Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disorder that mainly affects children and young women. The Fas system contains both membrane-bound versions of Fas (mFas) and Fas ligand (mFasL), and soluble versions (sFas and sFasL), which play important roles in apoptosis and regulation of the immune system. Both the levels of sFas and sFasL and the role they play in anti-NMDAR disease pathogenesis remain unclear. Methods: Forty-eight pairs of cerebrospinal fluid (CSF) and serum were collected from patients with anti-NMDAR encephalitis, encephalitis of other causes or peripheral neuropathy. The CSF and serum concentrations of sFas and sFasL were determined with enzyme-linked immunosorbent assay. Results: CSF concentrations of sFas and sFasL were both incresased in anti-NMDAR encephalitis patients compared with controls patients. Serum sFas levels were also elevated in anti-NMDAR encephalitis patients relative to controls. sFas and sFasL concentrations in CSF positively correlated with the modified Rankin scale (mRS) both at onset and 6-month follow-up. Conclusion: CSF sFas and sFasL levels were elevated in anti-NMDAR encephalitis patients, and reflect the disease severity of anti-NMDAR encephalitis.
Objective: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis predominantly affects children and young women; the disease can have a multistage presentation and exhibit a wide variety of neuropsychiatric features. This study aimed to investigate the profile of YKL-40 (Chitinase 3-like 1) in anti-NMDAR encephalitis patients and evaluate its association with modified Rankin Scale (mRS) scores and expression of inflammatory cytokines. Methods: A total of 66 patients were enrolled in this study, 33 with anti-NMDAR encephalitis, 13 with viral meningitis and 20 with non-inflammatory neurological disease. Patients were evaluated to determine mRS scores at disease onset and at the 3-month follow-up; cerebrospinal fluid (CSF) samples were collected in the meantime. CSF levels of YKL-40 and cytokines (TNF-α, IL-6, IL-10) were measured by enzyme-linked immunosorbent assay. Results: CSF levels of YKL-40 and inflammatory cytokines (TNF-α, IL-6, IL-10) were all more highly elevated in patients with anti-NMDAR encephalitis at the acute stage of disease compared with the controls. Levels of CSF YKL-40 were correlated with levels of IL-6 both at disease onset and at the 3-month follow-up. Changes in YKL-40 levels were significantly correlated with improved mRS scores in patients with anti-NMDAR encephalitis. Conclusion: Our study suggests that CSF levels of YKL-40 in patients with anti-NMDAR encephalitis were increased and correlated with clinical mRS scores. This may be reflective of the underlying neuroinflammatory process. YKL-40 demonstrates potential as a possible biomarker for the prognosis of anti-NMDAR encephalitis.
Abstract Anti-N-methyl-D-aspartate receptor (NMDA) receptor encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesias, and seizures. Ectopic expression of NMDA receptors associated with ovarian teratoma is thought to mediate the initial autoimmune response against NMDA receptor encephalitis. Due to the lack of suitable animal models, the underlying mechanism of the disease remains unclear. This study described a new mice model of active immunization against the NMDA receptor with amino-terminal domain (ATD) peptides. After 12 weeks of immunization, mice were showed significant behavioral disorders and memory loss. Antibodies from CSF of immunized mice decreased surface NMDAR cluster density on hippocampus neurons. It also impaired the LTP induced at the Schaffer collateral to CA1 synapse and reduced NMDA receptors-induced calcium influx. The new model may help further research into the pathogenesis of the disease and the development of potential new therapies.
Abstract BackgroundIDO1 is the initial and rate-limiting enzyme that metabolizes tryptophan (TRP) to kynurenine (KYN). IDO1-dependent neurotoxic KYN metabolism plays a crucial role in pathogenesis of many neurodegenerative disorders. However, the function of IDO1 in epilepsy is still unclear. MethodsPatients with epilepsy and controls were enrolled. Male C57BL/6 mice and IDO1 knockout (KO) mice were subjected to intraperitoneal injection of lithium and pilocarpine to induce epilepsy. The level of IDO1 and concentrations of TRP and KYN in the patients with epilepsy and epileptic mice were evaluated by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry (LC-MS) respectively. Then, SRS and neuronal damage was compared between KO and wild-type (WT) mice in lithium-pilocarpine-induced epilepsy. To explore underlying pathways involved in IDO1 deficiency, concentrations of kynurenic acid (KYNA) and quinolinic acid (QUIN), glial cells activation, major pro-inflammatory cytokines, and antioxidant enzymes activity were measured by LC-MS, immunohistochemistry and ELISA.ResultsIn this study, IDO1 level and KYN/TRP ratio were increased in the patients with epilepsy and epileptic mice. IDO1 deficiency attenuated the frequency, duration and severity of SRS and improved neuronal survival. Additionally, IDO1 -/- epileptic mice showed a progressive decline in QUIN production, glial cells activation and pro-inflammatory cytokines and enhanced antioxidant enzymes activity.ConclusionsIDO1 deletion alleviated SRS and neuronal damage in the chronic period after SE through a reduction in IDO1-dependent neurotoxic metabolites, which finally inhibited pro-inflammatory cytokine production and glial cells activation and improved antioxidant enzymes activity. Our study demonstrates that IDO1 may be involved in the pathogenesis of epilepsy and has potential to be a therapeutic target for the treatment of epilepsy.
Abstract Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. This study describes a novel mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using amino-terminal domain peptides. After 12 weeks of immunization, the mice showed significant behavioral disorders and memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice lowered the surface NMDAR cluster density in hippocampal neurons. Immunization also impaired long-term potentiation at Schaffer collateral–CA1 synapses and reduced NMDAR-induced calcium influx. This novel mouse model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.
Abstract Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently discovered autoimmune syndrome associated with psychosis, dyskinesia, and seizures. However, the underlying mechanisms of this disease remain unclear, in part because of a lack of suitable animal models. Methods This study describes a novel female C57BL/6 mouse model of anti-NMDAR encephalitis that was induced by active immunization against NMDARs using an amino terminal domain (ATD) peptide from the GluN1 subunit (GluN1 356–385 ). Results Twelve weeks after immunization, the immunized mice showed significant memory loss. Furthermore, antibodies from the cerebrospinal fluid of immunized mice decreased the surface NMDAR cluster density in hippocampal neurons which was similar to the effect induced by the anti-NMDAR encephalitis patients’ antibodies. Immunization also impaired long-term potentiation at Schaffer collateral–CA1 synapses and reduced NMDAR-induced calcium influx. Conclusion We established a novel anti-NMDAR encephalitis model using active immunization with peptide GluN1 356–385 targeting the ATD of GluN1. This novel model may allow further research into the pathogenesis of anti-NMDAR encephalitis and aid in the development of new therapies for this disease.
Abstract The circadian rhythm system consists of a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks dispersed throughout other brain areas (including striatum, Str) as well as various tissues and organs. Circadian rhythm disturbance is a major risk factor and common comorbidity for mood disorders, especially anxiety and depression. Bmal1 is one of the fundamental clock protein genes that is required to maintain circadian rhythm. Recent research has revealed a link between suprachiasmatic nucleus dysfunction and anxiety and depression, but the underlying mechanisms remain to be fully elucidated. This study aimed to investigate how circadian rhythm disturbance may lead to anxiety and depression-like behaviors. Through behavioral tests, virus tracing, molecular biology and other techniques, we found neural connection from the suprachiasmatic nucleus to the striatum. SCN lesions and Bmal1flox/flox+pAAV-hSyn-Cre-GFP (conditional knockout, cKO) mice exhibited disruptions in core body temperature rhythm, as well as anxiety- and depression-like behaviors. Importantly, these mice displayed altered expression patterns of clock protein genes and an upregulation of the Brain-Derived Neurotrophic Factor (BDNF) - Tyrosine Kinase receptor B (TrkB) signaling pathway within the striatum. Microinjection of the TrkB inhibitor ANA-12 can effectively reverse anxiety and depression-like behaviors. These findings indicate that suprachiasmatic nucleus dysfunction may contribute to the pathogenesis of anxiety and depression through upregulation of the BDNF-TrkB pathway in the striatum, potentially mediated by neural projections from the SCN. Bmal1 gene within SCN may represent a novel therapeutic target for mood disorders.
Background: There is conflicting data regarding transcatheter aortic valve replacement in patients with paradoxical low-flow, low-gradient aortic stenosis (pLFLG-AS). The authors aimed to examine the hemodynamic and clinical benefit of transcatheter aortic valve replacement in symptomatic patients with pLFLG-AS compared with high-gradient severe AS. Methods: A single-center retrospective analysis of patients who underwent transcatheter aortic valve replacement using a transfemoral approach was performed. Patients with a mean gradient ≥40 mm Hg were included in the high-gradient aortic stenosis (HG-AS) group (n=217). Patients with mean gradient <40 mm Hg, Vmax <4.0 m/s, and stroke volume index ≤35 mL/m 2 were included in the pLFLG-AS group (n=73). Clinical end points including treatment futility, survival, changes in functional status and quality of life, and echocardiographic outcomes of left ventricular reverse remodeling were evaluated. Two primary composite outcomes were used for treatment futility. The first as a composite outcome defined as death or New York Heart Association class III/IV at 1 year. The second was a composite of death or Kansas City Cardiomyopathy Questionnaire 12 score of ≤25 at 1 year. Results: There were no differences in mortality, the Kansas City Cardiomyopathy Questionnaire-based treatment futility outcome (HG-AS: 8.8% versus pLFLG-AS: 6.1%; P =0.482), or New York Heart Association-based treatment futility outcome (HG-AS: 9.1% versus pLFLG-AS: 11.6%; P =0.546) at 1 year. Both groups had similar improvement in mean Kansas City Cardiomyopathy Questionnaire 12 score when compared to baseline (HG-AS: 88.56±12.38% versus pLFLG-AS: 137.24±31.75%; P =0.382). There was a similar relative interval decrease in the proportion of patients with New York Heart Association class III/IV (HG-AS: 53.6% versus pLFLG-AS: 55.1%; P =0.838). Echocardiographic evidence of reverse remodeling of the left ventricle in pLFLG-AS group was documented by improvements in global longitudinal strain (pre: −13.95±0.36% versus post: −14.83±0.38%, P =0.004) and stroke volume index at 30 days. Conclusions: pLFLG-AS did not confer a worse prognosis. Mortality rate and functional class improvement at 1 year was similar in both groups. Left ventricular reverse remodeling in the pLFLG-AS group was apparent.
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