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

Malashenkova, I K; Ushakov, Vadim L.; Zakharova, Natalia; Krynskiy, Sergey; Ogurtsov, Daniil; Hailov, N A; Chekulaeva, Ekaterina; Ratushnyy, A. Yu.; Kartashov, Sergey; Kostyuk, Georgiy; Didkovsky, Nikolay

doi:10.17691/stm2021.13.6.03

Cited by 10 publications

(8 citation statements)

References 42 publications

(51 reference statements)

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“…Отметим, что по данным наших предыдущих исследований [18,19], структурные изменения при МРТ, часть из которых по результатам данной работы ассоциирована с повышенным уровнем IL-17A, также связаны с наличием у больных выраженной негативной симптоматики. Это указывает на роль IL-17A не только в качестве показателя выраженной активации провоспалительных механизмов и дисрегуляции адаптивного иммунитета у больных шизофренией, но и как потенциального биомаркера клинически значи-Малашенкова И.К.…”

Section: Discussionunclassified

Association of IL-17A levels with immuneinflammatory profile and structural MRI data in patients with schizophrenia

et al. 2022

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IL-17A is a proinflammatory cytokine involved in pathogenesis of some neuroinflammatory diseases of the brain. However, its role in schizophrenia is poorly understood. Currently, noninvasive neuroimaging techniques are widely used to assess abnormalities in brain morphology and interactions of neuronal networks in schizophrenia. The aim of this work was to study associations between IL-17A level and brain morphometric parameters in schizophrenia, in order to clarify immune factors of pathogenesis and search for biomarkers of unfavorable disease course. 45 patients with schizophrenia and 30 healthy volunteers were included into the study. The levels of cytokines (IL-5, IL-6, IL-8, IL-10, IL-17A) and inflammatory markers were determined by ELISA or multiplex analysis. MRI scans were performed with a Siemens Magnetom Verio 3T MRI scanner. We used Kruskal–Wallis test to assess significant differences in immunological parameters followed by Mann–Whitney paired comparison; Student test to assess the significance of differences in morphometric parameters of the brain; Fisher exact test to assess the differences in discrete variables, with the differences considered statistically significant at p < 0.05. IL-17A levels were found to be increased in schizophrenia. Its elevated content was associated with increased levels of C-reactive protein, IL-5, IL-6, IL-8, IL-10, and the presence of morphometric changes of frontal and temporal cortex in the patients. So far, the relationships between IL-17A levels, immunoinflammatory parameters and structural brain changes have not been studied in schizophrenia. In the present work, we found an association of elevated IL-17A levels with decreased cortical thickness in several brain regions, systemic inflammation and activation of Th2-link of adaptive immunity in the patients with schizophrenia. According to the literature, a number of brain areas, where cortical thickness was associated with IL-17A levels may be relevant to pathogenesis of the disease and, in particular, to the development of negative symptoms, including impoverishment of interests, speech, and emotions. The results are important for understanding the role of immune disorders in pathogenesis of schizophrenia, including structural changes of the brain, and suggest that IL-17A may be a biomarker of these disorders. Confirmation of associations between structural neuroimaging findings, laboratory markers of inflammation and immune disorders may provide the basis for new multidisciplinary approaches to the diagnosis and prognosis of schizophrenia.

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Section: Discussionunclassified

Association of IL-17A levels with immuneinflammatory profile and structural MRI data in patients with schizophrenia

et al. 2022

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“…The levels of IL-1β and IL-6 are also elevated in chronic schizophrenia, as shown in the same meta-analysis. According to our data, the increased IL-8 level is noted in patients with schizophrenia irrespective of the intensity of clinical symptoms [26]. IFN-γ is an important cytokine activating functions of CD3+CD4+ T helpers type 1, CD3+CD8+ cytotoxic T cells, and CD3-CD16+CD56+ NK cells, which provide antiviral defense, and stimulating presentation of antigens to lymphocytes by the cells of the innate immunity.…”

Section: Discussionmentioning

confidence: 52%

Identification of Diagnostic Schizophrenia Biomarkers Based on the Assessment of Immune and Systemic Inflammation Parameters Using Machine Learning Modeling

Malashenkova,

Krynskiy,

Ogurtsov

et al. 2023

Sovrem Tehnol Med

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Materials and Methods.We have analyzed 17 immunological parameters in 63 schizophrenia patients and 36 healthy volunteers. The parameters of humoral immunity, systemic level of the key cytokines of adaptive immunity, anti-inflammatory and pro-inflammatory cytokines, and other inflammatory markers were determined by enzyme immunoassay. Applied methods of machine learning covered the main group of approaches to supervised learning such as linear models (logistic regression), quadratic discriminant analysis (QDA), support vector machine (linear SVM, RBF SVM), k-nearest neighbors algorithm, Gaussian processes, naive Bayes classifier, decision trees, and ensemble models (AdaBoost, random forest, XGBoost). The importance of features for prediction from the best fold has been analyzed for the machine learning methods, which demonstrated the best quality. The most significant features were selected using 70% quantile threshold.Results. The AdaBoost ensemble model with ROC AUC of 0.71±0.15 and average accuracy (ACC) of 0.78±0.11 has demonstrated the best quality on a 10-fold cross validation test sample. Within the frameworks of the present investigation, the AdaBoost model has shown a good quality of classification between the patients with schizophrenia and healthy volunteers (ROC AUC over 0.70) at a high stability of the results (σ less than 0.2). The most important immunological parameters have been established for differentiation between the patients and healthy volunteers: the level of some systemic inflammatory markers, activation of humoral immunity, pro-inflammatory cytokines, immunoregulatory cytokines and proteins, Th1 and Th2 immunity cytokines. It was for the first time that the possibility of differentiating schizophrenia patients from healthy volunteers was shown with the accuracy of more than 70% with the help of machine learning using only immune parameters.The results of this investigation confirm a high importance of the immune system in the pathogenesis of schizophrenia.

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“…We found a significant correlation between CYFIP2 and negative symptoms in our SZ cohort. Negative symptoms are the most resistant to currently available pharmacological interventions in SZ ( Correll and Schooler, 2020 ; Malashenkova et al, 2021 ). Negative symptoms in PANSS include seven specific domains, including blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking ( Shankar and Nate, 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of networks in the dorsolateral prefrontal cortex in chronic schizophrenia: Relevance of altered immune response

et al. 2023

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The dorsolateral prefrontal cortex (DLPFC) has a crucial role in cognitive functioning and negative symptoms in schizophrenia. However, limited information of altered protein networks is available in this region in schizophrenia. We performed a proteomic analysis using single-shot liquid chromatography-tandem mass spectrometry of grey matter of postmortem DLPFC in chronic schizophrenia subjects (n = 20) and unaffected subjects (n = 20) followed by bioinformatic analysis to identify altered protein networks in schizophrenia (PXD024939 identifier in ProteomeXchange repository). Our results displayed a proteome profile in the DLPFC of 1989 proteins. 43 proteins were found significantly altered in schizophrenia. Analysis of this panel showed an enrichment of biological processes implicated in vesicle-mediated transport, processing and antigen presentation via MHC class II, intracellular transport and selenium metabolism. The enriched identified pathways were MHC class II antigen presentation, vesicle-mediated transport, Golgi ER retrograde transport, Nef mediated CD8 downregulation and the immune system. All these enriched categories were found to be downregulated. Furthermore, our network analyses showed crosstalk between proteins involved in MHC class II antigen presentation, membrane trafficking, Golgi-to-ER retrograde transport, Nef-mediated CD8 downregulation and the immune system with only one module built by 13 proteins. RAB7A showed eight interactions with proteins of all these pathways. Our results provide an altered molecular network involved in immune response in the DLPFC in schizophrenia with a central role of RAB7A. These results suggest that RAB7A or other proteins of this network could be potential targets for novel pharmacological strategies in schizophrenia for improving cognitive and negative symptoms.

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

Cited by 10 publications

References 42 publications

Association of IL-17A levels with immuneinflammatory profile and structural MRI data in patients with schizophrenia

Association of IL-17A levels with immuneinflammatory profile and structural MRI data in patients with schizophrenia

Identification of Diagnostic Schizophrenia Biomarkers Based on the Assessment of Immune and Systemic Inflammation Parameters Using Machine Learning Modeling

Analysis of networks in the dorsolateral prefrontal cortex in chronic schizophrenia: Relevance of altered immune response

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