The serum metabolomic profile of a distinct, inflammatory subtype of acute psychosis.

A range of studies suggest that a proportion of psychosis may have an autoimmune basis, but this has not translated through into clinical practice-there is no biochemical test able to accurately identify psychosis resulting from an underlying inflammatory cause. Such a test would be an important step towards identifying who might require different treatments and have the potential to improve outcomes for patients. To identify novel subgroups within patients with acute psychosis we measured the serum nuclear magnetic resonance (NMR) metabolite profiles of 75 patients who had identified antibodies (anti-glycine receptor [GlyR], voltage-gated potassium channel [VGKC], Contactin-associated protein-like 2 [CASPR2], leucine-rich glioma inactivated 1 [LGI1], N-methyl-D-aspartate receptor [NMDAR] antibody) and 70 antibody negative patients matched for age, gender, and ethnicity. Clinical symptoms were assessed using the positive and negative syndrome scale (PANSS). Unsupervised principal component analysis identified two distinct biochemical signatures within the cohort. Orthogonal partial least squared discriminatory analysis revealed that the serum metabolomes of NMDAR, LGI1, and CASPR2 antibody psychosis patients were indistinct from the antibody negative control group while VGKC and GlyR antibody patients had significantly decreased lipoprotein fatty acids and increased amino acid concentrations. Furthermore, these patients had more severe presentation with higher PANSS scores than either the antibody negative controls or the NMDAR, LGI1, and CASPR2 antibody groups. These results suggest that a proportion of patients with acute psychosis have a distinct clinical and biochemical phenotype that may indicate an inflammatory subtype.

Anti-NR2 glutamate receptor antibodies as an early biomarker of cerebral small vessel disease.

OBJECTIVES: Cerebral small vessel disease (SVD) associated with age and vascular risk factors is one of the leading causes of cognitive disorders as well as ischemic and hemorrhagic strokes. The pathogenesis of this disease has not been fully understood yet. The previously established association of the antibodies against the NR2 subunit of the NMDA receptor (NR2ab) with the mechanisms of SVD such as ischemia and blood-brain barrier (BBB) disruption, might suggest their importance in the brain damage. DESIGN & METHODS: We studied the NR2ab serum level in 70 patients (45 females, 61.1 ± 6.3 y.o.) with different severity of cognitive impairment and MRI features of SVD and 20 healthy volunteers (12 females, 58.5 ± 6.4 y.o.). RESULTS: The elevated level of NR2ab was associated with subjective cognitive impairment (SCI) (p = 0.028) and mild cognitive impairment (MCI) (p = 0.017), Fazekas grade (F) 2 (p = 0,002) and F3 (p = 0,009) of white matter hyperintensities (WMH) and the numbers of lacunes in the cerebral white matter (less than 5) (p = 0,039). CONCLUSION: The detected increase in serum NR2ab level in patients with SCI, as well as the minimal amount of white matter lacunes, is most likely caused by hypoxia-induced endothelial damage in the early stage of SVD. Normal NR2ab values in patients with F1 WMH, the increased NR2ab level in patients with F2 and F3 WMH and those with the minimal number of lacunes can indicate that NR2bs are involved in diffuse brain damage due to hypoxia-induced loss of BBB integrity.

Influence of methodological and patient factors on serum NMDAR IgG antibody detection in psychotic disorders: a meta-analysis of cross-sectional and case-control studies.

BACKGROUND: Antibodies targeting the N-methyl-D-aspartate receptor (NMDAR) have been detected in patients with psychosis. However, studies measuring the IgG subclass in serum have provided variable estimates of prevalence, and it is unclear whether these antibodies are more common in patients than controls. Because these inconsistencies could be due to methodological approaches and patient characteristics, we aimed to investigate the effect of these factors on heterogeneity. METHODS: We searched Web of Science and Ovid (MEDLINE and PsycINFO) for cross-sectional and case-control studies published between Jan 1, 2000, and May 5, 2019, that reported NMDAR IgG antibody seropositivity in patients with psychosis. Pooled proportions and odds ratios (ORs) were derived using random-effects models. We estimated between-study variance (τ2) and the proportion of observed variance due to heterogeneity (I2). We then used univariable random-effects meta-regression analysis to investigate the effect of study factors on heterogeneity of proportions and ORs. Our protocol was registered on PROSPERO (CRD42018099874). FINDINGS: Of 1276 articles in the initial search, 28 studies were eligible for inclusion, including 14 cross-sectional studies and 14 case-control studies. In cross-sectional studies, NMDAR IgG antibodies were detected in 0·73% (95% CI 0·09-1·38; I2 56%; p=0·026) of patients with psychosis, and in case-control studies, patients with psychosis were not significantly more likely to be seropositive than healthy individuals (OR 1·57, 95% CI 0·78-3·16; I2 15%; p=0·20). Meta-regression analyses indicated that heterogeneity was significantly associated with assay type across both study designs, illness stage in cross-sectional studies, and study quality in case-control studies. Compared with studies using a fixed cell-based assay, cross-sectional and case-control studies using the live method yielded higher pooled prevalence estimates (0·36% [95% CI -0·23 to 0·95] vs 2·97% [0·70 to 5·25]) and higher ORs (0·65 [0·33 to 1·29] vs 4·43 [1·73 to 11·36]). In cross-sectional studies, the prevalence was higher in exclusively first-episode samples than in multi-episode or mixed samples (2·18% [0·25 to 4·12] vs 0·16% [-0·31 to 0·63]), and in case-control studies, higher ORs were reported in low-quality studies than in high-quality studies (3·80 [1·47 to 9·83] vs 0·72 [0·36 to 1·42]). INTERPRETATION: Higher estimates of NMDAR IgG antibody prevalence have been obtained with the live cell-based assay, and studies using this method find that seropositivity is more common in patients with psychosis than in controls. The effects of illness stage and study quality on heterogeneity were not consistent across study designs, and we provide clear recommendations for clinicians and researchers regarding interpreting these findings. FUNDING: None.

Exploratory investigation on antibodies to GluN1 and cognitive dysfunction in patients with chronic autoimmune psychosis.

INTRODUCTION: Mild cognitive dysfunction has been implicated in a number of psychiatric diseases and affects social functioning. Although clinical criteria were recently proposed for autoimmune psychosis (AP), biomarkers have not yet been established for the severity and prognosis of cognitive dysfunction. We herein investigated the relationships between 3 types of serum antibodies and cognitive dysfunction in chronic psychiatric patients suspected of AP. METHODS: We included 31 patients suspected of AP and obtained information on their clinical characteristics. Three types of autoantibodies (the anti-N-methyl-D-aspartate receptor (anti-NMDAR Ab), anti-N-terminal of GluN1 (anti-GluN1-NT Ab), and anti-thyroid antibodies) were evaluated in serum. Cognitive function was assessed using Wechsler Adult Intelligence Scale-III. We examined the relationships between serum autoantibodies and cognitive dysfunction in patients using multiple regression models. RESULTS: Serum titers of anti-GluN1-NT Ab significantly contributed to the estimated score of working memory (B= -55.85, ß= -0.46, p= 0.01), while no correlation was observed between the other 2 types of antibodies and cognitive function. CONCLUSIONS: The present results indicate the potential of serum anti-GluN1-NT Ab as a biomarker for the severity and prognosis of cognitive dysfunction underlying various psychiatric symptoms in patients with AP. The pathological significance of anti-GluN1-NT Ab needs to be verified in future studies.

Paroxysmal dysarthria-ataxia syndrome: Literature review on MRI findings and report of a peculiar case with clinically isolated syndrome coexisting with anti-N-methyl-d-aspartate receptor antibodies.

Paroxysmal dysarthria and ataxia (PDA) syndrome constitutes a rare neurological disorder, and is generally reported in cases of multiple sclerosis (MS) involving the midbrain. We present an illustrative case of 32-year-old female who developed clinically isolated syndrome manifested paroxysmal dysarthria, ataxia, ptosis and diplopia, coexisting with anti-N-methyl-d-aspartate receptor antibodies. We review the literature and identify 23 other cases with brain MRI examinations to summarize the lesion locations and clinical characteristics of PDA syndrome, and ultimately provide a new framework for understanding this rare condition. The current case expands the spectrum of symptoms in PDA syndrome, which was including but not limited to dysarthria and ataxia. Caudal paramedian midbrain lesions involving decussation of the superior cerebellar peduncles appear to be critical for PDA syndrome.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Challenging Diagnosis in the Emergency Department.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an underdiagnosed disease that has been described thus far only in case series. Patients, the majority of which are females, develop neuropsychiatric symptoms that can often be misdiagnosed as purely psychiatric illness. Although teratomas are nearly pathognomonic for anti-NMDAR encephalitis, these are less common in children and males. This case illustrates some common features of anti-NMDAR encephalitis and some of the challenges in diagnosis.

Elevated serum anti-NMDA receptor antibody levels in first-episode patients with schizophrenia.

Accumulating evidence has shown that N-methyl-D-aspartate (NMDA) glutamate receptors (NMDAR) are implicated in the pathophysiology of neurological and psychiatric disorders, and that patients with NMDAR antibody encephalitis develop psychopathological symptoms. Therefore, we hypothesized that NMDAR antibodies play a key role in the etiology of schizophrenia. In this study, we enrolled 110 first-episode patients with schizophrenia (FEP) and 50 healthy controls (HC). Cognitive function and psychopathology were assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. NMDAR antibody levels were measured using enzyme-linked immunosorbent assay. Our results showed that FEP with schizophrenia exhibited cognitive deficits in all domains of the MCCB and had elevated levels of serum anti-NMDAR antibody compared with the healthy controls (9.2 ±â€¯3.5 vs. 7.3 ±â€¯2.9 ng/ml, t = 3.10, p = 0.002). Furthermore, serum antibody levels were positively correlated with PANSS positive, negative and total score, and inversely correlated with performances of verbal learning and memory, working memory, speed of processing and MCCB total score in the patient group. These results indicate that elevated levels of NMDAR antibody may play a role in the pathogenesis of schizophrenia, leading to NMDAR dysfunction, thereby inducing symptoms of psychosis and cognitive impairment. Therefore, NMDAR antibodies may serve as a biomarker and provide a new avenue for treatment of schizophrenia.

Longitudinal brain morphology in anti-NMDA receptor encephalitis: a case report with controls.

BACKGROUND: Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is a severe autoimmune condition, which typically affects young females. The long-term clinical consequences and brain morphology changes after anti-NMDAR encephalitis are not well known. CASE PRESENTATION: We present clinical and neuroimaging follow-up data on a 25-year female patient with typically presenting anti-NMDAR encephalitis. Longitudinal analyses of brain morphology were done using 3 T structural magnetic resonance imaging (sMRI) and Freesurfer analysis at the time of diagnosis and after symptomatic remission. The presented case attained good functional recovery after standard immunoglobulin-corticosteroid treatment but elevated serum NMDAR antibody levels persisted. The patient had no symptomatic relapses during a 3-year clinical follow-up. In the baseline brain sMRI scan there were no marked volume changes. However, a follow-up sMRI after 9 months indicated clear volume reductions in frontal cortical regions compared to matched controls with identical sMRI scans. CONCLUSIONS: This case report of anti-NMDAR encephalitis suggests that despite clinical recovery long-term brain morphological changes can develop in the frontal cortex. Longer clinical and imaging follow-up studies are needed to see whether these frontocortical alterations are fully reversible and if not, can they result in trait vulnerabilities for e.g. neuropsychiatric disorders.

MiR-664-2 impacts pubertal development in a precocious-puberty rat model through targeting the NMDA receptor-1†.

Precocious puberty (PP) commonly results from premature activation of the hypothalamic-pituitary-gonadal axis (HPGA). Gonadotropin-releasing hormone (GnRH) is the initial trigger for HPGA activation and plays an important role in puberty onset. N-methyl-D-aspartate (NMDA) can promote pulsatile GnRH secretion and accelerates puberty onset. However, the mechanism of N-methyl-D-aspartate receptors (NMDARs) in PP pathogenesis remains obscure. We found that serum GnRH, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen (E2) levels, hypothalamic NMDAR1, and GnRH mRNA expression peaked at the vaginal opening (VO) day. Next, the hypothalamic NMDAR1 mRNA and protein levels in rats treated with danazol, a chemical commonly effecting on the reproductive system, were significantly increased at the VO day (postnatal day 24) compared to controls, accompanied by enhanced serum GnRH, LH, FSH, and E2 levels. Further, microRNA-664-2 (miR-664-2) was selected after bioinformatics analysis and approved in primary hypothalamic neurons, which binds to the 3'-untranslated regions of NMDAR1. Consistently, the miR-664-2 expression in hypothalamus of the Danazol group was decreased compared to Vehicle. Our results suggested that attenuated miR-664-2 might participate in PP pathogenesis through enhancing the NMDAR1 signaling.

N-methyl-D-aspartate receptor dysfunction by unmutated human antibodies against the NR1 subunit.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most common autoimmune encephalitis related to autoantibody-mediated synaptic dysfunction. Cerebrospinal fluid-derived human monoclonal NR1 autoantibodies showed low numbers of somatic hypermutations or were unmutated. These unexpected germline-configured antibodies showed weaker binding to the NMDAR than matured antibodies from the same patient. In primary hippocampal neurons, germline NR1 autoantibodies strongly and specifically reduced total and synaptic NMDAR currents in a dose- and time-dependent manner. The findings suggest that functional NMDAR antibodies are part of the human naïve B cell repertoire. Given their effects on synaptic function, they might contribute to a broad spectrum of neuropsychiatric symptoms. Ann Neurol 2019;85:771-776.

Gut permeability and mimicry of the Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) as potential mechanisms related to a subgroup of people with schizophrenia with elevated antigliadin antibodies (AGA IgG).

About one third of people with schizophrenia have elevated IgG antibodies to gliadin (AGA IgG) and increased inflammation. Understanding the mechanism by which this immune response occurs is critical to the development of personalized treatments. We examined gut permeability and mimicry to the glutamate receptor as possible mechanisms related to high gliadin antibodies (AGA IgG) seen in some people with schizophrenia. The Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1 (GRINA) has a similar protein structure to gliadin representing a potential target for cross reactivity or mimicry. In a population of schizophrenia subjects (N = 160) and healthy controls (N = 80) we analyzed serum samples for both GRINA and Anti-Saccharomyces Cerevisiae antibodies (ASCA), related to gut permeability. Schizophrenia patients compared to controls had a higher prevalence of positivity to ASCA IgA (p = 0.004) and IgG (p < 0.001). Multinomial logistic regression showed an association between AGA IgG and ASCA IgG in schizophrenia (p = 0.05 for the estimated regression coefficient) but not in healthy controls (p = 0.13). GRINA IgG was higher in schizophrenia patients than in healthy controls (0.43 ±â€¯0.30 vs. 0.22 ±â€¯0.24, p < 0.001). Logistic regressions showed an association between AGA IgG and GRINA IgG in schizophrenia (p = 0.016 for the estimated regression coefficient) but not for the controls (p = 0.471). Thus, we propose that mimicry through the presence of cross-reactivity between gliadin and GRINA might disrupt the functions of the glutamate system and relate to illness pathophysiology in those with schizophrenia and elevated AGA IgG.

Predictors of neural-specific autoantibodies and immunotherapy response in patients with cognitive dysfunction.

Recognition of autoimmunity as a cause of encephalopathy has increased. Recent studies have validated the use of Antibody-Prevalence-in-Epilepsy (APE) and Responsive-to-immunotherapy-in-Epilepsy (RITE) scores in the evaluation and management of autoimmune-epilepsy. We aim to assess the utility of these models for patients with cognitive dysfunction. Among the evaluated patients, 17% had antibodies universally associated with autoimmune-encephalopathy. NMDA-R-IgG and LGI1-IgG were the most common antibody specificities. Antibody-Prevalence-in-Epilepsy-and-Encephalopathy (APE2) score ≥ 4 was 99% sensitive and 93% specific for neural-specific-antibodies. Responsive-to-immunotherapy-in-Epilepsy-and-Encephalopathy (RITE2) score ≥ 7 had 96% sensitivity and 86% specificity for favorable initial immunotherapy response. Application of these models may optimize autoantibody evaluations and immunotherapeutic trials.

Expression analysis of GRIN2B, BDNF, and IL-1ß genes in the whole blood of epileptic patients.

Epilepsy is a brain disorder with a global prevalence of 1%. It has been attributed to genetics and environmental factors. Despite efforts to identify the molecular pathology of epilepsy, the underlying mechanism is not understood yet. This study was carried out to compare GRIN2B, BDNF, and IL-1ß gene expressions in 50 patients suffering from generalized epilepsy with tonic-colonic seizures and 50 age- and sex-matched healthy subjects using TaqMan Real-time PCR. Our results demonstrated significant upregulation of these genes in people with epilepsy compared with healthy subjects. We also found a positive correlation between GRIN2B and BDNF expression (r2=0.4619, p < 0.0001), BDNF and IL-1ß expression (r2 = 0.515, p < 0.0001), and GRIN2B and IL-1ß gene expressions (r2 = 0.666, p < 0.0001) which implies the possibility to estimate the expression level of these genes by assessment of expression of one of them. Considering the results of the previous animal studies which showed upregulation of these genes in brain tissues of epileptic animals, the expression levels of GRIN2B, BDNF, and IL-1ß in blood samples might be related to their expression in brain samples. Future studies are needed to assess the role of these genes in the pathogenesis of epilepsy and evaluate whether altered expression of these genes along with imaging methods can facilitate subtyping the epilepsy.

Low plasma concentrations of N-methyl-d-aspartate receptor subunits as a possible biomarker for psychosis.

BACKGROUND: N-methyl-d-aspartate receptor (NMDAR) has been largely implicated in the neurobiology of schizophrenia and other psychosis. Aiming to evaluate their potential as peripheral biomarkers for psychosis, we quantified the plasma concentrations of NR1 and NR2 NMDAR subunits of first-episode psychosis patients in their first contact with mental health services due to psychotic symptoms, compared with siblings and matched community-based controls. METHODS: The quantifications of NR1 and NR2 plasma concentrations were performed by ELISA. Data were analysed by nonparametric tests and Receiver Operating Curve (ROC) analysis. RESULTS: We included 166 first-episode psychosis patients (mean age = 30.3 ±â€¯12.2 years; 64% men), with the diagnosis of schizophrenia spectrum (n = 84), bipolar disorder (n = 51) and psychotic depression (n = 31), 76 siblings (mean age = 31.5 ±â€¯11.0 years; 30.3% men) and 166 healthy community-based controls (mean age = 31.4 ±â€¯12.0 years; 63.9% men). NMDAR subunits were significantly lower in patients compared with siblings and controls (p < 0.001), except by NR1 plasma concentrations of bipolar patients compared with siblings and controls. NR1 plasma concentrations lower than 17.65 pg/ml (AUC = 0.621) showed sensitivity of 42.8%, specificity of 84.3%, positive predictive value (PPV) of 73.2% and negative predictive value (NPV) of 59.6%. Individuals with NR2 plasma concentrations lower than 2.92 ng/ml (AUC = 0.801) presented a 10.61-fold increased risk of psychosis, with a sensibility of 71.9%, specificity of 80.6%, PPV of 79.0% and NPV of 73.9%. CONCLUSIONS: This is the first study reporting the measurement and the reduction of NR1 and NR2 NMDAR subunits plasma concentrations in psychiatric disorders. In particular, the NR2 subunit may be a possible plasma biomarker for psychosis.

Unusual case of anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis and autoimmune polyglandular syndrome (APS).

Anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis is a novel disease discovered within the past 10 years. It is an autoimmune disease (AD) that has been associated with other ADs, such as Graves' disease. However, association with autoimmune polyglandular syndromes (APS) has not been previously described. A 58-year-old woman presented with altered mental status and an 8-month history of weight loss, apathy and somnolence. Laboratory evaluation confirmed Graves' disease with thyrotoxicosis and type 1 diabetes mellitus. Despite treatment, she continued to have a fluctuating mental status. Further diagnostic evaluation included an abdominal MRI that showed a cystic lobular left adnexal mass. Serum anti-NMDA-R antibodies were positive, raising concern for NMDA-R encephalitis. Bilateral salpingo-oophorectomy was performed, with pathology consistent with cystadenofibroma. She had a favourable recovery with marked clinical improvement. Anti-NMDA-R antibodies were negative 2 months following surgery. The concomitant occurrence of APS and anti-NMDA-R encephalitis suggests a shared mechanism of autoimmune pathophysiology.

Anaesthetic management of a patient with a unique combination of anti-N-methyl-D-aspartate receptor encephalitis and stiff-person syndrome.

Stiff-person syndrome (SPS) and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis are rare paraneoplastic syndromes caused by antibodies that target the central nervous system. Here, we describe a 26-year-old woman who presented with psychosis, amnesia, rigidity and fever. After extensive diagnostic and laboratory workup, she was diagnosed with an ovarian teratoma which was causing the symptoms of anti-NMDAR encephalitis and SPS. The patient was successfully treated with laparoscopic removal of the ovarian tumour under general anaesthesia. She was placed on immunosuppressant medications preoperatively and postoperatively, and her symptoms gradually resolved. Although there are case reports regarding the anaesthetic management of SPS and anti-NMDAR encephalitis, our study is the first report of a patient afflicted with both conditions.

N-methyl-D-aspartate receptor antibody production from germinal center reactions: Therapeutic implications.

INTRODUCTION: N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1-IgG production and the contribution of germinal center B cells to NR1-IgG levels are unknown. METHODS: Clinical data and longitudinal paired serum NR1-reactive IgM and IgG levels from 10 patients with NMDAR-antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1-specific antibodies. RESULTS: In addition to disease-defining NR1-IgG, serum NR1-IgM was found in 6 of 10 patients. NR1-IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+ CD27++ CD38++ antibody-secreting cells in vitro and, from 90% of patients, secreted NR1-IgM and NR1-IgG. Secreted levels of NR1-IgG correlated with serum NR1-IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1-IgG in culture. INTERPRETATION: Serum NR1-IgM and NR1-IgG, alongside the consistent production of NR1-IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1-IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR-antibody encephalitis. Ann Neurol 2018;83:553-561.

A Simple Cell-based Immunofluorescence Assay to Detect Autoantibody Against the N-Methyl-D-Aspartate (NMDA) Receptor in Blood.

The presence of anti-NMDA receptor autoantibody can cause various neuropsychiatric symptoms in the affected patients, termed anti-NMDA receptor autoimmune encephalitis. Detection of the specific autoantibody against the NMDA receptor in the blood or cerebrospinal fluid (CSF) is essential for the accurate diagnosis of this condition. The NMDA receptor is an ion channel protein complex that contains four subunits, including two mandatory NMDA receptor subunit 1 (NR1) and one or two NMDA receptor subunit 2A (NR2A), NMDA receptor subunit 2B (NR2B), NMDA receptor subunit 2C (NR2C), or NMDA receptor subunit 2D (NR2D). The epitope of anti-NMDA receptor autoantibody was reported to be present at the extracellular N-terminal domain of the NR1 subunit of the NMDA receptor. The goal of this study is to develop a simple cell-based immunofluorescence assay that can be used as a screening test to detect the presence of autoantibodies against NR1 subunit of the NMDA receptor in the blood to facilitate the clinical and basic research of anti-NMDA receptor autoimmune encephalitis.

A Phase Ib Randomized Controlled Study to Evaluate the Effectiveness of a Single-Dose of the NR2B Selective N-Methyl-D-Aspartate Antagonist MK-0657 on Levodopa-Induced Dyskinesias and Motor Symptoms in Patients With Parkinson Disease.

OBJECTIVES: Blockade of N-methyl-D-aspartate receptors containing the NR2B subunit has been shown to be therapeutic in animal models of Parkinson disease (PD). However, findings with investigational NR2B receptor antagonists in PD patients have been mixed. The objective of this study was to evaluate the effects of the NR2B selective N-methyl-D-aspartate receptor antagonist MK-0657 on levodopa-induced dyskinesias and motor symptoms in PD patients. METHODS: A randomized, double-blind, single-dose, 2-period crossover study was conducted in 22 patients with PD and levodopa-induced peak-dose dyskinesias. Patients received oral MK-0657 (7 mg) or placebo, in randomized order, on each of 2 test days. On both days, levodopa was administered as a 2-hour intravenous infusion at greater than or equal to 1 mg/kg per hour with frequent assessments of dyskinesia, motor function, and pharmacokinetics. RESULTS: MK-0657 7 mg had no significant effect on dyskinesias (difference versus placebo in modified Abnormal Involuntary Movement Scale mean change from baseline area under the curve over 5 hours, -2.3; 95% confidence interval, -5.1 to 0.4) or motor function (difference versus placebo in Unified Parkinson's Disease Rating Scale Part III mean change from baseline area under the curve over 5 hours, 13.9; 95% confidence interval, -1.7 to 29.5). MK-0657 7 mg achieved the target mean maximum plasma concentration of 400 nM. CONCLUSIONS: These data suggest that a single dose of MK-0657 7 mg is not effective in improving levodopa-induced dyskinesias and motor symptoms in PD patients. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT00505843.