Over last years, the world’s aging populations are rising rapidly, and the phenotypes of cognitive insufficiency, such as old age, depression and dementia, are increasing. Search for approaches to discrimination between such phenotypes is extremely relevant. Current studies present compelling evidence of the key role of immune system (its peripheral compartment), and the stress response system in physiological brain health. Therefore, assessment of complex interactions between immune and neuroendocrine systems may be an effective way to differentiate between depression and early stages of dementia in elderly people. Our purpose was to reveal peripheral molecular messages, e.g., cytokines and stress hormones, in the context of cognitive impairment phenotypes: healthy old age/old age depression/dementia. Eighty elderly people were included into groups as follows: “Healthy ageing”, “Dementia”, “Depression”. Levels of certain cytokines: IL-6, IL-1β, TNFα, IFNγ, IL-10, and stress hormones (cortisol, ACTH, dopamine, noradrenaline, and adrenaline) were determined in blood plasma by ELISA. The intergroup differences were evaluated by the Kruskal-Wallis test with Conover-Inman post-hoc pairwise comparisons. For differential diagnostics between the groups of elderly people with varying grades of cognitive impairment, we used linear canonical discriminant analysis performed on the ranks. It has been shown that cognitive insufficiency phenotypes—old age depression and dementia—differ from the healthy ageing phenotype with their high peripheral levels of TNFα cytokine and low levels of IL-1β. The differences between depression in elderly and dementia included lower level of IL-10 in depression (lower than in “Healthy ageing”), and high IL-6 in dementia (compared to “Healthy ageing”). Evaluation of the hypothalamic-pituitary and sympatho-adreno-medullary axes hormones showed hyporesponsiveness of hypothalamic-pituitary axis, regardless of cognitive insufficiency phenotypes, along with activation of sympatho-adreno-medullary axis, i.e., high dopamine level in old age depression with dementia, and high adrenaline level in dementia, than in depression of elderly phenotype and healthy ageing. Such significant differences in the levels of molecular messages, i.e., cytokines and stress hormones among the old age person groups, enabled diagnostic efficacy of 87.5% to differentiate cognitive phenotypes of aging: healthy ageing, old age depression, and dementia.
According to new views on communication ways and principles in the main regulatory systems of the body, i.e., immune and neuroendocrine, there is a risk for disintegration of pathways and structures in these systems which may underlie disorders such as autism-spectrum disorders (ASD) and schizophreniaspectrum disorders (SSD). Both disorders are classified as neurodevelopmental disorders, with unclear etiology and partially overlapping pathophysiological developmental mechanisms. Diagnosis of ASD and SSD is based on patterns of clinical symptoms/syndromes that demonstrate high heterogeneity and similarity. Therefore, it is very important to find the ways of discerning children with ASD from those with SSD. Our aim was to identify peripheral activity indexes for immune and neuroendocrine systems, and their integration for usage as information hubs of congruency and phenotypic plasticity of these systems in children with ASD, as compared to SSD patients. The levels of 14 indexes of the immune and neuroendocrine systems in blood plasma were determined in 82 children with ASD, 9 children with SSD and 45 children with typical neurodevelopment (TD). To assess peripheral activity of the immune and neuroendocrine systems and their relationships, we applied a multivariate exploratory analysis using a method of nonlinear principal components. The following results were obtained: (1) absence of differences in proinflammatory cytokines between ASD and TD children; (2) patients with SSD have significantly higher values of IL-6 and IFNγ, and lower values of IL-1β, TNFα and IL-10 in blood plasma compared to children with ASD and TRD; (3) the level of neurohormones in children with ASD is in accordance with physiological reference values. The children with SSD have lower levels of epynephrine and dopamine compared to ASD and TD, respectively; (4) integration degree of regulatory systems assessed by principal component analysis has shown the following: (4.1) TD children have strong correlations within each of the systems and between them, thus showing their communicative abilities and plasticity, characteristic of normal values; (4.2) In SSD children, minimal numbers of strong relations were demonstrated within the cytokine system; (4.3) The children with ASD exhibited two clusters: one of them had a complete similarity with TDC, in terms of tension and assortment of immune and neuroendocrine indices; the other one presented low coupling between the parameters of regulatory systems, similar to the children with SSD; (4.4) Analysis of peripheral indices of cytokine and neuroendocrine systems for clusters 1 and 2 in children with ASD compared to children with SSD and TD demonstrated that, in children with ASD of cluster 1, the indices did not differ from TDC, except of epinephrine, ACTH, kynurenine, and tryptophan. In the children with ASD of cluster 2, the values of the indices are equal to children with SSD, except of dopamine and tryptophan. Thus, we have shown phenomenon of transdiagnostic clustering, i.e., allocation of two clusters among ASD children. One of them is similar to levels of indices and connections between the immune and neuroendocrine systems with TD, and another cluster is similar to SSD children. Therefore, they could be potentially useful as diagnostic criteria when discriminating the two disorders.
Due to the steady increase in the number of children with autism and the high heterogeneity of clinical groups, the diagnosis of these disorders and their severity is an urgent problem in modern medicine. In the course of the work, 126 children from 3 to 13 years old with typical neurodevelopment and with severe and mild autism spectrum disorders (ASD) were examined. Disease severity was determined according to the Childhood Autism Rating Scale (CARS). The levels of pro-/anti-inflammatory cytokines and neurotrophic factors (nerve growth factor beta and brain-derived neurotrophic factor) in blood plasma were assessed by enzyme immunoassay. Associations between indicators in each group of patients were assessed using the Spearman test and visualized as a heatmap of correlations. Statistical data processing was carried out in the R software. Significantly high levels of IL-4 in blood plasma and a decrease in the number of significant correlations within/between systems were revealed in children with mild autism compared with children with typical neurodevelopment. Such data can probably reflect the theory that some children with ASD are characterized by slow brain development, as a variant of the evolutionary norm. On the contrary, in children with severe ASD, high systemic levels of IL-6 and IFNg are shown against the background of low values of IL-10, IL-1β, TNFα and NGFβ, supported by the almost complete absence of intra/ and intersystem interactions. This may act as an indicator of maladaptation of the immune and nervous systems in severe autism, which contributes to the pathogenesis of the disease. Thus, a set of indicators: high levels of key pro-inflammatory cytokines - IL-6 and IFNg, low levels of IL-10, NGFβ and disintegration of the cytokine and nervous systems in the periphery can be proposed as an approach to indicate the severity of the condition in children with ASD.
Aim. Detect connection between cognitive dysfunction in senior people with systemic infection profile and small intestine microbiota structure. Materials and methods. 42 senior individuals were included into the study All the examined have been divided into 2 groups based on the results of psychic status: 20 individuals with moderate cognitive disorders - «active longevity» group and 22 individuals with pronounced cognitive deficiency - «mercy» group. Systemic inflammation status and structure and quantitative composition of microbiota of small intestine was determined in all the senior individuals using gas chromatography mass-spectrometry of microbial markers. Results. Interconnection between systemic level of cytokines and microbiota structure of small intestine in senior people with various cognitive status was determined. Significant correlations between levels of pro-inflammatory cytokine IL-6 in blood plasma and quantity of Propionibacterium jensenii, Moraxella spp., Bacillus cereus and Fusobacterium spp. in small intestine and the degree of cognitive failure were detected for the first time. Conclusion. The parameters obtained could be used as predictive biomarkers of cognitive dysfunction in senior people.
Сomplex intergenic interactions should be taken into account when predicting the risk of adverse course in a pathological process. This presumption is at the heart of evolving multifactorial diseases (ulcerative colitis and irritable bowel syndrome). A single genetic polymorphism seems to be a weak risk factor when predicting the disease evolution and it could not be used as a prognostic model for development of multifactorial pathologies, especially in cases of rare alleles. However, it is well known that the combination of unfavorable alleles of several genes with an additive effect is dangerous. Therefore, identification of such polymorphisms is very important.Previously we conducted a test panel, in order to evaluate associations of alleles and genotypes of some cytokine genes (IL1β, TNFα, IL1rа, IL10, IL6) with predisposal, or resistance for ulcerative colitis and irritable bowel syndrome in the Russian Chelyabinsk region. Distribution of alleles and genotypes of these genes have been assessed in irritation bowel disease (IBD) and ulcerative colitis (UC). The following methods were used: isolation of DNA samples from whole blood, genotyping of the studied gene polymorphisms with PCR, RFLP. A comparative analysis of intergenic interactions between the cytokine genes IL1β, TNFα, IL1ra, IL10, IL6 in the IBD and UC patients was carried out by the Multifactor Dimensionality Reduction method. The analysis is based on the use of polymorphic loci of IL1β, TNFα, IL1ra, IL10, IL6 combinations chosen for analysis of intergenic interactions, with respect to the risk for IBS and UC predisposition. As a result of this study, a fourlocus model IL1β(+3953)*Т/TNFα(-308)*A/IL10(-1082)*G/IL6(-174)*G was identified for IBS, which was characterized by 90% repeatability and prediction accuracy of 74.5%. This model of gene interactions between the cytokine IL1β, TNFα, IL1ra, IL10, IL6 genes had the greatest prediction potential (p < 0.001) in IBS, whereas the model for UC was not statistically significant. The following types of genetic interactions were established: synergism between the IL1β(+3953)*Т and TNFα(-308)*A loci, whereas IL6(-174)*G и IL10(-1082)*G, TNFα(-308)*A seem to be in antagonistic relationships. The study made it possible to establish that the -174G/C IL-6 polymorphism may play a central role and provide intergenic interactions with SNPs of IL1β, TNFα, IL10 for predisposal to irritable bowel syndrome in Chelyabinsk Region of Russia.
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