Neuro-Immune Aspects of Schizophrenia with Severe Negative Symptoms: New Diagnostic Markers of Disease Phenotype.

The aim of the study was to analyze the immune-inflammatory profile of patients with paranoid schizophrenia and relate it to the severity of negative symptoms and the MRI data in order to identify biomarkers of schizophrenia severity, search for new approaches to therapy, and control its effectiveness. Materials and Methods: The main group included 51 patients with paranoid schizophrenia, the control group - 30 healthy subjects. Patients underwent MRI scans and immunological studies, which included an assessment of natural and adaptive immunity, the systemic level of key pro-inflammatory and anti-inflammatory cytokines, and other markers of inflammation. Results: Disorders of immunity and immunoinflammatory profile in patients with paranoid schizophrenia with severe negative symptoms were revealed for the first time: in the presence of severe negative symptoms (>15 points according to the NSA-4 scale), the levels of humoral immunity factors, cytokines IL-10 and IL-12p40 and neurotrophin NGF were increased as well as the markers of systemic inflammation. Morphometric changes in the brain, typical for patients with schizophrenia, and also specific for patients with severe negative symptoms, were determined. The data analysis revealed correlations between the immune changes with structural changes in some of the brain areas, including the frontal cortex and hippocampus. Associations were found between the levels of anti-inflammatory IL-10, IL-12p40 cytokines and morphometric parameters of the brain, specific only for schizophrenic patients with severe negative symptoms. Conclusion: The interdisciplinary approach, combining brain morphometry with in-depth immunological and clinical studies, made it possible to determine neurobiological, immune, and neurocognitive markers of paranoid schizophrenia with severe negative symptoms. The results are important for further deciphering the pathogenesis of schizophrenia and its subtypes, as well as for the search for new approaches to the treatment of severe forms of the disease.

[The relationship between inflammation, cognitive disorders and neuroimaging data in schizophrenia]. / Svyaz' mezhdu vospaleniem, kognitivnymi narusheniyami i dannymi neirovizualizatsii pri shizofrenii.

OBJECTIVE: To search for the relationship between the results of functional imaging, immunological parameters and laboratory markers of inflammation in schizophrenia, taking into account cognitive impairment in patients, and to consider the possibility of using a multidisciplinary approach to diagnosis, treatment and prognosis of schizophrenia. MATERIAL AND METHODS: The study included 25 patients with schizophrenia and 13 healthy volunteers. Psychiatric scales were administered to evaluate the patient's condition. The main indicators of humoral immunity, the level of markers of inflammation, key pro-inflammatory and anti-inflammatory cytokines, and growth factor VEGF were determined by ELISA. Brain MRI was performed. All calculated tractographic data are included in the connection database to study the effect of immunological markers and the degree of severity of cognitive impairment. RESULTS AND CONCLUSION: Levels of markers of systemic inflammation and growth factor VEGF-A as well as the activation of humoral immunity are increased in patients with schizophrenia compared with controls. For the first time, the relationship of immunological parameters with the coefficient of quantitative anisotropy in the area of the corpus callosum in schizophrenia was revealed. The results indicate the possible value of indicators of the activation of the humoral immune response and systemic inflammation as markers of neurophysiological changes and cognitive dysfunction in schizophrenia.

[Immunological variants of amnestic mild cognitive impairment]. / Immunologicheskie varianty myagkogo kognitivnogo snizheniya amnesticheskogo tipa.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is considered as a possible earliest pre-dementia clinical stage of Alzheimer's disease (AD). Taking into account the prominent role of neuroinflammation in the pathogenesis of AD, it is quite important to study possible immunological markers of the risk of aMCI progression and the changes in immune parameters in patients. OBJECTIVE: To study the immunological variants of aMCI and AD based on the parameters of humoral and cell immunity, levels of key cytokines and presence of systemic inflammation, and to explore the link between changes in the immune parameters and clinical prognosis. MATERIAL AND METHODS: One hundred patients with a diagnosis of aMCI, 45 patients with AD at the stage of mild to moderate dementia and 40 people without cognitive impairment (the control group) were enrolled into the study. Immunological assessment included determination of the concentration of key cytokines, C-reactive protein, circulating immune complexes and immunoglobulins (Ig A, M, G) in blood serum by ELISA, determination of the main subpopulations of lymphocytes by flow cytometry. RESULTS AND CONCLUSION: Four main immunological variants of aMCI syndrome associated with clinical prognosis were identified. The detected changes in immune parameters are important for further studies to assess an effect of viral and bacterial infections, intestinal microflora disorders on a clinical prognosis in patients with different immunological variants of aMCI syndrome.

[Effectiveness of the DNA double-strand breaks repair system in lymphocytes of patients with cognitive impairments and healthy volunteers]. / Aktivnost' sistemy reparatsii dvunitevykh razryvov DNK v limfotsitakh patsientov s kognitivnym snizheniem v sravnenii so zdorovymi dobrovol'tsami.

The individual differences in the efficiency of DNA DSB repair were estimated by the level of residual γH2AX foci after γ-irradiation at a dose of 2 Gy, in lymphocytes of patients with amnestic mild cognitive impairment (AMCI) and Alzheimer's disease (AD) and of healthy volunteers. Lymphocytes were isolated from the peripheral blood of the examined patients and were frozen in a medium for freezing cells. Before the study, the lymphocytes were thawed, suspended in RPMI 1640 culture medium supplemented with 10% inactivated fetal bovine serum, and half of the cells were γ-irradiated at 4°C from a 60Co source on a GUT-200M facility at a dose of 2 Gy (a dose rate of 0.75 Gy/min). Control and irradiated lymphocytes were cultured for 24 h, collected, fixed, and stored until the study of the number of spontaneous and residual foci of γH2AX using fluorescent microscopy after staining with fluorescent labeled antibodies. In lymphocytes of patients with AMCI and AD a higher number of residual γH2AX foci in lymphocytes and the higher number of lymphocytes with foci were found compared with healthy volunteers. This indicates a decrease in the ability to repair DNA DSB in these patients. Indicators of cellular immunity and the concentration of TNF-α in the blood serum in the group of examined patients were normal. In the group of patients with the cognitive impairments (AMCI+AD), a correlation was found between the number of residual foci of γH2AX and the number of CD3+CD4+ lymphocytes and the concentration of proinflammatory cytokine TNF-α in the blood serum. This suggests the development of stronger neuroinflammation in patients with reduced ability to repair DNA DSB in this pathology.

[Anti-inflammatory effects of neurotrophic therapy (a pilot study)]. / Protivovospalitel'nye éffekty neirotroficheskoi terapii (primenenie tserebrolizina pri miagkom kognitivnom snizhenii).

AIM: To study clinical effects of cerebrolysin and its impact on systemic inflammation markers and immunity in mild cognitive impairment (MCI). MATERIAL AND METHODS: Twenty patients with MCI were treated with cerebrolysin administered intravenously during 4 weeks. Serum levels of immunoglobulins, inflammatory markers, neurotrophic factors were measured in dynamics in patients and controls using ELISA. RESULTS: An effect of cerebrolysin was found in MCI patients including the older group (mean age 78±1.1 years). An improvement was seen 6 and/or 22 weeks after treatment. Four types of response to neurotrophic treatment (fast long-term, fast short-term, delayed long-term), without effect were determined, the longer duration of positive effect of cerebrolysin was shown. There were differences in the indices of humoral immunity, clinical blood test results, cortisol and neurotrophin levels assessed before and after treatment between the patients with- and without positive effect of cerebrolysin. CONCLUSION: The high clinical effect of neurotrophic therapy with cerebrolysin in MCI shows its anti-inflammatory and immunotropic action that suggests the impact of cerebrolysin on the pathogenesis of MCI.

[Levels of proinflammatory cytokines and vascular endothelial growth factor in patients with Alzheimer's disease and mild cognitive impairment]. / Uroven' provospalitel'nykh tsitokinov i faktora rosta VEGF u patsientov s bolezn'yu Al'tsgeimera i myagkim kognitivnym rasstroistvom.

OBJECTIVE: to evaluate the levels of cytokines (IFNα, IFNγ, IL-2, Il-4, IL-6, IL-8, IL-10, IL-12, IL-15), IL-1ß receptor antagonist (IL-1RA), vascular endothelial growth factor (VEGF) and its antagonist, the soluble form of receptor 1 (sVEGFR1) in the blood serum of patients with Alzheimer's disease, with early onset (ADEO) and late onset (ADLO), and in patients with mild cognitive impairment (MCI). MATERIAL AND METHODS: Levels of interleukins, IL-1RA, VEGF and sVEGFR1 were measured in 20 patients with AD and 11 patients with MCI using ELISA. These parameters were compared to the severity of cognitive impairment assessed by the performance on neurocognitive tests. RESULTS AND CONCLUSION: The levels of key cytokines (IL-8, TNFα, IL-12), VEGF and sVEGFR1 as well as anti-inflammatory proteins were different in patients with ADEO, ADLO and MCI. These differences suggest the phenotypic and genotypic heterogeneity of the disease that demands further research.