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OBJECTIVES: Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context. METHODS: Therefore, two patients with psychosis and anti-MOG antibodies - detected in fixed cell-based and live cell-based assays - are presented. RESULTS: Patient 1 suffered from late-onset psychosis with singular white matter lesions in magnetic resonance imaging (MRI) and intermittent electroencephalography (EEG) slowing. Patient 2 suffered from a chronic paranoid-hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganised alpha rhythm on EEG, and elevated cerebrospinal fluid protein. Both patients had anti-MOG antibody titres of 1 : 320 in serum (reference < 1 : 20). CONCLUSIONS: The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titres, they may have caused a rather 'subtle clinical picture' consisting of psychosis instead of 'classical' MOG encephalomyelitis.
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Autoanticuerpos , Encefalomielitis , Glicoproteína Mielina-Oligodendrócito , Trastornos Psicóticos , Humanos , Imagen por Resonancia Magnética , Glicoproteína Mielina-Oligodendrócito/inmunologíaRESUMEN
Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), and PAI-1 (p < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.
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INTRODUCTION: Although the link between autoimmune thyroiditis and mental illnesses is well established, the precise underlying pathophysiology and the influence of anti-thyroid antibodies on diagnostic findings require further research. PATIENTS AND METHODS: A total of 530 patients with schizophreniform and affective syndromes were screened for anti-thyroid antibodies against thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid-stimulating hormone receptor (TSH-R). The patient group analyzed here is a patient subgroup of a previously published cohort (Endres et al., 2020, Translational Psychiatry). The anti-thyroid antibody positive (N = 91) and negative (N = 439) patients were compared in terms of various clinical parameters, routine cerebrospinal fluid (CSF) findings, and the number of positive anti-neuronal antibodies in serum and/or CSF, as well as electroencephalography (EEG), magnetic resonance imaging (MRI), and [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) findings. RESULTS: Anti-TPO antibodies were increased in 17%, anti-TG antibodies in 15%, and anti-TSH-R antibodies in 2% of all patients. In CSF, higher protein concentrations (p = 0.018) and albumin quotients (p = 0.008) were found in the anti-thyroid antibody positive patient group. Also, there were more patients with elevated age-corrected albumin quotients in this group (p = 0.031). FDG-PET hypometabolism was significantly more frequent and the number of positive anti-neuronal intracellular antibodies was significantly higher in patients with anti-thyroid antibodies (p = 0.048, N = 29 and p = 0.032, N = 497 respectively). In addition, there was a trend for higher white blood cell (WBC) counts in all patients with anti-thyroid antibodies (p = 0.090). In the patient subgroup with anti-TPO antibodies this difference was statistically significant (p = 0.027). No relevant differences were found in the other CSF routine parameters, the number of anti-neuronal antibodies against cell surface antigens in serum and/or CSF, EEG and MRI findings. DISCUSSION: The present study provides evidence of impaired blood CSF barrier (BCSFB) function in patients with anti-TPO and anti-TG antibodies. An influence of anti-TG antibodies on BCSFB structures has been shown in previous laboratory studies, which reported that the antibodies bind to vascular smooth muscle cells. Due to BCSFB breakdown anti-thyroid antibodies might lead to increased autoimmune susceptibility. The alterations in the FDG-PET, WBC count, and anti-neuronal antibody findings against intracellular structures indicate that it could be useful to extend diagnostic investigations in patients with anti-thyroid antibodies. Further studies should investigate whether anti-thyroid antibodies can also act as "drivers of disease".
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Autoanticuerpos , Trastornos del Humor , Trastornos Psicóticos , Anticuerpos , Autoanticuerpos/metabolismo , Líquido Cefalorraquídeo/metabolismo , Electroencefalografía , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética , Trastornos del Humor/inmunología , Trastornos del Humor/metabolismo , Neuronas/inmunología , Tomografía de Emisión de Positrones , Trastornos Psicóticos/inmunología , Trastornos Psicóticos/metabolismoRESUMEN
Inflammatory processes involving altered microglial activity may play a relevant role in the pathophysiology of depressive disorders. Glial fibrillary acidic protein (GFAP) and calcium-binding protein S100B are considered microglial markers. To date, their role has been studied in the serum and tissue material of patients with unipolar depression but not in the cerebrospinal fluid (CSF). Therefore, the aim of the current study was to examine GFAP and S100B levels in the CSF of patients with major depression to better understand their role in affective disorders. In this retrospective study, 102 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension were investigated. GFAP and S100B levels were measured using commercially available ELISA kits. CSF routine parameters were collected during routine clinical care. The mean values of GFAP and S100B were compared using age (and sex) corrected ANOVAs. Matched subgroups were analyzed by using an independent sample t-test. In addition, correlation analyses between GFAP/S100B levels and CSF routine parameters were performed within the patient group. Patients with unipolar depression had significantly higher levels of GFAP than controls (733.22 pg/ml vs. 245.56 pg/ml, p < 0.001). These results remained significant in a sub-analysis in which all controls were compared with patients suffering from depression matched 1:1 by age and sex (632.26 pg/ml vs. 245.56 pg/ml, p < 0.001). Levels of S100B did not differ significantly between patients and controls (1.06 ng/ml vs. 1.17 ng/ml, p = 0.385). GFAP levels correlated positively with albumin quotients (p < 0.050), S100B levels correlated positively with white blood cell counts (p = 0.001), total protein concentrations (p < 0.001), and albumin quotients (p = 0.001) in the CSF. The significance of the study is limited by its retrospective and open design, methodological aspects, and the control group with idiopathic intracranial hypertension. In conclusion, higher GFAP levels in patients with depression may be indicative of altered microglia activity, especially in astrocytes, in patients with unipolar depression. In addition, correlation analyses support the idea that S100B levels could be related to the integrity of the blood-brain/CSF barrier. Further multimodal and longitudinal studies are necessary to validate these findings and clarify the underlying biological processes.
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Astrocitos , Astrocitos/metabolismo , Biomarcadores , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Estudios Retrospectivos , Subunidad beta de la Proteína de Unión al Calcio S100RESUMEN
Introduction: Secondary schizophrenia spectrum disorders (SSDs) have clearly identifiable causes. The Department for Psychiatry and Psychotherapy at the University Hospital Freiburg has continued to expand its screening practices to clarify the organic causes of SSDs. This retrospective analysis was carried out to analyze whether a comprehensive organic diagnostic procedure could be informative in patients with SSDs. Methods and Participants: The "Freiburg Diagnostic Protocol in Psychosis" (FDPP) included basic laboratory analyses (e.g., thyroid hormones), metabolic markers, pathogens, vitamin status, different serological autoantibodies, rheumatic/immunological markers (e.g., complement factors), cerebrospinal fluid (CSF) basic and antineuronal antibody analyses, as well as cranial magnetic resonance imaging (cMRI) and electroencephalography (EEG). The findings of 76 consecutive patients with SSDs (55 with paranoid-hallucinatory; 14 with schizoaffective; 4 with hebephrenic; and 1 each with catatonic, acute polymorphic psychotic, and substance-induced psychotic syndromes) were analyzed. Results: Overall, vitamin and trace element deficiency was identified in 92%. Complement factor analyses detected reduced C3 levels in 11%. Immunological laboratory alterations were detected in 76%. CSF analysis revealed general alterations in 54% of the patients, mostly with signs of blood-brain barrier dysfunction. cMRI analyses showed chronic inflammatory lesions in 4%. Combination of EEG, cMRI, and CSF revealed alterations in 76% of the patients. In three patients, autoimmune psychosis was suspected (4%). Discussion: On the basis of these findings, we conclude that a comprehensive diagnostic procedure according to the FDPP in patients with SSD is worthwhile, considering the detection of secondary, organic forms of SSDs, as well as alterations in "modulating factors" of the disease course, such as vitamin deficiency. Larger studies using comprehensive diagnostic protocols are warranted to further validate this approach.
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BACKGROUND: Therapeutic sleep deprivation (SD) presents a unique paradigm to study the neurobiology of major depressive disorder (MDD). However, the rapid antidepressant mechanism, which differs from today's slow first-line treatments, is not sufficiently understood. We recently integrated two prominent hypotheses of MDD and sleep, the synaptic plasticity hypothesis of MDD and the synaptic homeostasis hypothesis of sleep-wake regulation, into a synaptic plasticity model of therapeutic SD in MDD. Here, we further tested this model positing that homeostatically elevating net synaptic strength through therapeutic SD shifts the initially deficient inducibility of associative synaptic long-term potentiation (LTP)-like plasticity in patients with MDD into a more favorable window of associative plasticity. METHODS: We used paired associative stimulation (PAS), a transcranial magnetic stimulation protocol (TMS), to quantify cortical LTP-like plasticity after one night of therapeutic sleep deprivation in 28 patients with MDD. RESULTS: We demonstrate a significantly different inducibility of associative plasticity in clinical responders to therapeutic SD (> 50% improvement on the 6-item Hamilton-Rating-Scale for Depression, n=13) compared to non-responders (n=15), which was driven by a long-term depression (LTD)-like response in SD-non-responders. Indices of global net synaptic strength (wake EEG theta activity, intracortical inhibition and BDNF serum levels) were increased after SD in both groups, with responders showing a generally lower intracortical inhibition than non-responders. LIMITATIONS: Repetitive assessments prior to and after treatment would be needed to further determine potential mechanisms. CONCLUSION: After a night of therapeutic SD, clinical responders show a significantly higher inducibility of associative LTP-like plasticity than non-responders.
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Trastorno Depresivo Mayor , Trastorno Depresivo Mayor/terapia , Potenciales Evocados Motores , Humanos , Potenciación a Largo Plazo , Plasticidad Neuronal , Privación de Sueño , Estimulación Magnética TranscranealRESUMEN
The central role played by cerebrospinal-fluid (CSF) examinations including antineuronal autoantibody (Ab) testing is increasingly recognized in psychiatry. The rationale of this study was to present a multimodally investigated group of patients. In total, 992 patients were analyzed for CSF alterations: 456 patients with schizophreniform and 536 with affective syndromes. Ab measurement included testing for established antineuronal IgG-Abs against intracellular antigens in serum (Yo/Hu/Ri/cv2[CRMP5]/Ma1/Ma2/SOX1/TR[DNER]/Zic4/amphiphysin/GAD65) and for cell surface antigens in the CSF (NMDAR/AMPA-1/2-R/GABA-B-R/LGI1/CASPR2/DPPX). In 30 patients with "red flags" for autoimmune psychosis, "tissue tests" were performed. Additional diagnostics included MRI and EEG analyses. CSF white-blood-cell counts were increased in 4% and IgG indices in 2%; CSF-specific oligoclonal bands were detected in 4%; overall, 8% displayed signs of neuroinflammation. In addition, 18% revealed increased albumin quotients. Antineuronal Abs against intracellular antigens were detected in serum in 0.6%. Antineuronal Abs against established cell surface antigens were detected in serum of 1% and in the CSF of 0.3% (CSF samples were only questionably positive). Abnormal IgG binding in "tissue tests" was detected in serum of 23% and in CSF of 27%. In total, 92% of the Ab-positive patients demonstrated at least one sign of brain involvement in additional diagnostics using CSF, MRI, EEG, and FDG-PET. In summary, CSF basic analyses revealed signs of blood-brain-barrier dysfunction and neuroinflammation in relevant subgroups of patients. Established antineuronal IgG-Abs were rare in serum and even rarer in the CSF. "Tissue tests" revealed frequent occurrences of Ab-binding; therefore, novel antineuronal Abs could play a relevant role in psychiatry.
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Autoanticuerpos , Trastornos Psicóticos , Encéfalo , Electroencefalografía , Humanos , Imagen por Resonancia Magnética , Trastornos Psicóticos/diagnóstico por imagenRESUMEN
INTRODUCTION: The risk of developing depression is increased in patients with autoimmune thyroiditis. Autoimmune Hashimoto thyroiditis is diagnosed using the serum markers anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies. In rare cases, patients with autoimmune thyroiditis can also suffer from the heterogeneous and ill-defined syndrome of Hashimoto encephalopathy. Biomarkers for Hashimoto encephalopathy or for any brain involvement of autoimmune thyroiditis are currently lacking. The aim of the present descriptive study was therefore to determine whether a subgroup of seropositive patients shows intrathecal anti-thyroid antibody synthesis in the cerebrospinal fluid (CSF). PARTICIPANTS AND METHODS: Paired serum and CSF samples from 100 patients with unipolar depression were examined for anti-TPO and anti-TG antibodies using enzyme-linked immunosorbent assays. Antibody-specific indices (ASIs) were calculated for seropositive samples. These ASIs allow the differentiation between the brain-derived fraction of antibodies and antibodies which are passively diffused from the serum. ASIs >1.4 were assessed as positive for brain-derived antibodies. Additionally, for explorative evaluations, a stricter ASI limit of >2 was applied. RESULTS: Anti-TPO antibodies were increased in the serum of 16 patients (16%); increased anti-TPO ASIs (>1.4) were detected in 11 of these patients (69%). Anti-TG antibodies in the serum were detected in three patients (3%), with two of them (67%) showing increased ASIs (>1.4). Overall, the authors found increased anti-thyroid antibodies in 17 of 100 patients (17%), with 13 out of 17 patients showing increased ASIs (76%; range 1.4-4.1). Choosing ASI levels of >2 led to positive findings in six out of 16 patients (38%) with anti-TPO antibodies in their serum but no increase in ASIs in three patients (0%) who were seropositive for anti-TG antibodies. The patients with elevated ASIs (N = 13) were younger than the ASI-negative patients (N = 87; p = 0.009); no differences were noted in the frequency of CSF, electroencephalography, and/or magnetic resonance imaging alterations. DISCUSSION: A subgroup of seropositive patients showed intrathecal synthesis of anti-TPO and, more rarely, of anti-TG antibodies, which might be an indication of central autoimmunity in a subgroup of patients with unipolar depression. The confirmation of elevated ASIs as a biomarker for Hashimoto encephalopathy must await further studies. The relevance of the findings is limited by the study's retrospective and uncontrolled design.