Diagnosis of Schizophrenia Based on the Data of Various Modalities: Biomarkers and Machine Learning Techniques (Review).

Schizophrenia is a socially significant mental disorder resulting frequently in severe forms of disability. Diagnosis, choice of treatment tactics, and rehabilitation in clinical psychiatry are mainly based on the assessment of behavioral patterns, socio-demographic data, and other investigations such as clinical observations and neuropsychological testing including examination of patients by the psychiatrist, self-reports, and questionnaires. In many respects, these data are subjective and therefore a large number of works have appeared in recent years devoted to the search for objective characteristics (indices, biomarkers) of the processes going on in the human body and reflected in the behavioral and psychoneurological patterns of patients. Such biomarkers are based on the results of instrumental and laboratory studies (neuroimaging, electro-physiological, biochemical, immunological, genetic, and others) and are successfully being used in neurosciences for understanding the mechanisms of the emergence and development of nervous system pathologies. Presently, with the advent of new effective neuroimaging, laboratory, and other methods of investigation and also with the development of modern methods of data analysis, machine learning, and artificial intelligence, a great number of scientific and clinical studies is being conducted devoted to the search for the markers which have diagnostic and prognostic value and may be used in clinical practice to objectivize the processes of establishing and clarifying the diagnosis, choosing and optimizing treatment and rehabilitation tactics, predicting the course and outcome of the disease. This review presents the analysis of the works which describe the correlates between the diagnosis of schizophrenia, established by health professionals, various manifestations of the psychiatric disorder (its subtype, variant of the course, severity degree, observed symptoms, etc.), and objectively measured characteristics/quantitative indicators (anatomical, functional, immunological, genetic, and others) obtained during instrumental and laboratory examinations of patients. A considerable part of these works has been devoted to correlates/biomarkers of schizophrenia based on the data of structural and functional (at rest and under cognitive load) MRI, EEG, tractography, and immunological data. The found correlates/biomarkers reflect anatomic disorders in the specific brain regions, impairment of functional activity of brain regions and their interconnections, specific microstructure of the brain white matter and the levels of connectivity between the tracts of various structures, alterations of electrical activity in various parts of the brain in different EEG spectral ranges, as well as changes in the innate and adaptive links of immunity. Current methods of data analysis and machine learning to search for schizophrenia biomarkers using the data of diverse modalities and their application during building and interpretation of predictive diagnostic models of schizophrenia have been considered in the present review.

[Herpesvirus infections and immunological disturbances in patients with different stages of Alzheimer's disease].

INTRODUCTION: Alzheimer's disease (AD) is a multifactorial disease that leads to a progressive memory loss, visualspatial impairments, emotional and personality changes. As its earliest pre-dementia clinical stage, amnestic mild cognitive impairment syndrome (aMCI) is currently considered. Neuroinflammation plays a role in the development and progression of aMCI and the initial stage of AD, which can be supported by immunological disorders of a systemic character. Study of factors, including infections, influencing immune disorders and systemic inflammatory response in patients with aMCI, is of great importance.The aim of this study was to obtain new data on the possible role of herpesvirus infections in the development and progression of aMCI. MATERIAL AND METHODS: 100 patients with aMCI diagnosis, 45 patients with AD, 40 people from the control group were enrolled into the study. The frequency of DNA detection of herpesviruses (Epstein-Barr virus (EBV), human herpesviruses (HHV) type 6 and 7, cytomegalovirus (CMV)), the levels of viral load and the serological markers of herpesvirus infections (IgG to HHV-1, IgG to CMV) were determined. Immunological studies included an assessment of the level of the main pro-inflammatory and anti-inflammatory cytokines, and indicators of humoral and cellular immunity. RESULTS: The study found an increased detection rate of EBV in saliva and a higher level of EBV DNA in saliva in aMCI and AD than in the control group. A relationship between the presence of active EBV infection and changes in immunological parameters in patients with aMCI were found. It was also discovered that the level of IgG antibodies to CMV is associated with the stage of AD. DISCUSSION: The results indicate a possible role of EBV- and CMV-induced infections in the development of immunological changes which are typical for mild cognitive impairment and in the progression of AD. CONCLUSION: The obtained data can be important for prognostic methods addressing AD development, including its pre-dementia stage, and for new approaches to individualized treatment and prevention.

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.

[A role of the immune system in the pathogenesis of schizophrenia]. / Rol' immunnoi sistemy v patogeneze shizofrenii.

The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.

[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.

[Neutrophil bactericidal and absorptive function in gout].

AIM: To study neutrophil bacterial and absorptive functions and the specific features of their impairments in gout. SUBJECTS AND METHODS: The study included 48 male patients with a valid diagnosis of gout (mean age, 59.7 +/- 10.3 years; duration of the disease, 9.2 +/- 2.1 years; blood uric acid (UA), 520 +/- 80 micromol) (Group 1); 25 apparently healthy volunteers (mean age 55.1 +/- 6.2 years; blood UA, 350 micromol/l) (Group 2). Neutrophil functional activity was estimated from the phagocytic-nitroblue tetrazolium reduction (NBT test) and myeloperoxidase (MPO) activity, the determination of non-enzyme cationic proteins (CP) and their spontaneous and induced indices. Neutrophil phagocytic function was also studied. RESULTS: In Group 1, the content of active oxygen forms (AOF) was increased, on average, to 113.3 +/- 8.65 conventional units (CI) versus 88.22 +/- 5.23 CI in Group 2; p < 0.05). In 34 (70.8%) of the 48 male patients with gout, spontaneous MPO activity was significantly reduced as compared with that in Group 2: 348.4 +/- 13.6 and 509.2 +/- 12.2 CI, respectively (p < 0.01). In Group 1, the level of CP was noticeably decreased to 60.1 +/- 2.06 CI whereas in Group 2, it was 84.91 +/- 5.36 CI (p < 0.05). In gouty patients, the CP stimulation index averaged 0.70 +/- 0.13; in Group 2, it was significantly higher--1.2 +/- 0.05 (p < 0.05). CONCLUSION: In the majority of gouty patients, neutrophil functional activity suffers due to its lower phagocytic function, which suppresses the body's antioxidant defense and contributes to the chronic pattern of an inflammatory process.

Pathogenetic aspects of severe course of herpetic infection.

We studied the state of antiviral defense in patients with severe course of herpetic infection of anogenital and labial localization and the frequency of its combination with other herpes virus infections. It was found that severe course of herpetic infection caused by herpes simplex virus occurs against the background of combined secondary immunodeficiency and its complication. We first demonstrated that severe course of the disease is associated with mixed viral infection.

[Drug intolerance]. / K voprosu o neperenosimosti lekarstvennykh sredstv.

The authors present experimental data on luminol-dependent neutrophil chemiluminescence of blood from patients with drug intolerance. A decrease in intensity of neutrophil and whole blood chemiluminescence was registered in the presence of intolerated drugs. In acute phase of generalized intolerance reaction the chemiluminescence test showed readiness of the blood cells to react inadequately to the contact with different drugs leading to variations in generation of active oxygen forms. Improvement in patients' condition was followed by narrowing spectrum of drugs causing a decrease in the intensity of the chemiluminescence. Later, the chemiluminescence ratio remained low in testing only those drugs causing intolerance reaction.

[Treatment of patients with hypertonic disease with plasmapheresis]. / Lechenie bol'nykh gipertonicheskoi bolezn'iu s ispol'zovaniem plazmafereza.

The paper presents a discussion on therapeutic results obtained with plasmapheresis treatment in 16 patients with stage II essential hypertension. Thirty-three comparable patients entered a control group of conventional treatment. The test and control patients with stage II hypertension were examined for time-course changes in T- and B-lymphocytes counts, the activity of the energetic enzymes (alpha-glycerophosphate dehydrogenase, succinic dehydrogenase, lactate dehydrogenase), serum immunoglobulins and circulating immune complex levels. It was established that the standard antihypertensive treatment failed to restore normal parameters of immunity and to favor positive alterations in the activity of the enzymes in the blood lymphocytes, whereas therapeutic plasmapheresis was found to stimulate immunity, especially cellular one. This occurred in line with a rise in the levels of lymphocytic dehydrogenases.

[The course of ischemic heart disease in rheumatic defects in persons over 45]. / Techenie ishemicheskoi bolezni serdtsa pri revmaticheskikh porokakh ulits starshe 45 let.

Coronary heart disease (CHD) was followed up in 239 patients with rheumatic heart disease. According to the clinical data 40 (16.73%) patients had myocardial infarction (MI), 100 (41.84%) cardiosclerosis (CS), 185 (77.4%) angina pectoris (AP). AP (44.35%) prevailed among the isolated (66.1%) forms of valvular disease, associated AP and CS (23%) among the combined (33.9%) forms. In the majority of patients, AP originated and ran its course as stable throughout many years; in one-fifth of patients, the disease occurred as unstable. The incidence of AP was significantly higher in the senior age group, in women with aortic valvular disease, in men with stage III circulatory failure, and in cardiomegaly, AP aggravated the disease and life prognosis. MI was manifested by a moderately pronounced painful attack; it was frequently complicated by acute or incremental chronic circulatory failure. Small-focal MI was seen more frequently while the electrocardiographic changes associated with the disease resembled those seen in rheumatic carditis. Postinfarction CS stimulated the onset and progress of chronic congestive heart failure in 93.02% of patients.