The presence of autoantibodies against myelin oligodendrocyte glycoprotein (MOG) is a hallmark of MOG antibody-associated disease (MOGAD), a recently defined demyelinating disease entity presenting with core clinical features of optic neuritis, myelitis, and acute disseminated encephalomyelitis. Although MOG antibodies have also been described in a small number of patients with other conditions, including mental disorders, their prevalence and clinical specificity in patients with isolated psychotic symptoms remain unclear. Here, we screened sera from 262 patients with at least one psychotic episode and 166 control subjects for the presence of MOG antibodies of the immunoglobulin G (IgG) isotype with a live cell-based assay. Serum reactivity to additional antigens was assessed by immunohistochemistry. Four patients, representing 1.5% of the patient cohort, and one control individual, representing. 0.6% of the healthy control cohort, were seropositive for MOG-IgG antibodies. Of the four MOG-IgG seropositive patients, three experienced visual hallucinations. Overall, MOG antibodies were detected at a low frequency in patients with psychotic episodes. While we cannot exclude the possibility of false-positive results or seroconversion due to secondary myelin damage, the association with visual hallucinations in three out of four MOG-IgG seropositive patients may point toward an underlying autoimmune etiology.

BackgroundAnti-GAD65 autoantibodies (GAD65-Abs) may occur in patients with epilepsy and other neurological disorders, but the clinical significance is not clear-cut. Whereas high levels of GAD65-Abs are considered pathogenic in neuropsychiatric disorders, low or moderate levels are only considered as mere bystanders in, e.g., diabetes mellitus type 1 (DM1). The value of cell-based assays (CBA) and immunohistochemistry (IHC) for GAD65-Abs detection has not been clearly evaluated in this context. ObjectiveTo re-evaluate the assumption that high levels of GAD65-Abs are related to neuropsychiatric disorders and lower levels only to DM1 and to compare ELISA results with CBA and IHC to determine the additional value of these tests. Methods111 sera previously assessed for GAD65-Abs by ELISA in routine clinical practice were studied. Clinical indications for testing were, e.g., suspected autoimmune encephalitis or epilepsy (neuropsychiatric cohort; n = 71, 7 cases were initially tested positive for GAD65-Abs by ELISA), and DM1 or latent autoimmune diabetes in adults (DM1/LADA cohort (n = 40, all were initially tested positive)). Sera were re-tested for GAD65-Abs by ELISA, CBA, and IHC. Also, we examined the possible presence of GAD67-Abs by CBA and of other neuronal autoantibodies by IHC. Samples that showed IHC patterns different from GAD65 were further tested by selected CBAs. ResultsELISA retested GAD65-Abs level in patients with neuropsychiatric diseases was higher than in patients with DM1/LADA (only retested positive samples were compared; 6 vs. 38; median 47,092 U/mL vs. 581 U/mL; p = 0.02). GAD-Abs showed positive both by CBA and IHC only if antibody levels were above 10,000 U/mL, without a difference in prevalence between the studied cohorts. We found other neuronal antibodies in one patient with epilepsy (mGluR1-Abs, GAD-Abs negative), and in a patient with encephalitis, and two patients with LADA. ConclusionGAD65-Abs levels are significantly higher in patients with neuropsychiatric disease than in patients with DM1/LADA, however, positivity in CBA and IHC only correlates with high levels of GAD65-Abs, and not with the underlying diseases.

Finding new methods for generating human monoclonal antibodies is an active research field that is important for both basic and applied sciences, including the development of immunotherapeutics. However, the techniques to identify and produce such antibodies tend to be arduous and sometimes the heavy and light chain pair of the antibodies are dissociated. Here, we describe a relatively simple, straightforward protocol to produce human recombinant monoclonal antibodies from human peripheral blood mononuclear cells using immortalization with Epstein-Barr Virus (EBV) and Toll-like receptor 9 activation. With an adequate staining, B cells producing antibodies can be isolated for subsequent immortalization and clonal expansion. The antibody transcripts produced by the immortalized B cell clones can be amplified by PCR, sequenced as corresponding heavy and light chain pairs and cloned into immunoglobulin expression vectors. The antibodies obtained with this technique can be powerful tools to study relevant human immune responses, including autoimmunity, and create the basis for new therapeutics.

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders.

Hashimoto's encephalopathy is an encephalitis of presumed autoimmune origin characterized by the presence of autoantibodies against thyroid proteins. We present a case of a young patient with pre-existing Hashimoto's thyroiditis and progressive cognitive complaints, absence-like episodes, and sporadic bilateral epileptiform frontal and frontotemporal activity. No abnormalities were observed during the neurological examination and on MRI. Antibodies to thyroid peroxidase (TPO) were elevated and remained positive while the symptoms were present. Levothyroxine and methylprednisolone did not ameliorate the complaints. Subsequent treatment with high-dose intravenous immunoglobulins (IVIG) led to improved cognitive functions and to the disappearance of the absence-like-episodes. Patient's serum, but not CSF, gave a characteristic IgG-specific hippocampal pattern in rat brain immunohistochemistry; this immunoreactivity was maintained after specific and complete depletion of TPO antibodies. Serum IgG bound to primary neurons in cell culture, likely targeting a yet unidentified neuronal surface antigen. The clinical response to IVIG suggests but does not prove, that the circulating novel autoantibodies may induce the encephalopathy. It would be of interest to investigate more patients with Hashimoto's encephalopathy for the presence of neuronal surface autoantibodies, to define their role in the disease and their target antigen(s).

This study examines the prevalence of autoantibodies against neuronal surface antigens in the sera of individuals with psychotic disorders compared with control participants.

Psychotic disorders are debilitating mental illnesses associated with abnormalities in various neurotransmitter systems. The development of disease-modifing therapies has been hampered by the mostly unknown etiologies and pathophysiologies. Autoantibodies against several neuronal antigens are responsible for autoimmune encephalitis. These autoantibodies disrupt neurotransmission within the brain, resulting in a wide range of psychiatric and neurologic manifestations, including psychosis. The overlap of symptoms of autoimmune encephalitis with psychotic disorders raised the question as to whether autoantibodies against a number of receptors, ion channel and associated proteins could ultimately be responsible for some forms of psychosis. Here we review our current knowledge, on antibody mediated autoimmunity in psychotic disorders, the different diagnostic methods and their limitations, as well as on varying therapeutic approaches targeting the immune system.

Objective: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients. Methods: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N = 119). Results: Out of 119 patients, 17 (143%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30 years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p = 0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n = 8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group. Conclusion: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort. (C) 2018 Elsevier Inc. All rights reserved.

The conflict of interest section was missing in the published paper [1]. It has been updated as follows: [...]

The α7 acetylcholine receptor (AChR) has been linked with the onset of psychotic symptoms and we hypothesized therefore that it might also be an autoimmune target. Here, we describe a new radioimmunoassay (RIA) using iodine 125-labelled α-bungarotoxin and membrane extract from transfected HEK293 cells expressing human α7 AChR. This RIA was used to analyze sera pertaining to a cohort of 711 subjects, comprising 368 patients diagnosed with schizophrenia spectrum disorders, 140 with bipolar disorder, 58 individuals diagnosed of other mental disorders, and 118 healthy comparison subjects. We identified one patient whose serum tested positive although with very low levels (0.2 nM) for α7 AChR-specific antibodies by RIA. Three out of 711 sera contained antibodies against iodine 125-labelled α-bungarotoxin, because they precipitated with it in the absence of α7 AChR. This first evidence suggests that autoantibodies against α7 AChR are absent or very rare in these clinical groups.

Little is known about the etiology of neuropsychiatric disorders. The identification of autoantibodies targeting the N-methyl-d-aspartate receptor (NMDA-R), which causes neurological and psychiatric symptoms, has reinvigorated the hypothesis that other patient subgroups may also suffer from an underlying autoimmune condition. In recent years, a wide range of neuropsychiatric diseases and autoantibodies targeting ion-channels or neuronal receptors including NMDA-R, voltage gated potassium channel complex (VGKC complex), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R), γ-aminobutyric acid receptor (GABA-R) and dopamine receptor (DR) were studied and conflicting reports have been published regarding the seroprevalence of these autoantibodies. A clear causative role of autoantibodies on psychiatric symptoms has as yet only been shown for the NMDA-R. Several other autoantibodies have been related to the presence of certain symptoms and antibody effector mechanisms have been proposed. However, extensive clinical studies with large multicenter efforts to standardize diagnostic procedures for autoimmune etiology and animal studies are needed to confirm the pathogenicity of these autoantibodies. In this review, we discuss the current knowledge of neuronal autoantibodies in the major neuropsychiatric disorders: psychotic, major depression, autism spectrum, obsessive-compulsive and attention-deficit/hyperactivity disorders.

Autoimmune diseases are affecting around 7.6-9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs). It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders. However, less is known about other conditions such as depression. Depression is a psychiatric disorder with complex etiology and pathogenesis. The diagnosis criteria of depression are largely based on symptoms but not on the origin of the disease. The question which arises is whether in a subgroup of patients with depression, the symptoms might be caused by autoantibodies targeting membrane-associated antigens. Here, we describe how autoantibodies targeting membrane proteins and ion channels cause pathological effects. We discuss the physiology of these antigens and their role in relation to depression. Finally, we summarize a number of studies detecting NSAbs with a special focus on cohorts that include depression diagnosis and/or show depressive symptoms.

MHeNs Research Day | 23 Abstract Surname First name Division: Page 1 Aldehri Majed Division 3 24 2 Argyrousi Elentina Division 3 25 3 Banning Leonie Division 1 26 4 Beek, van Maarten Division 3 27 5 Berk Lotte Division 1 28 6 Bertens Christian Division 3 29 7 Bohler Sacha Other 30 8 Bos Isabelle Division 1 31 9 Crivelli Simone Division 3 32 10 Dam Alieske Division 1 33 11 Damas Marina Division 3 34 12 Damas Marina Division 3 35 12 Damas Marina Division 3 36 14 Deckers Kay Division 1 37 15 Douven Elles Division 1 38 16 Drenthen Gerhard Division 1 39 17 Duin, van Esther Division 2 40 18 Eijkenboom Ivo Other 41 19 Erdag Ece Division 3 42 20 Franken Glenn Division 3 43 21 Freeze Whitney Division 1 44 22 Greef, de Bianca Division 1 45 23 Gruters Angelique Division 1 46 24 Heckman Pim Division 3 47 25 Hoffmann Carolin Division 3 48 26 Hohnen Ramona Division 3 49 27 Hoogen, van den Nynke Division 3 51 28 Hubens Wouter Division 3 52 29 Janssen Niels Division 1 53 30 Janssen Paul Division 3 54 31 Kerpershoek Liselot Division 1 55 32 Kreiter Daniel Division 2 56 33 Lange Iris Division 2 57 34 Meuwissen Koen Division 3 58 35 Mulders Anne Division 3 59 36 Müller-Ehrenberg Lisa Division 1 60 37 Nijs, de Laurence Division 3 61 38 Priovoulos Nikos Division 1 62 39 Pruppers Mariëlle Division 1 63 40 Reij, van Roel Division 3 64 41 Rolf Linda Division 1 65 42 Schaper Frederic Division 3 66 43 Sopacua Maurice Division 1 67 44 Strekalova Tatyana Division 3 68 45 Veenendaal, van Tamar Division 1 69 46 Vergoossen Laura Division 1 70 47 Verhagen Simone Division 2 71 48 Verheggen Inge Division 1 72 49 Vruwink Marianne Division 1 73 50 Weidner Magdalena Division 3 74 51 Weijers Jonas Division 2 75 52 Wijesinghe Printha Division 3 76 53 Wong May Division 1 77 54 Xenakis Markos Other 78 55 Zalm, van der Yvonne Division 2 79 56 Zong Shenghua Division 3 80 57 Zwieten, van Gusta Division 3 81Surname First name Division: Page 1 Aldehri Majed Division 3 24 2 Argyrousi Elentina Division 3 25 3 Banning Leonie Division 1 26 4 Beek, van Maarten Division 3 27 5 Berk Lotte Division 1 28 6 Bertens Christian Division 3 29 7 Bohler Sacha Other 30 8 Bos Isabelle Division 1 31 9 Crivelli Simone Division 3 32 10 Dam Alieske Division 1 33 11 Damas Marina Division 3 34 12 Damas Marina Division 3 35 12 Damas Marina Division 3 36 14 Deckers Kay Division 1 37 15 Douven Elles Division 1 38 16 Drenthen Gerhard Division 1 39 17 Duin, van Esther Division 2 40 18 Eijkenboom Ivo Other 41 19 Erdag Ece Division 3 42 20 Franken Glenn Division 3 43 21 Freeze Whitney Division 1 44 22 Greef, de Bianca Division 1 45 23 Gruters Angelique Division 1 46 24 Heckman Pim Division 3 47 25 Hoffmann Carolin Division 3 48 26 Hohnen Ramona Division 3 49 27 Hoogen, van den Nynke Division 3 51 28 Hubens Wouter Division 3 52 29 Janssen Niels Division 1 53 30 Janssen Paul Division 3 54 31 Kerpershoek Liselot Division 1 55 32 Kreiter Daniel Division 2 56 33 Lange Iris Division 2 57 34 Meuwissen Koen Division 3 58 35 Mulders Anne Division 3 59 36 Müller-Ehrenberg Lisa Division 1 60 37 Nijs, de Laurence Division 3 61 38 Priovoulos Nikos Division 1 62 39 Pruppers Mariëlle Division 1 63 40 Reij, van Roel Division 3 64 41 Rolf Linda Division 1 65 42 Schaper Frederic Division 3 66 43 Sopacua Maurice Division 1 67 44 Strekalova Tatyana Division 3 68 45 Veenendaal, van Tamar Division 1 69 46 Vergoossen Laura Division 1 70 47 Verhagen Simone Division 2 71 48 Verheggen Inge Division 1 72 49 Vruwink Marianne Division 1 73 50 Weidner Magdalena Division 3 74 51 Weijers Jonas Division 2 75 52 Wijesinghe Printha Division 3 76 53 Wong May Division 1 77 54 Xenakis Markos Other 78 55 Zalm, van der Yvonne Division 2 79 56 Zong Shenghua Division 3 80 57 Zwieten, van Gusta Division 3 81 MHeNs Research Day | 24 Fornix DBS enhances long-term spatial memory independent of hippocampal neuroplasticity Majed Aldehri, Yasin Temel, Ali Jahanshahi, Sarah Hescham Departments of Neuroscience and Neurosurgery, Maastricht University, Maastricht, The Netherlands Introduction: Deep brain stimulation (DBS) of the fornix can restore memory functions in animals with experimental dementia. We have shown that one potential underlying mechanism is the enhanced release of acetylcholine in the hippocampus. Another suggested mechanism of action is neuronal plasticity. Objective: Here, we have tested the hypothesis that acute fornix DBS can have long-term beneficial effects on memory by enhancing histological parameters of neuronal and synaptic plasticity. Materials and Methods: Rats were implanted with bilateral electrodes at the site of the fornix and received DBS at 100 Hz, 100 μA and 100 μs pulse width for 4 h. Three days after stimulation, rats received BrdU injections twice daily for a period of 3 days. After 5 weeks, fornix DBS and sham rats were tested in the water maze task. Probe trials were given after 1 h and 48 h. About 6.5 weeks after DBS, rats were sacrificed and their brains processed for BrdU/NeuN, p-CREB or synaptophysin immunohistochemistry. Results: Fornix DBS rats visited the target annulus more frequently than sham rats in the probe trial with 1 h delay. We did not find any differences for the number of double-labelled BrdU/NeuN or p-CREB cells for fornix DBS rats when compared to sham. Synaptophysinimmunoreactive presynaptic boutons, however, were significantly decreased in the CA1 and CA3 subfield of the hippocampus for fornix DBS rats when compared to sham. Conclusion: Fornix DBS enhances long-term spatial memory independent of the neuroplasticity markers, which were used in the present study. An interesting finding is the decrease in the synaptic-neuroplasticity marker, which might suggest a long-term depression related mechanism.

BACKGROUND:Changes that occur in the behaviour of voltage-gated ion channels and ligand-gated receptor channels due to gene mutations or auto-immune attack are the cause of channelopathies in the central and peripheral nervous system. Although the relation between molecular channel defects and clinical symptoms has been explained in the case of many neuromuscular channelopathies, the pathophysiology of auto-immunity in neuropsychiatric syndromes is still unclear.AIM:To review recent findings regarding neuronal auto-immune reactions in severe neuropsychiatric syndromes.METHOD:Using PubMed, we consulted the literature published between 1990 and August 2014 relating to the occurrence of auto-immune antibodies in severe and persistent neuropsychiatric syndromes.RESULTS:Auto-antibodies have only limited access to the central nervous system, but if they do enter the system they can, in some cases, cause disease. We discuss recent findings regarding the occurrence of auto-antibodies against ligand-activated receptor channels and potassium channels in neuropsychiatric and neurological syndromes, including schizophrenia and limbic encephalitis.CONCLUSION:Although the occurrence of several auto-antibodies in schizophrenia has been confirmed, there is still no proof of a causal relationship in the syndrome. We still have no evidence of the prevalence of auto-immunity in neuropsychiatric syndromes. The discovery that an antibody against an ion channel is associated with some neuropsychiatric disorders may mean that in future it will be possible to treat patients by means of immunosuppression, which could lead to an improvement in a patient's cognitive abilities.

large number of acutely ill patients with first-episode psycho-

Finding new methods for generating human monoclonal antibodies is an active research field that is important for both basic and applied sciences, including the development of immunotherapeutics. However, the techniques to identify and produce such antibodies tend to be arduous and sometimes the heavy and light chain pair of the antibodies are dissociated. Here, we describe a relatively simple, straightforward protocol to produce human recombinant monoclonal antibodies from human peripheral blood mononuclear cells using immortalization with Epstein-Barr Virus (EBV) and Toll-like receptor 9 activation. With an adequate staining, B cells producing antibodies can be isolated for subsequent immortalization and clonal expansion. The antibody transcripts produced by the immortalized B cell clones can be amplified by PCR, sequenced as corresponding heavy and light chain pairs and cloned into immunoglobulin expression vectors. The antibodies obtained with this technique can be powerful tools to study relevant human immune responses, including autoimmunity, and create the basis for new therapeutics.