Moreover, hippocampal atrophy and periventricular lesions in EAE mice were reversed in KD-treated EAE mice. Finally, we found that the increased expression of inflammatory cytokines and chemokines, as well as the production of reactive oxygen species (ROS), in our EAE model were both suppressed by the KD. Collectively, our findings indicate that brain inflammation in EAE mice is associated with impaired spatial learning and memory function, and that KD treatment can exert protective effects, likely via attenuation of the robust immune response and increased oxidative stress seen in these animals.

Experimental autoimmune encephalomyelitis (EAE) models are important vehicles for studying the effect of infectious elements such as Pertussis toxin (PTx) on disease processes related to acute demyelinating encephalomyelitis (ADEM) or multiple sclerosis (MS). PTx has pleotropic effects on the immune system. This study was designed to investigate the effects of PTx administered intracerebroventricularly (icv) in preventing downstream immune cell infiltration and demyelination of the spinal cord.EAE was induced in C57BL/6 mice with MOG(35-55). PTx icv at seven days post MOG immunization resulted in mitigation of clinical motor symptoms, minimal T cell infiltration, and the marked absence of axonal loss and demyelination of the spinal cord. Integrity of the blood brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact. PTx icv markedly increased microglia numbers in the brain preventing their migration to the spinal cord. An in vitro transwell study demonstrated that PTx inhibited migration of microglia.Centrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.

Tocilizumab, a humanized IL-6R monoclonal antibody, has been used in autoimmune diseases closely related to humoral immunity. This report aims to evaluate the efficacy and safety in patients with antiacetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG). We performed a prospective, open-label, single-arm study in patients with gMG in a 48-week follow-up. All patients were AChR+ and were given tocilizumab by intravenous infusion at a dose of 8 mg/kg at intervals of 4 weeks. The primary endpoint was mean change from baseline in quantitative MG (QMG) score at week 12. The secondary endpoints were mean changes from baseline in MG activities of daily living (MG-ADL) score, AChR-ab titers, and the dosage of oral prednisone at week 12. At week 48, QMG, MG-ADL, and the use of prednisone were also evaluated. Fourteen gMG patients were enrolled and all of them completed the study. Tocilizumab treatment started 8 (4-192) months after the onset of gMG. During tocilizumab treatment, the QMG score was significantly decreased from 15.5 (interqualile range, 9-26) at baseline to 4 (0-9) at week 12 (p < 0.001). The change of ADL was decreased from 14.5(11-19) at baseline to 4 (0-19) at week 12 (p < 0.001) and the change of AChR-ab titers from 15 (7.5-19) at baseline to 6.8 (11.6-4.3) at week 12 (p < 0.001). The dosage of prednisone decreased from baseline 60 (20-65) mg/d to 30 (30-50) mg/d at week 12 (p < 0.001). By the end of the study, the QMG score was 2 (0-7) and MG-ADL score was 1.5 (0-6). 12 (85.7%) patients achieved minimal manifestations. 4 (28.6%) patients were able to discontinue prednisone. No patients experienced exacerbation at the end of the study. No serious adverse events were observed during follow-up. Tocilizumab treatment was associated with a good clinical response and safety over a 48-week observation period, as evidenced by significant improvements in QMG and MG-ADL. [ABSTRACT FROM AUTHOR]

Damage or microstructural alterations of the white matter can cause dysfunction of the intrinsic neural networks in a condition termed as white matter disease (WMD). Frequently detected on brain computed tomography and magnetic resonance imaging scans, WMD is commonly presented in inflammatory demyelinating diseases like multiple sclerosis (MS) and vascular diseases such as cerebral small vessel disease (CSVD). Prevention of MS and CSVD progression requires early treatments with drastically different medications and approaches, as such, early and accurate diagnosis of WMD, derived from vascular or demyelinating etiologies, is of paramount importance. However, the clinical and imaging similarities between MS, especially during the early stage, and CSVD, pose a significant dilemma in differentiating these two conditions. In this review, we attempt to summarize and contrast the distinguishing features of MS and CSVD for aiding accurate diagnosis to ensure timely corresponding management in the early stages of MS and CSVD.

Background Acute brain ischaemia elicits pronounced inflammation, which aggravates neural injury. However, the mechanisms governing the resolution of acute neuroinflammation remain poorly understood. In contrast to regulatory T and B cells, group 2 innate lymphoid cells (ILC2s) are immunoregulatory cells that can be swiftly mobilised without antigen presentation; whether and how these ILC2s participate in central nervous system inflammation following brain ischaemia is still unknown.Methods Leveraging brain tissues from patients who had an ischaemic stroke and a mouse model of focal ischaemia, we characterised the presence and cytokine release of brain-infiltrating ILC2s. The impact of ILC2s on neural injury was evaluated through antibody depletion and ILC2 adoptive transfer experiments. Using Rag2−/−γc−/− mice receiving passive transfer of IL-4−/− ILC2s, we further assessed the contribution of interleukin (IL)-4, produced by ILC2s, in ischaemic brain injury.Results We demonstrate that ILC2s accumulate in the areas surrounding the infarct in brain tissues of patients with cerebral ischaemia, as well as in mice subjected to focal cerebral ischaemia. Oligodendrocytes were a major source of IL-33, which contributed to ILC2s mobilisation. Adoptive transfer and expansion of ILC2s reduced brain infarction. Importantly, brain-infiltrating ILC2s reduced the magnitude of stroke injury severity through the production of IL-4.Conclusions Our findings revealed that brain ischaemia mobilises ILC2s to curb neuroinflammation and brain injury, expanding the current understanding of inflammatory networks following stroke.

Background: Brain injury triggers neuroaxonal injury and neural death, that leads to the development of secondary sequelae. Throughout this process, brain injury factors released into circulation via the injured neurovascular unit are important prognostic parameters. Plasma NfL, NfH, MCP-1, and MMP-9 have been identified as potential indicators in this regard. Methods: Using a microfluidic ELISA platform, we measured plasma from 273 healthy subjects that underwent quantifications of NfL, NfH, MCP-1, and MMP-9 levels. We investigated the possible associations between biomarkers and basic demographics. Results: The median concentration of plasma NfL was 10.40 (IQR = 6.73 - 16.60) pg/mL, NfH was 70.70 (IQR = 39.75 - 125.50) pg/mL, MCP-1 was 191.0 (IQR = 162.0 - 237.5) pg/mL, and MMP-9 was 169,255 (IQR = 107,657 - 231,276) pg/mL. Among all four biomarkers, plasma NfL and NfH levels were positively correlated with age (r = 0.557, p < 0.001, r = 0.364, p = 0.003). NfL was also correlated with NfH (r = 0.391, p = 0.002). Conclusions: These data provide a basis for the potential application of a brain-injury biomarker panel in routine clinical practice. It lays a significant foundation in supporting circulating CNS-biomarkers as noninvasive biomarkers for neurological disorders. [ABSTRACT FROM AUTHOR]