B Cell-activating factor (BAFF): A promising trans-nosographic biomarker of inflammation and autoimmunity in bipolar disorder and schizophrenia.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Patients with psychosis spectrum disorders hospitalized during the COVID-19 pandemic unravel overlooked SARS-CoV-2 past infection clustering with HERV-W ENV expression and chronic inflammation.

Epidemiology has repeatedly associated certain infections with a risk of further developing psychiatric diseases. Such infections can activate retro-transposable genetic elements (HERV) known to trigger immune receptors and impair synaptic plasticity of neuroreceptors. Since the HERV-W ENV protein was recently shown to co-cluster with pro-inflammatory cytokines in a subgroup of patients with schizophrenia or bipolar disorder, we questioned the influence of the COVID-19 pandemic on patients with psychosis spectrum disorders (PSD). Present results revealed that (i) SARS-CoV-2 serology shows high prevalence and titers of antibodies in PSD, (ii) HERV-W ENV is detected in seropositive individuals only and (iii) SARS-CoV-2 and HERV-W ENV positivity co-clustered with high serum levels of pro-inflammatory cytokines in psychotic patients. These results thus suggest that SARS-CoV-2 infection in many patients with psychotic disorders now admitted in the psychiatry department did not cause severe COVID-19. They also confirm the previously reported association of elevated serum pro-inflammatory cytokines and HERV-W ENV in a subgroup of psychotic patients. In the context of the COVID-19 pandemic, this cluster is only found in SARS-CoV-2 seropositive PSD cases, suggesting a dominant influence of this virus on HERV-W ENV and cytokine expression, and/or patients' greater susceptibility to SARS-CoV-2 infection. Further investigation on an interplay between this viral infection and the clinical evolution of such PSD patients is needed. However, this repeatedly defined subgroup of psychotic patients with a pro-inflammatory phenotype and HERV expression calls for a differential therapeutic approach in psychoses, therefore for further precision medicine development.

Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia.

BACKGROUND: Cognitive deficits such as poor selective attention and executive functions decline have been reported in patients with schizophrenia. Many studies have emphasized the role of dopamine in regulating cognitive functions in the general population as well as in schizophrenia. However, the relationship between cognitive processes, schizophrenia and dopaminergic candidate genes is an original approach given interesting results. The purpose of the current exploratory study was to examine the interaction of dopaminergic genes (coding for dopamine receptor D2, DRD2, and for Catecholamine-O-Methyl-Transferase, COMT) with the diagnostic of schizophrenia in (i) the executive control of attention, (ii) selective attention, and (iii) executive functions. METHODS AND RESULTS: We recruited 52 patients with schizophrenia and 53 healthy controls who performed the Stroop Color-Word Test, the Attention Network Test and the Wisconsin Card Sorting test. Four single nucleotide polymorphisms (SNPs) in the DRD2 gene (rs6275, rs6277, rs2242592 and rs1800497) and two SNPs in the COMT gene (rs4680 and rs165599) have been genotyped. Patients with schizophrenia performed significantly worse than controls in all cognitive performance, taking into account demographic variables. A significant gene by disease interaction was found for the Stroop interference (p = 0.002) for rs6275 of the DRD2 gene. The COMT Val/Val genotype and schizophrenia were associated with increased number of perseverative errors (p = 0.01). CONCLUSIONS: In our study, the DRD2 gene is involved in attention while the COMT gene is implicated in executive functions in patients with schizophrenia.

Does COMT val158met polymorphism influence P50 sensory gating, eye tracking or saccadic inhibition dysfunctions in schizophrenia?

Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.

Impaired smooth pursuit in schizophrenia results from prediction impairment only.

BACKGROUND: Oculomotor abnormality is one of the endophenotypes in schizophrenia. The predictive component of smooth pursuit can be studied by comparing the gain, i.e., the ratio of smooth eye position to target position, during predictable (pure sinusoidal) and unpredictable (pseudorandom) target motions. The aim of this experiment was to study predictive and nonpredictive components of smooth pursuit in two groups of schizophrenia patients compared with control subjects. METHODS: Fifty-one schizophrenia patients (40 nondeficit and 11 deficit) and 21 control subjects were studied. During a predictable task, subjects were asked to track a sinusoidal target (.4 Hz). For the unpredictable task, the pseudorandom target motion consisted of five superimposed sinusoidal waveforms (.1, .2, .4, .6, and .8 Hz). The smooth eye position (eye position without saccades), gain, and phase were calculated for each frequency in each participant and for both tasks. RESULTS: The mean sinusoidal smooth eye position gain was significantly lower in patients than in control subjects with no significant difference between deficit and nondeficit patients. During the pseudorandom task, all groups had a similar gain at .4 Hz. CONCLUSIONS: Our study reveals that patients have a normal nonpredictive component of smooth pursuit, regardless of their level of negative symptoms. In contrast, the predictive mechanisms involved in eye pursuit were impaired in schizophrenia patients. These results indicate that poor pursuit performance during smooth pursuit is primarily a consequence of a predictive problem and is not related to the ability to generate an accurate pursuit maintenance response.

A concordance study of three electrophysiological measures in schizophrenia.

OBJECTIVE: The authors evaluated concordance rates among three electrophysiological measures in patients with schizophrenia, nonschizophrenic first-degree relatives of schizophrenia patients, and healthy comparison subjects. The purpose of the study was to provide data for defining a common endophenotype for genetic studies of schizophrenia and for improving the criteria for diagnosis. METHOD: P50 event-related potential inhibition, antisaccade, and smooth pursuit eye tracking paradigms were measured. Data for all three paradigms were available for 81 patients with schizophrenia, 25 parents of patients with schizophrenia, and 60 healthy comparison subjects. RESULTS: The schizophrenia patients and the patients' parents showed a high rate of inhibitory deficits measured by the P50 inhibition and antisaccade paradigms. Both groups had a high prevalence of eye tracking dysfunction. Smooth pursuit gain and the error rate in the antisaccade paradigm were significantly correlated in the schizophrenia patients and the parents, whereas P50 inhibition showed no correlation with smooth pursuit gain or antisaccade paradigm measurements. CONCLUSIONS: Despite superficial similarities, two paradigms designed to measure central inhibition processes (antisaccade and P50 inhibition) do not appear to reflect the same neurobiological substrates. In contrast, the convergence in performance data for the antisaccade and eye tracking paradigms suggests that the neural circuitry underlying these tasks may overlap. P50 inhibition and antisaccade errors were the optimal paradigms for discrimination between comparison subjects, patients with schizophrenia, and the parents of patients with schizophrenia.