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Yalin Guan,1,2,* Wenchao Zuo,1,2,* Kun Jia,1,2,* Changshen Yu,2 Feng Liu,2 Zhaoyang Lv,2 Dong Wang,3 Fu-Dong Shi,1 Xinping Wang2 1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China; 2Department of Neurology, Tianjin Huanhu Hospital, Tianjin, 300350, People’s Republic of China; 3Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinping Wang, Department of Neurology, Tianjin Huanhu Hospital, 6 Jizhao Road, Jinnan District, Tianjin, 300350, People’s Republic of China, Tel +86-22-59065906, Fax +86-22-59065662, Email tjhhwxp@126.com Fu-Dong Shi, Department of Neurology, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China, Tel +86-22-60362255, Fax +86-22-60362400, Email fshi@tmu.edu.cnObjective: Stroke is the leading cause of mortality and disability worldwide. However, there is no study on the relationship between red blood cell distribution width and the prognosis of small artery occlusion, which is a stroke subtype. This study aimed to assess the association of red blood cell distribution width at admission with outcomes among patients with small artery occlusion.Methods: In this hospital-based follow-up study, all included patients were diagnosed with small artery occlusion. Outcomes included death, recurrence, and dependency at 3, 12, and 36 months after stroke onset. Multivariate analysis was performed to explore the association of red blood cell distribution width with stroke outcomes.Results: This study included 1576 patients with small artery occlusion who were followed up at 3, 12, and 36 months. For every unit increase in red blood cell distribution width, the risk of stroke recurrence and dependency increased by 5.1% (95% CI 1.002– 1.102, P=0.039) at 3 months after stroke onset. At the 12-month follow-up, for every unit increase in red blood cell distribution width, the risk of stroke recurrence increased by 3.4% (95% CI 1.000– 1.069, P=0.047). However, the relationship between red blood cell distribution width and mortality rate was not significant at 36 months after stroke onset after adjustment of covariates.Conclusion: Red blood cell distribution width is an important hematological index of small artery occlusion. It may be used to predict the recurrence of acute ischemic stroke in small artery occlusion. Therefore, patients with higher baseline values of red blood cell distribution width may need more risk factor control to reduce recurrence and dependency.Keywords: red blood cell distribution width, stroke prognosis, risk factors, small artery occlusion, prospective follow-up study

Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,4,5 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USAObjectives: Immunotherapy with immunostimulants is an attractive therapy against gliomas. C-type lectin receptors specific for galactose/N-acetylgalactosamine (GCLR) regulate cellular differentiation, recognition, and trafficking of monocyte-derived cells. A peptide mimetic of GCLR ligands (GCLRP) was used to activate blood monocytes and populations of myeloid-derived cells against a murine glioblastoma.Methods: The ability of GCLRP to stimulate phagocytosis by human microglia and monocyte-derived cells of the brain (MDCB) isolated from a human glioblastoma was initially assessed in vitro. Induction of activation markers on blood monocytes was assayed by flow cytometry after administration of GCLRP to naive mice. C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells and were randomized for tumor size by magnetic resonance imaging, which was also used to assess increase in tumor size. Brain tumor tissues were analyzed using flow cytometry, histology, and enzyme-linked immunosorbent assay with respect to tumor, peritumoral area, and contralateral hemisphere regions.Results: GCLRP exhibited strong stimulatory effect on MDCBs and blood monocytes in vitro and in vivo. GCLRP was associated with an increased percentage of precursors of dendritic cells in the blood (P = 0.003), which differentiated into patrolling macrophages in tumoral (P = 0.001) and peritumoral areas (P = 0.04), rather than into dendritic cells, as in control animals. Treatment with GCLRP did not result in a significant change in survival of mice bearing a tumor.Conclusions: In vitro and in vivo activation of monocytes was achieved by administration of GCLR to mice. GCLRP-activated blood monocytes were recruited to the brain and exhibited specific phenotypes corresponding with tumor region (glioma, peritumoral zone, and contralateral glioma-free hemisphere). GCLRP treatment alone was associated with increased glioma mass as the result of the infiltration of phagocytic cells. Regional specificity for MDCB may have significant tumor treatment implications.Keywords: microglia, macrophages, peptide, brain tumor, glioblastoma, mouse, C-type lectin receptors, galactose/N-acetylgalactosamine, immunotherapy

Sergiy V Kushchayev,1 Tejas Sankar,1 Laura L Eggink,5,6 Yevgeniya S Kushchayeva,5 Philip C Wiener,1,5 J Kenneth Hoober,5,6 Jennifer Eschbacher,3 Ruolan Liu,2 Fu-Dong Shi,2 Mohammed G Abdelwahab,4 Adrienne C Scheck,4 Mark C Preul11Neurosurgery Research Laboratory, 2Neuroimmunology Laboratory, 3Department of Pathology, 4Neurooncology Research, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, 5School of Life Sciences, Arizona State University, Tempe, 6Susavion Biosciences, Inc, Tempe, AZ, USABackground: A peptide mimetic of a ligand for the galactose/N-acetylgalactosamine-specific C-type lectin receptors (GCLR) exhibited monocyte-stimulating activity, but did not extend survival when applied alone against a syngeneic murine malignant glioma. In this study, the combined effect of GCLRP with radiation was investigated.Methods: C57BL/6 mice underwent stereotactic intracranial implantation of GL261 glioma cells. Animals were grouped based on randomized tumor size by magnetic resonance imaging on day seven. One group that received cranial radiation (4 Gy on days seven and nine) only were compared with animals treated with radiation and GCLRP (4 Gy on days seven and nine combined with subcutaneous injection of 1 nmol/g on alternative days beginning on day seven). Magnetic resonance imaging was used to assess tumor growth and correlated with survival rate. Blood and brain tissues were analyzed with regard to tumor and contralateral hemisphere using fluorescence-activated cell sorting analysis, histology, and enzyme-linked immunosorbent assay.Results: GCLRP activated peripheral monocytes and was associated with increased blood precursors of dendritic cells. Mean survival increased (P < 0.001) and tumor size was smaller (P < 0.02) in the GCLRP + radiation group compared to the radiation-only group. Accumulation of dendritic cells in both the tumoral hemisphere (P < 0.005) and contralateral tumor-free hemisphere (P< 0.01) was associated with treatment.Conclusion: Specific populations of monocyte-derived brain cells develop critical relationships with malignant gliomas. The biological effect of GCLRP in combination with radiation may be more successful because of the damage incurred by tumor cells by radiation and the enhanced or preserved presentation of tumor cell antigens by GCLRP-activated immune cells. Monocyte-derived brain cells may be important targets for creating effective immunological modalities such as employing the receptor system described in this study.Keywords: microglia, macrophages, peptide, brain tumor, glioblastoma, mouse, C-type lectin receptors

Purpose: This study aims to investigate μ-calpain expression profiles in the anterior temporal neocortex in patients with intractable epilepsy, and to determine whether its pattern of expression is related to pathological changes seen in these patients.Methods: The study subjects consisted of 30 patients with intractable epilepsy and a control group of 10 patients with brain trauma who underwent resection of the anterior temporal lobe. μ-Calpain expression in surgically resected anterior temporal cortices of patients with intractable epilepsy were analyzed using the RT-PCR, Western blot, immunohistochemistry and immunofluorescence staining. GFAP expression was detected by immunohistochemical staining. The related pro-inflammatory cytokines were quantified by elisa. Clinicopathological characteristics were evaluated by HE staining.Results: Analysis by Western blot and RT-PCR revealed that inactive μ-calpain expression and the calpain-cleaved spectrin fragment in surgically resected anterior temporal cortices of patients with intractable epilepsy were significantly increased compared to the tissues from corresponding regions of the control group. Immunohistological staining demonstrated that μ-calpain was overexpressed in the cell cytoplasm of neurons and glial cells in patients with intractable epilepsy and GFAP was overexpressed in the cell cytoplasm of glial cells in patients with intractable epilepsy. The level of pro-inflammatory cytokines, such as IL-1β, IL-6 and TGF-β1 were significantly increased in patients with intractable epilepsy. HE staining indicated μ-calpain overexpression is an independent prognostic factor for pathological changes such as neuronal loss, neuronal degeneration, gliosis and astrocytosis.Conclusion: These data suggest that overexpression of μ-calpain is relationship with intractable epilepsy as well as the clinicopathological characteristics in these patients. [ABSTRACT FROM AUTHOR]

Objective: The role of natural killer (NK) cells in regulating multiple sclerosis (MS) is not well understood. Additional studies with NK cells might provide insight into the mechanism of action of MS therapies such as daclizumab, an antibody against the interleukin (IL)-2R α-chain, which induces expansion of CD56(bright) NK cells.Methods: In a relapsing-remitting form of the experimental autoimmune encephalomyelitis (EAE) model of MS induced in SJL mice, we expanded NK cells with IL-2 coupled with an anti-IL-2 monoclonal antibody (mAb) and evaluated the effects of these NK cells on EAE. Further, we investigated the effect of the human version of IL-2/IL-2 mAb on NK cells from MS patients and its effect on central nervous system (CNS) inflammation and pathology in a human-mouse chimera model and assessed the underlying mechanisms.Results: IL-2/IL-2 mAb dramatically expands NK cells both in the peripheral lymphoid organs and in the CNS, and attenuates CNS inflammation and neurological deficits. Disease protection is conferred by CNS-resident NK cells. Importantly, the human version of IL-2/IL-2 mAb restored the defective CD56(+) NK cells from MS patients in a human-mouse chimera model. Both the CD56(bright) and CD56(dim) subpopulations were required to attenuate disease in this model.Interpretation: These findings unveil the immunotherapeutic potential of NK cells, which can act as critical suppressor cells in target organs of autoimmunity. These results also have implications to better understand the mechanism of action of daclizumab in MS. [ABSTRACT FROM AUTHOR]

Objective: Prevalence, susceptibility genes, and clinical and radiological features may differ across different ethnic groups of multiple sclerosis (MS). We aim to characterize brain lesions in Chinese patients with MS by use of 7-T MRI., Methods: MS participants were enrolled from the ongoing China National Registry of Neuro-Inflammatory Diseases (CNRID) cohort. 7-T MRI of the brain was performed. Each lesion was evaluated according to a standardized procedure. Central vein sign (CVS) and paramagnetic rim lesions were identified. The characteristics of lesions at patient-level and at lesion-level from previous 7-T MRI literature were also summarized., Results: We included 120 MS patients. Their mean (SD) age was 34.6 (9.4) years. The female-to-male ratio was 1.7:1 and mean disease duration of patients with MS was 5.5 ± 6.1 years. The median EDSS score was 2 (range, 0-8). A total of 8502 lesions were identified with a median lesion count of 45 (IQR, 18-90) (range, 2-370). The median (IQR) percentage for these special locations were as follows: cortical lesions (CLs) 2.7% (0%-5.7%), juxtacortical lesions 16.2% (7.8%-25.7%), periventricular lesions 30.2% (17.2%-38.7%), and infratentorial lesions 5.8% (0.4%-11.9%). CLs occurred in 70 (58%) patients, accounting for only 443 (5%) of the total lesions. Out of the 443 CLs, 309 (69.8%) were leukocortical lesions. CVS appeared in 5392 (63%) lesions from 117 (98%) patients. 1792 (21%) lesions and 104 (87%) patients exhibited a paramagnetic rim., Interpretation: Our study elaborated on the lesion features of Chinese patients with MS by use of 7-T MRI. Lesion burden is heavy in Chinese patients with MS. The median lesion count and proportion of PRL are high. The reported heavy lesion burden calls for ramping up regional and global efforts to care for MS patients. The management and research of Chinese population with MS needs to be further strengthened., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4-) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: To identify predictors for relapse in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to develop and validate a simple risk score for predicting relapse., Methods: In China National Registry of Neuro-Inflammatory Diseases (CNRID), we identified patients with MOGAD from March 2023 and followed up prospectively to September 2023. The primary endpoint was MOGAD relapse, confirmed by an independent panel. Patients were randomly divided into model development (75%) and internal validation (25%) cohorts. Prediction models were constructed and internally validated using Andersen-Gill models. Nomogram and relapse risk score were generated based on the final prediction models., Results: A total of 188 patients (comprising 612 treatment episodes) were included in cohorts. Female (HR: 0.687, 95% CI 0.524-0.899, p = 0.006), onset age 45 years or older (HR: 1.621, 95% CI 1.242-2.116, p < 0.001), immunosuppressive therapy (HR: 0.338, 95% CI 0.239-0.479, p < 0.001), oral corticosteroids >3 months (HR 0.449, 95% CI 0.326-0.620, p < 0.001), and onset phenotype ( p < 0.001) were identified as factors associated with MOGAD relapse. A predictive score, termed MOG-AR (Immunosuppressive therapy, oral Corticosteroids, Onset Age, Sex, Attack phenotype), derived in prediction model, demonstrated strong predictive ability for MOGAD relapse. MOG-AR score of 13-16 indicates a higher risk of relapse (HR: 3.285, 95% CI 1.473-7.327, p = 0.004)., Discussion: The risk of MOGAD relapse seems to be predictable. Further validation of MOG-AR score developed from this cohort to determine appropriate treatment and monitoring frequency is warranted., Trial Registration Information: CNRID, NCT05154370, registered December 13, 2021, first enrolled December 15, 2021.

The differential diagnosis of multiple sclerosis can present specific challenges in patients from Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific. In these areas, environmental factors, genetic background, and access to medical care can differ substantially from those in North America and western Europe, where multiple sclerosis is most common. Furthermore, multiple sclerosis diagnostic criteria have been developed primarily using data from North America and western Europe. Although some diagnoses mistaken for multiple sclerosis are common regardless of location, a comprehensive approach to the differential diagnosis of multiple sclerosis in Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific regions requires special consideration of diseases that are prevalent in those locations. A collaborative effort has therefore assessed global differences in multiple sclerosis differential diagnoses and proposed recommendations for evaluating patients with suspected multiple sclerosis in regions beyond North America and western Europe., Competing Interests: Declaration of interests JC declares receiving grants or research contracts from Biogen and Merck; personal compensation for consulting from Merck; payment or honoraria for lectures from Biogen, Merck, Bristol Myers Squibb, Novartis, and Roche; and support for attending meetings and travel from Merck. JC is a deputy chair International Medical and Scientific Board of Multiple sclerosis International Federation (MSIF), unpaid; and has received equipment, materials, drugs, medical writing, gifts, or other services from Novartis (Investigator initiated award). AJS declares receiving grant funding from National Institute of Neurological Disorders and Stroke, National Institutes of Health and Bristol Myers Squibb (investigator initiated award); has done contracted research with Sanofi, Biogen, Novartis, Actelion, and Genentech; has received personal compensation for consulting from Emmanuel Merck, Darmstadt, Serono and Octave Bioscience; has received payments or honoraria for lectures from Emmanuel Merck, Darmstadt, Serono; has received expert testimony from The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; is a participant on a Data Safety Monitoring Board for the Patient Centered Research Institute, and Yale University; declares participation on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics; and is a content Chair for the American Academy of Neurology (AAN) Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. JAC declares personal compensation for consulting from Astoria, Bristol-Myers Squibb, Convelo, EMD Serono, FiND Therapeutics, INMune, and Sandoz; and serving as an editor of Multiple Sclerosis Journal. BLB is funded by the National Multiple Sclerosis Society, and National Institute of Health; is a consultant for Roche, and Sanofi; and is a Board Director AAN (unpaid). TG has served as a consultant and received compensation from Genentech, Horizon, Sanofi, Alexion, and Greenwich Biosciences. BH declares grants from the European Union, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft; received personal compensation for consulting from Sandoz, Novartis, and GLG consulting; holds patents for antibodies against KIR4·1 in a subpopulation of patients with multiple sclerosis (2012) and genetic determinants of neutralising antibodies to interferon (filed 2010); and participated in a Data Safety and Monitoring Board for Novartis, Allergy Care DSMB, TG Therapeutics, and Polpharma, and Advisory Board for Novartis. HJK declares a research grant from the National Research Foundation of Korea and research support from Aprilbio, UCB, and Eisai; has received consultancy fees from Altos Biologics, AstraZeneca, Biogen, Daewoong, Kaigene, Kolon Life Science, MDimune, Merck Serono, and Roche; declares honoraria for lectures from Alexion, Eisai, GCPharma, Handok, Mitsubishi Tanabe Pharma, and Sanofi Genzyme; has received personal compensation for participation on a Data Safety Monitoring Board from Sanofi-Genzyme; has received compensation as Co-editor for the Multiple Sclerosis Journal and Associate Editor for the Journal of Clinical Neurology; and is a Vice President of Pan-Asian Committee on Treatment and Research in Multiple Sclerosis (unpaid). RAM declares grants or contracts from Biogen, Idec, and Roche. FM has received research funding to her institution from Sumaira Foundation, Genentech, Biogen, Horizon Therapeutics, US National Histitute Institute of Health, US Department of State, Foundation Pierre Fabre, and Novartis; has received consulting fees from Alexion, EMD Serono, Genentech, TG Therapeutics, and Horizon Therapeutics; and declares shares of the startup company Brain Capture (not related to the content of this manuscript). SDN declares grants or contracts (paid directly to institution) from Biogen, Roche, Genentech, National MS Society, Department of Defense, and Patient Centered Outcomes Research Institute; has received personal compensation for consulting from Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, Horizon Therapeutics, and TG Therapeutics; and is a study lead principal investigator for a Roche clinical trial programme. MAS declares personal honoraria for lectures from Roche, Biogen, Cinnagen, NanoAlvand, Merck, Novartis, and Abidi. DKS declares grants or research contracts from CNPq / Brazil 425331/2016–4 and 308636/2019–8, and Brazilian National Council for Scientific and Technological Development; has received investigator initiated awards from TEVA, Merck, and Biogen; has received personal compensation for consulting from Roche, and Alexion; declares personal honoraria for lectures from Roche, Alexion, Horizon, Merck, Americas Health Foundation; and is a member of International Society of Neuroimmunology, International Advisory Board (unpaid), and Academia Brasileira de Neurologia, Educational Committee (unpaid). DS declares a pilot research grant from the National MS Society paid to the Institution; declares receipt of personal honoraria for lecturing from Roche Pharmaceuticals; declares travel support from Roche Pharmaceutical; and is a Committee member and chair of Multiple Sclerosis International Federation (unpaid). AS has received grants or contracts from the Turkish MS Society, Istanbul University-Cerrahpasa Research Support Funds, and The Scientific and Technological Research Council of Türkiye Health Sciences Research Grants; has received consulting fees from Roche, Merck-Serono, Biogen Idec/Gen Pharma of Turkey , Sanofi-Genzyme, Novartis, and Alexion; has received honoraria for lectures from Sanofi-Genzyme, Novartis, TEVA, and Roche; and has received support for attending meetings from Sanofi-Genzyme, Roche, Merck-Serono, and Alexion. KT declares personal consulting fees from Merck and Eisai; declares payment for lectures from Merck, Eisai, Roche, and Terumo Blood and Cell Technology; and is a member of the Organizing Committee Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid). MW has received publication royalties from Springer and Elsevier; has received consultancy honoraria from Icometrix, Imcyse, Novartis, Sanofi, Merck, and Biologix; declares personal compensation for lectures or presentations from Alexion, Bayer Healthcare, Biogen, Biologix, Bristol Myers Squibb, Celgene, Genilac, Imcyse, Icometrix, Merck-Serono, Novartis, Roche, and Sanofi-Genzyme; and declares support for attending meetings from Merck-Serono. BGW declares royalties from RSR, Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR , and Oxford University; declares personal consulting fees from Roche, Horizon Therapeutics, Cambridge Pharmaceuticals, and Mitsubishi Tanabe; has received payments for lecture presentations from Roche and Horizon; has a patent planned for NMO-IgG for diagnosis of neuromyelitis optica; and declares participation on a Data Safety Monitoring Board and Advisory borads for Alexion MedImmune/VielaBio/Horizon, and UCB Biosciences. KF declares grants from Ministry of Education, Culture, Sports, Science and Technology of Japan and Ministry of Health, Welfare and Labor of Japan; has received personal compensation for consulting from Merck Biopharma, Japan Tobacco, and Abbvie; has received payment or honoraria forlectures and presentations from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, Teijin, Asahi Kasei Medical, Merck, and Takeda; declares participation in an Advisory Board for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, and UCB; serves as President of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid), President of the Japanese Society of Neuroimmunology (unpaid), is a Board Member of the Japan Multiple Sclerosis Society (unpaid), is a board member of theEuropean Charcot Foundation (unpaid), and is a Member of the International Medical and Scientific Board, MSIF (unpaid). All other authors declared no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The objective is to characterize differentially expressed proteins (DEPs) in Guillain-Barré Syndrome (GBS) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) through high-throughput analysis. Sera from 11 healthy controls (HCs), 21 GBS and 19 CIDP patients were subjected to Olink Proteomics Analysis. In the comparison between CIDP and GBS groups, up-regulation of ITM2A and down-regulation of NTF4 were observed. Comparing GBS with HCs revealed 18 up-regulated and 4 down-regulated proteins. Comparing CIDP with the HCs identified 15 up-regulated and 4 down-regulated proteins. Additionally, the correlation between clinical characteristics and DEPs were uncovered. In conclusion, the DEPs have significant potential to advance our understanding of the pathogenesis in these debilitating neurological disorders., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Intravenous thrombolysis using recombinant tissue plasminogen activator (tPA) remains the primary treatment for patients with acute ischemic stroke (AIS). However, the mechanism of tPA-related hemorrhagic transformation (HT) remains poorly understood. Elevation of histidine-rich glycoprotein (HRG) expression was detected by nano-liquid chromatography tandem mass spectrometry at 1 h following tPA infusion as compared to baseline prior to tPA infusion (discovery cohort, n = 10), which was subsequently confirmed in a validation cohort (n = 157) by ELISA. Surprisingly, no elevation of HRG was detected in individuals who subsequently developed HT. During in vitro experiments, HRG reduced neutrophil NETosis, inflammatory cytokine production, and migration across the blood-brain barrier induced by tPA. In a photothrombotic murine AIS model, HRG administration ameliorated HT with delayed thrombolysis, by inhibiting neutrophil immune infiltration and downregulating pro-inflammatory signaling pathways. Neutrophil depletion or NETosis inhibition also alleviated HT, whereas HRG siRNA treatment exacerbated HT. In conclusion, fluctuations in HRG levels may reflect tPA therapy and its associated HT. The inhibitory effect of HRG on neutrophils may counteract tPA-induced immune abnormalities and HT in patients with AIS., (© 2024. The Author(s).)

Objective: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON)., Methods: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present., Results: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%)., Interpretation: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic., Methods: This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records., Results: The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection ( p  < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p  = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p  < 0.001) emerged as independent risk factors for early MG exacerbation., Conclusion: Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Xu, Qin, Liu, Guo, Huang, Fan, Zhang, Qi, Zhang, Yang, Shi and Yang.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Neovascular age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Although it is known that nvAMD is associated with focal inflammation, understanding of the precise immune components governing this process remains limited. Here, we identified natural killer (NK) cells as a prominent lymphocyte population infiltrating the perivascular space of choroidal neovascularization (CNV) lesions in patients with nvAMD and in mouse models. Olink proteomic analysis and single-cell RNA sequencing combined with knockout studies demonstrated the involvement of C-C chemokine receptor 5 (CCR5) in NK cell recruitment and extravasation at the CNV sites of mice. Depletion of NK cells or inhibition of activating receptor NK group 2, member D (NKG2D) inhibited the formation of neutrophil extracellular traps, increased vascular leakage, and exacerbated pathological angiogenesis, indicating that NK cells restrain pathogenesis in this mouse model. Age is the strongest risk factor for AMD, and we show that NK cells from aged human donors exhibited a less cytotoxic phenotype. NK cells from old mice exhibited compromised protective effects in the CNV mouse model. In addition, interleukin-2 complex-mediated expansion of NK cells improved CNV formation in mice. Collectively, our study highlights NK cells as a potential therapeutic target for patients with nvAMD.

Background: Although trigeminal nerve involvement is a characteristic of multiple sclerosis (MS), its prevalence across studies varies greatly due to MRI resolution and cohort selection bias. The mechanism behind the site specificity of trigeminal nerve injury is still unclear. We aim to determine the prevalence of trigeminal nerve involvement in patients with MS in a consecutive 7T brain MRI cohort., Methods: This observational cohort originates from an ongoing China National Registry of Neuro-Inflammatory Diseases. Inclusion criteria were the following: age 18 years or older, diagnosis of MS according to the 2017 McDonald criteria and no clinical relapse within the preceding 3 months. Each participant underwent 7T MAGNETOM Terra scanner (Siemens, Erlangen, Germany), using a 32-channel phased array coil at Beijing Tiantan Hospital. T1-weighted magnetisation-prepared rapid acquisition gradient echoes, fluid-attenuated inversion recovery (FLAIR) and fluid and white matter suppression images were used to identify lesions. FLAIR* and T2* weighted images were used to identify central vein sign (CVS) within the trigeminal lesions., Results: 120 patients underwent 7T MRI scans between December 2021 and May 2023. 19/120 (15.8%) patients had a total of 45 trigeminal lesions, of which 11/19 (57.9%) were bilateral. The linear lesions extended along the trigeminal nerve, from the root entry zone (REZ) (57.8%, 26/45) to the pontine-medullary nucleus (42.2%, 19/45). 26.9% (7/26) of the lesions in REZ showed a typical central venous sign., Conclusion: In this 7T MRI cohort, the prevalence of trigeminal nerve involvement was 15.8%. Characteristic CVS was detected in 26.9% of lesions in REZ. This suggests an inflammatory demyelination mechanism of trigeminal nerve involvement in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Primary angiitis of the central nervous system (PACNS) is a rare vasculitis restricted to the brain, spinal cord, and leptomeninges. This study aimed to describe the imaging characteristics of patients with small vessel PACNS (SV-PACNS) using 7 T magnetic resonance imaging (MRI)., Methods: This ongoing prospective observational cohort study included patients who met the Calabrese and Mallek criteria and underwent 7 T MRI scan. The MRI protocol includes T1-weighted magnetization-prepared rapid gradient echo imaging, T2 star weighted imaging, and susceptibility-weighted imaging. Two experienced readers independently reviewed the neuroimages. Clinical data were extracted from the electronic patient records. The findings were then applied to a cohort of patients with large vessel central nervous system (CNS) vasculitis., Results: We included 21 patients with SV-PACNS from December 2021 to November 2023. Of these, 12 (57.14%) had cerebral cortical microhemorrhages with atrophy. The pattern with microhemorrhages was described in detail based on the gradient echo sequence, leading to the identification of what we have termed the "coral-like sign." The onset age of patients with coral-like sign (33.83 ± 9.93 years) appeared younger than that of patients without coral-like sign (42.11 ± 14.18 years) (P = 0.131). Furthermore, the cerebral lesions in patients with cortical microhemorrhagic SV-PACNS showed greater propensity toward bilateral lesions (P = 0.03). The coral-like sign was not observed in patients with large vessel CNS vasculitis., Interpretation: The key characteristics of the coral-like sign represent cerebral cortical diffuse microhemorrhages with atrophy, which may be an important MRI pattern of SV-PACNS. ANN NEUROL 2024;96:194-203., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3)., Design: Multicentre, double blind, randomised, placebo controlled trial., Setting: 244 hospitals in China between 11 August 2022 and 13 April 2023., Participants: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled., Interventions: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days., Main Outcome Measures: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat., Results: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83)., Conclusions: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L., Trial Registration: ClinicalTrials.gov, NCT05439356., Competing Interests: Declaration of interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from National Key R&D Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: We declare no competing interests. We thank the members of Beijing-Tianjin Center for Neuroinflammation for support and Elaine Shi and Samuel Shi for editorial assistance. The authors’ laboratories are funded in part by the National Natural Science Foundation of China (grant numbers 82171777 and 82320108007).

Background: Cardio-metabolic disorders (CMDs) are common in aging people and are pivotal risk factors for cardiovascular diseases (CVDs). Inflammation is involved in the pathogenesis of CVDs and aging, but the underlying inflammatory molecular phenotypes in CMDs and aging are still unknown., Method: We utilized multiple proteomics to detect 368 inflammatory proteins in the plasma of 30 subjects, including healthy young individuals, healthy elderly individuals, and elderly individuals with CMDs, by Proximity Extension Assay technology (PEA, O-link). Protein-protein interaction (PPI) network and functional modules were constructed to explore hub proteins in differentially expressed proteins (DEPs). The correlation between proteins and clinical traits of CMDs was analyzed and diagnostic value for CMDs of proteins was evaluated by ROC curve analysis., Result: Our results revealed that there were 161 DEPs (adjusted p < 0.05) in normal aging and EGF was the most differentially expressed hub protein in normal aging. Twenty-eight DEPs were found in elderly individuals with CMDs and MMP1 was the most differentially expressed hub protein in CMDs. After the intersection of DEPs in aging and CMDs, there were 10 overlapping proteins: SHMT1, MVK, EGLN1, SLC39A5, NCF2, CXCL6, IRAK4, REG4, PTPN6, and PRDX5. These proteins were significantly correlated with the level of HDL-C, TG, or FPG in plasma. They were verified to have good diagnostic value for CMDs in aging with an AUC > 0.7. Among these, EGLN1, NCF2, REG4, and SLC39A2 were prominently increased both in normal aging and aging with CMDs., Conclusion: Our results could reveal molecular markers for normal aging and CMDs, which need to be further expanded the sample size and to be further investigated to predict their significance for CVDs., (© 2024. The Author(s).)

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 anti-acetylcholine 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.

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.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)-rich ADEVs in patients with AQP4-Abs-positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE 130-149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor-related protein 1 (LRP1) could block the restorative effects of APOE 130-149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE -/- mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Objective: To characterize the susceptibility-weighted image (SWI) features including paramagnetic rim and nodular lesions with signal intensity changes and central vein sign (CVS) associated with aquaporin 4 (AQP4)-immunoglobulin G (IgG)-negative neuromyelitis optica spectrum disorder (NMOSD), and explore whether they can be used as potential imaging biomarkers for differentiating multiple sclerosis (MS) from this disorder., Methods: We prospectively recruited NMOSD with AQP4-IgG-negative (AQP4- NMOSD) and IgG-positive (AQP4+ NMOSD), and MS subjects from the Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE) project (NCT0410683) between 2019 and 2021. The SWI features including paramagnetic rim and nodular lesions with signal intensity changes and CVS were analyzed and compared among groups, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined for distinguishing MS from AQP4- NMOSD., Results: We enrolled a total of 160 consecutive patients (22 AQP4- NMOSD, 65 AQP4+ NMOSD, and 73 MS). We observed paramagnetic rim lesion (0/120 lesions, 0 %) and nodular (1/120, 1 %) lesions with hypointense signals on SWI in the AQP4- NMOSD group. These characteristics were similar to those recorded from AQP4+ NMOSD patients (rim: 0/369 lesions, 0 %, P = 1.000; nodular: 10/369 lesions, 2.7 %, P = 1.000), but differed significantly from those observed in the MS group (rim: 162/1665 lesions, 9.7 %, P<0.001; nodular: 392/1665 lesions, 23.5 %, P < 0.001). AQP4- NMOSD patients had fewer average CVS+ rate (12 %) than MS patients (46 %, p<0.001), similar to AQP4+ NMOSD (13 %, p = 1.000). The SWI imaging features denoting lesions with paramagnetic rim or nodular hypointense SWI signals showed 90.4 % sensitivity, 95.5 % specificity, 98.5 % PPV, and 75 % NPV, and the criteria with≥3 CVS lesions showed sensitivity of 91.8 %, specificity of 90.9 %%, PPV of 97.1 %, and NPV of 76.9 % in distinguishing MS from AQP4- NMOSD., Discussion: The SWI imaging features including lesions with paramagnetic rim or nodular hypointense SWI signals and 3 CVS lesions carries useful information in distinguishing MS from AQP4- NMOSD., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023. Published by Elsevier B.V.)

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., (© 2023. The Author(s).)

Intraventricular hemorrhage (IVH) commonly occurs as an extension of intracerebral hemorrhage (ICH) into the brain ventricular system, leading to worse outcomes without effective management. Using a mouse model of IVH, we found that impaired neurogenesis is evident in the subventricular zone (SVZ), along with persistent microglia activation, leukocyte infiltration and cell death. Pharmacological depletion of microglia using PLX3397, an inhibitor of colony stimulating factor 1 receptor (CSF1R), promotes neurogenesis, and alleviated delayed functional impairments in IVH mice. Meanwhile, an elevated level of microglia-derived CC chemokine ligand 20 (CCL20) is observed in the SVZ following IVH, which can induce the upregulation of pro-inflammatory factors in microglia and impair the proliferation and survival of neural stem cells (NSCs) in vitro. Blocking CCL20 in microglia leads to downregulation of protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/the nuclear factor-κB (NF-κB) signaling pathway, which may contribute to CCL20-dependent pro-inflammatory responses and neural injury. These findings demonstrate a detrimental role of microglia in the neurogenesis and neurorepair after IVH in which CCL20 likely plays a role., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

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.

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Intravenous thrombolysis via tPA (tissue-type plasminogen activator) is the only approved pharmacological treatment for acute ischemic stroke, but its benefits are limited by hemorrhagic transformation. Emerging evidence reveals that tPA swiftly mobilizes immune cells which extravasate into the brain parenchyma via the cerebral vasculature, augmenting neurovascular inflammation, and tissue injury. In this review, we summarize the pronounced alterations of immune cells induced by tPA in patients with stroke and experimental stroke models. We argue that neuroinflammation, triggered by ischemia-induced cell death and exacerbated by tPA, compromises neurovascular integrity and the microcirculation, leading to hemorrhagic transformation. Finally, we discuss current and future approaches to attenuate thrombolysis-associated hemorrhagic transformation via uncoupling immune cells from the neurovascular unit., Competing Interests: Disclosures None.

Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease., Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD 2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat., Trial Registry Name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356.

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 < 0.0001)., Interpretation: CBA has a higher diagnostic accuracy compared to RIPA or ELISA in detecting AChR and MuSK autoantibodies for MG diagnosis., Funding: New Terrain Biotechnology, Inc., Tianjin, China., Competing Interests: All authors declare no competing interests., (© 2023 The Author(s).)

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., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Ralf Gold has received research support and speaker’s honoraria from Bayer Schering, Biogen, Bristol Myers Squibb, Chugai, Eisai, Janssen, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi Genzyme and TEVA; and consulting honoraria from ZLB Behring, Baxter, Merck, MIMS and Talecris. He holds personal stock options in Bayer, Merck, Novartis and Roche. Dr Michael Barnett has received institutional support for research or speaking from Alexion, Biogen, Merck, Roche, BMS and Sanofi Genzyme; is Research Director, Sydney Neuroimaging Analysis Centre and Research Consultant, RxMx. Dr Andrew Chan has received speakers’/board honoraria from Actelion (Janssen/Johnson & Johnson), Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb (Celgene), Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche and Teva, all for hospital research funds. Beyond this project, Dr Huiyu Feng has no further disclosures. Dr Kazuo Fujihara serves as an advisor or on scientific advisory boards for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco and AbbVie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio, Teijin, Asahi Kasei Medical, Merck and Takeda and has received the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labour of Japan. In the last 2 years, Dr Gavin Giovannoni has received compensation for serving as a consultant or speaker for or has received research support from AbbVie, Aslan, Atara Bio, Biogen, Bristol Myers Squibb (Celgene), GlaxoSmithKline, Janssen/J&J, Japan Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi and Roche/Genentech. In the last 5 years, Dr Giovannoni has received grant support for research from Biogen, Merck KGaA/EMD Serono, Novartis, Sanofi, Roche/Genentech and Takeda. Dr Xavier Montalbán has received speaking honoraria and travel expenses for participation in scientific meetings, has been a Steering Committee member of clinical trials or participated in advisory boards of clinical trials in the past years with AbbVie, Actelion, Alexion, Biogen, Bristol Myers Squibb (Celgene), EMD Serono, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen, MedDay, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi Genzyme, Teva Pharmaceuticals, TG Therapeutics, Excemed, Multiple Sclerosis International Federation and National Multiple Sclerosis Society. Beyond this project, Dr Fu-Dong Shi has no further disclosures. Dr Mar Tintoré has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals and participates on the Data Safety Monitoring Boards for Parexel and UCB Biopharma. Beyond this project, Dr Qun Xue has no further disclosures. Beyond this project, Dr Chunsheng Yang has no further disclosures. Beyond this project, Dr Hongyu Zhou has no further disclosures., (© The Author(s), 2023.)

Competing Interests: Declaration of Competing Interest J.S, SY.X, DC.T, YY.D, XL.X, S.L, GM.C, FD.S, ZZ.Z, XH.Z and Y.L declared there is no conflict of interest. D.C. is a consultant for Biogen and Hoffmann-La Roche. In the last three years he has received research funding from Hoffmann-La Roche, the International Progressive MS Alliance, the MS Society, and the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research center, and a speaker's honorarium from Novartis. He co-supervises a clinical fellowship at the National Hospital for Neurology and Neurosurgery, London, which is supported by Merck. F.B acts as a consultant for Bayer-Schering, Biogen-Idec, GeNeuro, Ixico, Merck-Serono, Novartis and Roche. He has received grants, or grants are pending, from the Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) initiative, the Biomedical Research center at University College London Hospitals, the Dutch MS Society, ECTRIMS–MAGNIMS, EU-H2020, the Dutch Research Council (NWO), the UK MS Society, and the National Institute for Health Research, University College London. He has received payments for the development of educational presentations from Ixico and his institution from Biogen-Idec and Merck. He is on the editorial board of Radiology, Neuroradiology, Multiple Sclerosis Journal and Neurology.

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., (© 2023. The Author(s).)

Objective: To investigate the clinical efficacy and safety of percutaneous foraminal endoscopy in the treatment of lumbar lateral recess stenosis in elderly., Methods: The clinical data of 31 elderly patients with lumbar lateral recess stenosis treated by percutaneous foraminal endoscopic decompression from March 2018 to August 2019 were retrospectively analyzed. Including 16 males and 15 females, aged from 65 to 81 years with an average of (71.13±5.20) years, the course of disease ranged from 3 months to 7 years with an average of (14.36±6.52) months. Visual analogue scale (VAS) and Oswestry disability index (ODI) were used to assess clinical symptom and functional status before operation and 1, 6, 12 months after operation. At the final follow-up, the modified Macnab standard was used to evaluate clinical efficacy., Results: All patients were completed the operation successfully. The operation time was from 75 to 120 min with an average of (97.84±11.22 ) min. All 31 patients were followed up from 12 to 28 months with an average of (17.29±5.56) months. Postoperative lumbago-leg pain VAS and ODI were significantly improved at 1, 6, and 12 months( P <0.01). At the final follow-up, according to the modified Macnab standard to evaluate the effect, 23 got excellent results, 5 good, 3 fair. One patient had severe adhesions between peripheral tissues and nerve root, and postoperative sensory abnormalities in the lower extremities were treated conservatively with traditional Chinese medicine and neurotrophic drugs, which recovered at 2 weeks after surgery. No complications such as nerve root injury and infection occurred., Conclusion: The intervertebral foraminal endoscopy technique, which is performed under local anesthesia for a short period of operation, ensures adequate decompression while minimizing complications, and is a safe and effective surgical procedure for elderly patients with lumbar lateral recess stenosis.

Background: Epilepsy is a neurological condition that causes unprovoked, recurrent seizures. Accumulating evidence from clinical and experimental studies indicates that neuroinflammation exacerbates seizure activity., Methods: We investigated the transcriptional changes occurring in specific brain domains of a seizure mouse model, using 10× Genomics spatial transcriptomics. Differential gene expression and pathway analysis were applied to investigate potential signaling targets for seizure, including CCL5/CCR5 pathway. Maraviroc, an FDA-approved C-C chemokine receptor 5 (CCR5) antagonist, was used to verify the impact of CCL5/CCR5 signaling in seizure mice., Results: We found distinguished regional transcriptome features in the hippocampus of seizure mice. The hippocampus exhibited unique inflammatory gene signatures, including glia activation, apoptosis, and immune response in seizure mice. Especially, we observed notable expression of C-C chemokine ligand 5 (CCL5) throughout the entire seizure hippocampus. Blockade of CCL5/CCR5 signaling via maraviroc prevented microglia activation and neuron degeneration in seizure mice., Conclusions: This study supports the potential of CCL5/CCR5 signaling for targeting neuroinflammation after seizure., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Immunosuppression commonly occurs after a stroke, which is believed to be associated with the increased risk of infectious comorbidities of stroke patients, while the mechanisms underlying post-stroke immunosuppression is yet to be elucidated. In the brains of intracerebral hemorrhage (ICH) patients and murine ICH models, we identified that neuron-derived programmed death-ligand 1 (PD-L1) is reduced in the perihematomal area, associating increased soluble PD-L1 level in the peripheral blood. ICH induced a significant decrease of T and natural killer (NK) cell numbers in the periphery with an upregulation of programed death-1 (PD-1) in these cells. Blocking PD-1 pathway with an anti-PD1 monoclonal antibody prevented the T and NK cell compartment contraction and spleen atrophy post-ICH, with reduced pulmonary bacterial burden and improved neurological outcome. Thus, we here identified that brain-derived PD-L1 as a new mechanism driving post-stroke immunosuppression, and anti-PD1 treatment could be potentially developed to reducing the risk of post-stroke infections.

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 < 0.001, respectively), but comparable to AQP4-ON eyes. The vessel density in retina capillary plexus (RCP) was reduced significantly in MOGAD-ON than that in AQP4-ON (p < 0.05, respectively). The visual accuracy was positively correlated with vessel density of superficial RCP in MOG-ON (p = 0.001) and positively correlated with the thickness of the inner retina layer in AQP4-ON (p < 0.001)., Conclusion: The retinal neuro-axonal damages between MOGAD-ON and AQP4-ON were comparable. Unlike AQP4-ON eyes, microvascular densities were significantly reduced in MOGAD-ON and were positively correlated with the deterioration of visual acuity in MOGAD-ON., Trial Registration: Clinical and Imaging Patterns of Neuroinflammation Diseases in China (CLUE, NCT: 04106830)., (© 2022. The Author(s).)