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Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood-brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients., Methods: In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients' peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2 -/- Il2rg -/- Sirpα NOD Flk2 -/- mice., Results: We found that engraftment of patients' PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1β as a hub gene implicated in pathological changes. We further demonstrated that Il-1β was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors., Conclusions: Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient's lymphocytes., (© 2023. The Author(s).)

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis shows a predilection for affecting the limbic system, but structural MRI in most patients is usually unremarkable. However, the functional connectivity reorganization of limbic nodes remains unknown. Serum neurofilament light chains (sNfL) are clinically linked with the disease severity and neurological disability of anti-NMDAR encephalitis. However, the relationship between sNfL and limbic-based functional architecture has not been explored. We consecutively recruited 20 convalescent patients with anti-NMDAR encephalitis and 24 healthy controls from March 2018 to March 2021. Resting-state functional MRI metrics, including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), and atlas-based seed functional connectivity, were analyzed to investigate regional activities and functional connectivity alterations. Correlation analysis among functional connectivity, sNfL, Mini-Mental State Examination (MMSE), and Montreal cognitive assessment outcomes were explored in patients. Compared with those of healthy controls, the fALFF and ReHo were consistently increased in regions of the posterior default mode network (DMN) hub, mainly the bilateral supramarginal gyrus and precuneus, in patients with anti-NMDAR encephalitis (FWE-corrected p < 0.05). Patients demonstrated disturbed functional organization characterized by reduced connectivity of the posterior DMN hub with the sensorimotor cortex and hypoconnectivity of the parahippocampal gyrus (PHG) with the right fusiform gyrus but extensively enhanced thalamocortical connectivity (FWE-corrected p < 0.05). Furthermore, convalescent sNfL showed a positive correlation with enhanced thalamocortical connectivity (r = 0.4659, p = 0.0384). Onset sNfL with an independent linear correlation to convalescent MMSE performance (B coefficient, -0.013, 95% CI, -0.025 ~ -0.002, p = 0.0260) was positively correlated with intra-DMN connectivity (r = 0.8969, p < 0.0001) and limbic-sensory connectivity (r = 0.4866, p = 0.0346 for hippocampus seed and r = 0.5218, p = 0.0220 for PHG seed). Patients with anti-NMDAR encephalitis demonstrated disturbed functional organization with substantial thalamocortical hyperconnectivity, that was positively correlated with convalescent sNfL. Onset sNfL showed a positive correlation with intra-DMN connectivity and limbic-sensory connectivity., (© 2022 International Society for Neurochemistry.)

Introduction: Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum NfL levels as a prognostic marker for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE)., Methods: Serum levels of NfL of 64 patients with anti-NMDARE and 84 healthy controls were measured by Simoa. The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score, Modified Rankin Scale (mRS) scores, and clinical and cerebrospinal fluid parameters were evaluated in patients with anti-NMDARE. Meanwhile, we performed a receiver-operator characteristic analysis to assess the power of the serum NFL in predicting the 1-year functional status., Results: Serum NfL levels were significantly elevated in patients with anti-NMDARE compared to healthy controls (p < 0.001, p adjusted  < 0.001), especially in patients with severe impairments (mRS > 3 vs ≤ 3, p = 0.035) or with limited response to treatment (vs. favorable outcome, p = 0.011). Serum NFL was positively associated with the initial admission mRS (r = 0.23, p = 0.072) and 1-year mRS (r = 0.29, p = 0.018). The AUC of serum NfL and NEOS score for 1-year poor functional status was 0.697 (95% CI 0.527-0.866, p = 0.011), 0.753 (95% CI 0.616-0.890, p = 0.001), respectively. Furthermore, AUC of the combination of serum NfL and NEOS was 0.815 (95% CI 0.680-0.950, p < 0.001)., Conclusion: Our findings show that serum NfL levels evaluated in anti-NMDAR encephalitis may be a good predictor of the risk of 1-year poor functional status., (© 2022. Fondazione Società Italiana di Neurologia.)

Anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) is a B cell- and antibody-mediated autoimmune disease which may be regulated by CD40/CD40L signaling pathway. we enrolled anti-NMDARE patients and measured the serum CD40 and CD40L concentrations. The serum concentration of CD40 was decreased, while CD40L was increased in anti-NMDARE patients compared with that of healthy controls. The concentrations of CD40 and CD40L were both elevated in the acute stage of anti-NMDARE and were reduced during remission. Serum CD40L levels were positively correlated with serum CD40 levels. These results revealed that the CD40/CD40L signaling pathway might contribute to the pathogenesis of anti-NMDARE., (Copyright © 2021. Published by Elsevier B.V.)

Background: Uric acid (UA) levels are associated with autoimmune and neurodegenerative disorders, but their relationship with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is unknown., Methods: UA levels were evaluated in 58 patients with anti-NMDAR encephalitis, and 58 age- and sex-matched healthy controls (CTLs). Follow-up evaluations of 30 out of the 58 patients with anti-NMDAR encephalitis were conducted 3 months after admission. Modified Rankin scale (mRS) scores and clinical and cerebrospinal fluid parameters were evaluated in all anti-NMDAR encephalitis patients., Results: Serum UA levels were significantly lower in patients with anti-NMDAR encephalitis than those in CTLs (p < 0.001), and this was especially evident in patients with severe impairments (mRS ≥ 4 vs. <4, p = 0.004) or with limited response to treatment (vs. favourable outcome, p = 0.002). Follow-up evaluations revealed that serum UA levels normalized after treatment, with significantly increased serum UA levels (p < 0.001), and that mRS scores were significantly lower (p < 0.001) than those before treatment. In addition, serum UA levels were significantly associated with mRS scores (r = -0.463, p < 0.001)., Conclusion: Our results showed that serum UA levels in patients with anti-NMDAR encephalitis are reduced during attacks compared with those in CTLs, are normalized after treatment, and are associated with disease severity., (Copyright © 2017. Published by Elsevier Ltd.)