Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders.

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.

An observational study on the association of anti-thyroid autoantibodies with clinical, EEG, MRI, FDG-PET, cerebrospinal fluid and anti-neuronal antibody findings in 530 patients with schizophreniform and affective disorders.

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".

Increased GFAP concentrations in the cerebrospinal fluid of patients with unipolar depression.

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.

An observational study investigating cytokine levels in the cerebrospinal fluid of patients with schizophrenia spectrum disorders.

INTRODUCTION: The role of immunological mechanisms in the pathophysiology of mental disorders has been discussed with increasing frequency. In this context, especially schizophrenia has become the focus of attention after the discovery of autoimmune encephalitis, which might present with psychotic symptoms. Furthermore, multiple studies have identified associations between infections or autoimmune diseases and schizophreniform disorders. Cerebrospinal fluid (CSF) analysis plays a central role in identifying potential inflammatory processes in the central nervous system. Therefore, the rationale of this retrospective study was the analysis of different cytokines, including interleukin-8 (IL-8) levels, in the CSF of patients with schizophrenia spectrum disorders. METHODS: The authors examined the CSF of 40 patients with schizophrenia spectrum disorders, in comparison to the CSF of a mentally healthy control group of 39 patients with idiopathic intracranial hypertension (IIH). Magnetic bead multiplexing immunoassay was used to retrospectively determine different cytokines in the participants' CSF. RESULTS: Participants with schizophrenia spectrum disorders had significantly higher IL-8 levels in their CSF than controls (mean ± SD: 41.83 ± 17.50 pg/ml versus 21.40 ± 7.96 pg/ml; p < 0.001). CONCLUSION: The main finding of this study is the presence of significantly higher IL-8 concentrations in the CSF of patients with schizophrenia spectrum disorders when compared to the control group. This supports the hypothesis that immunological processes may be involved in the pathophysiology of a subgroup of patients with schizophrenia spectrum disorders. However, the study's results are limited by the retrospective design, methodological aspects, and the control group with IIH.

Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis.

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

Diagnosing Organic Causes of Schizophrenia Spectrum Disorders: Findings from a One-Year Cohort of the Freiburg Diagnostic Protocol in Psychosis (FDPP).

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.

Cerebrospinal fluid, antineuronal autoantibody, EEG, and MRI findings from 992 patients with schizophreniform and affective psychosis.

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.

Psychiatric Manifestation of Anti-LGI1 Encephalitis.

BACKGROUND: Anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis is typically characterized by limbic encephalitis, faciobrachial dystonic seizures and hyponatremia. The frequency with which milder forms of anti-LGI1 encephalitis mimic isolated psychiatric syndromes, such as psychoses, or may lead to dementia if untreated, is largely unknown. CASE PRESENTATION: Here, the authors present a 50-year-old patient who had suffered from neurocognitive deficits and predominant delusions for over one and a half years. He reported a pronounced feeling of thirst, although he was drinking 10-20 liters of water each day, and he was absolutely convinced that he would die of thirst. Due to insomnia in the last five years, the patient took Z-drugs; later, he also abused alcohol. Two years prior to admission, he developed a status epilepticus which had been interpreted as a withdrawal seizure. In his serum, anti-LGI1 antibodies were repeatedly detected by different independent laboratories. Cerebrospinal fluid analyses revealed slightly increased white blood cell counts and evidence for blood-brain-barrier dysfunction. Magnetic resonance imaging showed hyperintensities mesio-temporally and in the right amygdala. In addition, there was a slight grey-white matter blurring. A cerebral [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) examination of his brain showed moderate hypometabolism of the bilateral rostral mesial to medial frontal cortices. Treatment attempts with various psychotropic drugs remained unsuccessful in terms of symptom relief. After the diagnosis of probable chronified anti-LGI1 encephalitis was made, two glucocorticoid pulse treatments were performed, which led to a slight improvement of mood and neurocognitive deficits. Further therapy was not desired by the patient and his legally authorized parents. CONCLUSION: This case study describes a patient with anti-LGI1 encephalitis in the chronified stage and a predominant long-lasting psychiatric course with atypical symptoms of psychosis and typical neurocognitive deficits. The patient's poor response to anti-inflammatory drugs was probably due to the delayed start of treatment. This delay in diagnosis and treatment may also have led to the FDG-PET findings, which were compatible with frontotemporal dementia ("state of damage"). In similar future cases, newly occurring epileptic seizures associated with psychiatric symptoms should trigger investigations for possible autoimmune encephalitis, even in patients with addiction or other pre-existing psychiatric conditions. This should in turn result in rapid organic clarification and-in positive cases-to anti-inflammatory treatment. Early treatment of anti-LGI1 encephalitis during the "inflammatory activity state" is crucial for overall prognosis and may avoid the development of dementia in some cases. Based on this case, the authors advocate the concept-long established in many chronic inflammatory diseases in rheumatology-of distinguishing between an "acute inflammatory state" and a "state of organ damage" in autoimmune psychosis resembling neurodegenerative mechanisms.

Anti-N-Methyl-D-Aspartate-Receptor Encephalitis: A 10-Year Follow-Up.

BACKGROUND: Anti-N-methyl-D-aspartate-receptor (NMDA-R) encephalitis is an autoimmune disease of the brain first described in 2007. The aim of this paper is to present a 10-year follow-up case history. CASE PRESENTATION: The authors present the case of a 39-year-old female patient who developed an anti-NMDA-R encephalitis in 2009 with predominant severe catatonic symptoms. Anti-inflammatory therapy led to the disappearance of catatonic symptoms and was discontinued during the course of the disease. After acute therapy, the patient achieved an almost full recovery presenting with ongoing discrete symptoms of sensory overload, subtle cognitive deficits, and fatigue/reduced energy levels. The follow-up investigation in 2019 showed inconspicuous findings in laboratory diagnostics and magnetic resonance imaging. Electroencephalography (EEG) analysis using independent component analysis detected left hemispherical spike-wave complexes and intermittent slowing. Regarding the sensory overload and reduced energy level, the patient benefited from low-dose neuroleptics (risperidone, amisulpride). In terms of sensory overload associated with experiences of panic, cognitive deficits and coping with the disease, she improved with cognitive behavioral therapy (CBT). CONCLUSION: Anti-inflammatory treatment led to almost full recovery with persistent disappearance of catatonic symptoms; however, a dysexecutive syndrome led to ongoing relevant problems with good response to low-dose atypical neuroleptics and CBT. The patient had persistent EEG alterations that indicated continuing neuronal network instability. Therefore, the case demonstrates the importance of multidisciplinary outpatient treatment following acute therapy for anti-NMDA-R encephalitis in patients with ongoing psychiatric deficits. For the symptomatic treatment of executive dysfunctions, "classical" psychiatric treatment may be helpful in the course of the disease.

Parkinsonian Syndrome with Frontal Lobe Involvement and Anti-Glycine Receptor Antibodies.

Background: Atypical Parkinsonian syndromes with prominent frontal lobe involvement can occur in the 4R-taupathies progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Secondary forms of movement disorders may occur in the context of autoimmune encephalitis with antineuronal antibodies, such as anti-glycine receptor (anti-GlyR) antibodies, which are typically associated with Stiff-Person spectrum syndrome, or progressive encephalomyelitis with rigidity and myoclonus. Overlaps between neurodegenerative and immunological mechanisms have been recently suggested in anti-IgLON5 disease. In this case study, the authors describe a patient with a Parkinsonian syndrome with frontal lobe involvement and anti-GlyR antibodies. Case presentation: The patient presented was a 63-year-old female. Her symptoms had begun with insomnia at the age of 60, after which, since the age of 61, increasing personality changes developed, leading to a diagnosis of depression with delusional symptoms. Severe cognitive deficits emerged, along with a left-side accentuated Parkinsonian syndrome with postural instability. The personality changes involved frontal systems. Magnetic resonance imaging (MRI) showed low-grade mesencephalon atrophy. [18F]fluorodeoxyglucose positron emission tomography (FDG PET) depicted a moderate hypometabolism bilateral frontal and of the midbrain, while [123I]FPCIT single-photon emission computed tomography (SPECT) revealed severely reduced dopamine transporter availability in both striata, indicating pronounced nigrostriatal degeneration. In addition, anti-GlyR antibodies were repeatedly found in the serum of the patient (max. titer of 1:640, reference: <1:20). Therefore, an anti-inflammatory treatment with steroids and azathioprine was administered; this resulted in a decrease of antibody titers (to 1:80) but no detectable clinical improvement. The cerebrospinal fluid (CSF) and electroencephalography diagnostics showed inconspicuous findings, and negative CSF anti-GlyR antibody results. Conclusion: The patient presented here was suffering from a complex Parkinsonian syndrome with frontal lobe involvement. Because of the high anti-GlyR antibody titers, the presence of an autoimmune cause of the disorder was discussed. However, since no typical signs of autoimmune anti-GlyR antibody syndrome (e.g., hyperexcitability, anti-GlyR antibodies in CSF, or other inflammatory CSF changes) were detected, the possibility that the anti-GlyR antibodies might have been an unrelated bystander should be considered. Alternatively, the anti-GlyR antibodies might have developed secondarily to neurodegeneration (most likely a 4-repeat tauopathy, PSP or CBD) without exerting overt clinical effects, as in cases of anti-IgLON5 encephalopathy. In this case, such antibodies might also potentially modify the clinical course of classical movement disorders. Further research on the role of antineuronal antibodies in Parkinsonian syndromes is needed.