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Ischemic stroke (IS) and subsequent neuropsychiatric disorders are among the leading causes of disability worldwide. Several strategies have been previously proposed to utilize exosomes for assessing the risk of IS-related diseases. The aim of this work was to evaluate serum exosomal proteins in IS patients during the chronic post-stroke period and to search for their associations with the development of post-stroke mild cognitive impairment (MCI). Comparative quantitative proteomic analysis of serum exosomes of patients without post-stroke MCI (19 patients mean age 52.0 ± 8.1 years) and patients with post-stroke MCI (11 patients, mean age 64.8 ± 5.6 years) revealed significant differences in the levels of 62 proteins out of 186 identified. Increased levels of the proteins associated with immune system and decreased levels of the proteins involved in lipid metabolism were observed in the patients with MCI compared to the patients without MCI in the chronic post-stroke period. The obtained data suggest that the higher level of immune system activation in the patients during a relatively long period after IS may be one of the risk factors for the development of post-stroke cognitive disorders and suggest participation of exosomal transport in these processes.

Nonsuicidal self-injurious behavior (NSSI), prevalent in patients with non-psychotic mental disorders (NPMD), is associated with numerous adverse outcomes. Despite active research into the clinical and psychological aspects of NSSI, the underlying biological mechanisms remain obscure. Early adverse experiences are believed to induce long-lasting changes in neuroendocrine mechanisms of stress control playing a key role in NSSI development. The aim of the study was to evaluate parameters potentially predicting development of NSSI in female patients with NPMD and suicidal ideation. Eighty female patients over 18 years with NPMD and suicidal ideation (40 with and 40 without NSSI) and 48 age matching women without evidence of mental illness (healthy controls) were enrolled. Diagnostic interviews and self-report measures were used to assess childhood maltreatment, presence, frequency, and characteristics of suicidal and self-injurious thoughts and behaviors, the Beck Depression Inventory scale to assess severity of depression. Hypothalamic-pituitary-adrenal axis markers, hormones, and neurotrophic factors were measured in blood serum. The likelihood of developing NSSI in patients with NPMD and suicidal ideation was associated with early adverse family history and elevated adrenocorticotropic hormone levels. Dysregulation of hypothalamic-pituitary-adrenal axis as a result of early chronic stress experiences may represent critical biological mechanism promoting the development of NSSI behaviors in patients with NPMD., Competing Interests: The authors declare no conflicts of interest.

Our previous studies showed that in patients with brain diseases, neurotrophic factors in lacrimal fluid (LF) may change more prominently than in blood serum (BS). Since glial cell line-derived neurotrophic factor (GDNF) is involved in the control of neuronal networks in an epileptic brain, we aimed to assess the GDNF levels in LF and BS as well as the BDNF and the hypothalamic-pituitary-adrenocortical and inflammation indices in BS of patients with focal epilepsy (FE) and epilepsy and comorbid depression (FE + MDD) and to compare them with those of patients with major depressive disorder (MDD) and healthy controls (HC). GDNF levels in BS were similar in patients and HC and higher in FE taking valproates. GDNF levels in LF were significantly lower in all patient groups compared to controls, and independent of drugs used. GDNF concentrations in LF and BS positively correlated in HC, but not in patient groups. BDNF level was lower in BS of patients compared with HC and higher in FE + MDD taking valproates. A reduction in the GDNF level in LF might be an important biomarker of FE. Logistic regression models demonstrated that the probability of FE can be evaluated using GDNF in LF and BDNF in BS; that of MDD using GDNF in LF and cortisol and TNF-α in BS; and that of epilepsy with MDD using GDNF in LF and TNF-α and BDNF in BS.

Neuropsychiatric complications, in particular cognitive and depressive disorders, are common consequences of ischemic stroke (IS) and complicate the rehabilitation, quality of life, and social adaptation of patients. The hypothalamic-pituitary-adrenal (HPA) system, sympathoadrenal medullary system (SAMS), and inflammatory processes are believed to be involved in the pathogenesis of these disorders. This study aimed to explore these systems in IS patients, including those with post-stroke cognitive and depressive disorders, within a year after IS. Indices of the HPA axis, inflammatory system, and SAMS were measured in blood serum (cortisol, interleukin-6 (IL-6)), plasma (adrenocorticotropic hormone), and saliva (cortisol, α-amylase). During one year after mild/moderate IS (NIHSS score 5.9 ± 4.3), serum cortisol and salivary α-amylase levels remained elevated in the total cohort. In the group with further cognitive decline, serum and salivary cortisol levels were elevated during the acute period of IS. In the group with poststroke depressive disorder, salivary α-amylase was constantly elevated, while serum IL-6 was minimal during the acute period. The results suggest prolonged hyperactivation of the HPA axis and SAMS after IS. Specifically, post-stroke cognitive impairment was associated with hyperactivation of the HPA axis during the acute IS period, while post-stroke depressive disorder was associated with the chronic inflammatory process and hyperactivation of SAMS during the follow-up period.

Background: Many studies indicate a significant role of GDNF in the pathogenesis of the mood disorders, including bipolar disorder (BD) and major depressive disorder (MDD). Potentially, neurotrophic factors in lacrimal fluid (LF) could become biomarkers of various specific disorders. The aim of this study was to assess GDNF levels in LF and blood serum (BS) of patients with a current depressive episode (cDE)., Methods: We studied the glial cell line-derived neurotrophic factor (GDNF) concentration in the LF and BS of 39 healthy controls and 137 patients with a current depressive episode (cDE) (both subgroups members were 20-49 years): BD - 46 patients, MDD - 91 patients., Results: GDNF concentration in BS of women with MDD was significantly lower than in men. In BD patients, univariate linear regression analysis revealed significant correlations between GDNF concentration in the LF and the use of anxiolytics or antidepressants. These correlations were confirmed by the multivariate linear regression analysis. A significant correlation between GDNF concentrations in the LF and BS was found in controls., Limitations: The unequal proportion of men in the BD group did not permit adjusting GDNF concentrations for sex. The collected LF was stimulated, which could influence GDNF levels. It should also be noted that the patients included in the study were not treatment- naïve., Conclusions: Our findings suggest that GDNF concentration in LF could be a biomarker of the cDE (both unipolar and bipolar), though the sensitivity of this potential biomarker may be lower in depressive patients with anxiety symptoms., Competing Interests: Conflict of interest Authors declare they have no conflict of interest with respect to this study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The hypothalamic-pituitary-adrenal (HPA) axis, inflammatory processes and neurotrophic factor systems are involved in pathogenesis of both epilepsy and depressive disorders. The study aimed to explore these systems in patients with focal epilepsy (PWE, n = 76), epilepsy and comorbid depression (PWCED n = 48), and major depressive disorder (PWMDD, n = 62) compared with healthy controls (HC, n = 78)., Methods: Parameters of the HPA axis, neurotrophic factors, and TNF-α were measured in blood serum along with the hemogram., Results: Serum cortisol level was augmented in PWE, PWCED, and PWMDD compared with HC and was higher in PWMDD than in PWE. Serum cortisol negatively correlated with Mini-Mental State Examination (MMSE) score in PWE, and positively with depression inventory-II (BDI-II) score in PWMDD. Only PWMDD demonstrated elevated plasma ACTH. Serum TNF-α, lymphocytes, and eosinophils were augmented in PWMDD; monocytes elevated in PWE and PWCED, while neutrophils were reduced in PWE and PWMDD. Serum BDNF was decreased in PWE and PWCED, CNTF was elevated in all groups of patients. In PWE, none of above indices depended on epilepsy etiology., Conclusions: The results confirm the involvement of HPA axis and inflammatory processes in pathogenesis of epilepsy and depression and provide new insights in mechanisms of epilepsy and depression comorbidity.

Purpose: To study glial cell line-derived neurotrophic factor (GDNF) concentrations in aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG)., Methods: GDNF was studied in AH, LF, and BS in 47 patients with age-related cataract, and 30 patients with POAG combined with cataract (one eye in each person). AH was sampled during cataract surgery., Results: GDNF concentration (pg/ml) in patients with POAG and cataract was lower than in cataract-only patients (p<0.001), both in AH (46.3±31.1 versus 88.9±46.9) and in LF (222±101 versus 344±134). The difference was not significant for the GDNF concentration in BS (194±56 versus 201±45). In the earlier (early and moderate) stages of POAG, compared to later (advanced and severe) stages, GDNF concentration was significantly lower in LF (176±99 versus 258±91; p = 0.027) and in BS (165±42 versus 217±55; p = 0.017), while GDNF concentration in AH showed an insignificant difference (40.0±25.7 versus 51.1±34.7). In patients with POAG, GDNF concentration in LF and BS was inversely correlated with the Humphrey visual field index: Pearson's correlation coefficient r = -0.465 (p = 0.01) for LF and r = -0.399 (p = 0.029) for BS. When compared to the cataract group, patients in the earlier stages of POAG showed significantly lower GDNF concentrations in all studied biologic fluids., Conclusions: Compared to patients with cataract only, GDNF levels are lower in the AH and LF of patients with POAG and cataract, especially at earlier stages of the disease (at these stages, the GDNF level in BS is also lower). At earlier stages of POAG, compared to later stages, GDNF content is lower in LF and BS. These data could serve as a reason for the therapeutic use of GDNF in patients with POAG., (Copyright © 2022 Molecular Vision.)

Olfactory dysfunction is a serious symptom that requires careful differential diagnosis. The article presents convincing evidence that dysosmia is not only a symptom of rinological pathology, but also a manifestation of various neurodegenerative diseases. Some patients with SARS-CoV-2 have neurological symptoms. Modern studies show that olfactory and gustatory dysfunctions are significant symptoms in the clinical presentation of the COVID-19 infection. The importance of olfactory diagnostics in relatives of patients with hereditary neurodegenerative diseases for the purpose of early detection of pathology is noted. We consider the possibility of introducing new methods for the diagnosis of olfactory dysfunction, which is a promising task both in the field of neurology and otorhinolaryngology, in order to prevent the development of neurodegenerative diseases at an early stage, improve the quality of life and social adaptation of patients.

Objective: To evaluate brain-derived neurotrophic factor (BDNF) level in blood serum (BS) and lacrimal fluid (LF) of people with epilepsy (PWE)., Methods: It was a case-control study of 72 consecutive patients with focal epilepsy (cases, Epilepsy group) and 60 age- and gender-matched healthy volunteers (controls). Based on comorbid depression, two subgroups of PWE were formed. BDNF level was measured by enzyme-linked immunosorbent assay (ELISA) in BS and LF., Results: Compared to controls, BDNF level (pg/mL) in PWE was lower both in BS (22,520 ± 3810 vs. 26,360 ± 3090, P < 0.000) and in LF (100.8 ± 23.3 vs. 113.4 ± 19.3, P = 0.001). However, no significant correlation was found between BDNF level in BS and LF either in the Epilepsy group or in controls. No impact of comorbid depression on BDNF level was found either in BS or LF of PWE. We revealed a higher BDNF level in LF of men as compared to women in controls and a similar non-significant trend in PWE. Higher BDNF level in BS of PWE receiving valproates versus other AEDs was found, however, a relatively small number of observations and use of polytherapy in most cases should be taken into account., Significance: In patients with focal epilepsy, BDNF level is decreased both in BS and LF, though with no correlation between them. No association of BDNF levels with age and epilepsy characteristics, as well as the occurrence of depression, was found. Low BDNF level in LF could be considered as a non-invasive biomarker of focal epilepsy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

MicroRNAs (miRNAs) only recently have been recognized as promising molecules for both fundamental and clinical neuroscience. We provide a literature review of miRNA biomarker studies in three most prominent psychiatric disorders (depression, bipolar disorder and schizophrenia) with the particular focus on depression due to its social and healthcare importance. Our search resulted in 191 unique miRNAs across 35 human studies measuring miRNA levels in blood, serum or plasma. 30 miRNAs replicated in more than one study. Most miRNAs targeted neuroplasticity and neurodevelopment pathways. Various limitations do not allow us to make firm conclusions on clinical potential of studied miRNAs. Based on our results we discuss the rationale for future research investigations of exosomal mechanisms to overcome methodological caveats both in studying etiology and pathogenesis, and providing an objective back-up for clinical decisions.

Over the past years, the prevalence of brain diseases and, consequently, their social significance and economic burden for society has been steadily increasing throughout the world. Brain diseases are a heterogeneous group of diseases that unite a number of disorders that are within the competence of both neurology and psychiatry, often concurrent or comorbid with each other. Z. P. Soloviev Research and Clinical Center for Neuropsychiatry is a leading medical organization in Moscow, which performs a full treatment cycle, studies the data and has postgraduate training programs in this field of medicine. It is conducting a number of relevant research programs; some in collaboration with international clinics. This study deals with the following programs: fundamental aspects of depression and stress-reactivity, suicidal and self-damaging behavior, usage of biofeedback and gravity therapy in rehabilitation and training programs for medical workers in successful communication.

Background: Transcranial direct current stimulation (tDCS) can be an effective treatment for depression, however, the duration of the stimulation session, among other parameters, needs to be optimized., Methods: 69 mild to moderately depressed patients (age 37.6±10.5years, 19 men) were randomized into three groups - 30-, 20-minute or sham tDCS. 10 daily sessions of anodal/sham tDCS of the left DLPFC (0.5mA; electrode 3,5×7cm) combined with 50mg/day of sertraline were performed. Mood, cognition and BDNF level were assessed before and after the treatment., Results: A significant difference between groups was observed in the percent change of the Hamilton Depression Rating Scale (F(2, 66)=10.1; p<0.001). Sham group (43.4%±18.1) had a smaller improvement compared to the 30-minute (63.8%±13.4; 95% CI: 11.23-29.44; p=0.00003) and 20-minute group (53.2%±15.3; 95% CI: 0.21-19.26; p=0.045). 30-minute group had significantly greater percent improvement than 20-minute group (95% CI: 1.74-19.46; p=0.02). Responders constituted 89%, 68%, and 50% and remitters - 70%, 27%, and 35% in the 30-, 20-minute and sham groups, respectively. A significant difference in the number of responders was observed between 30-minute vs. sham group (odds ratio=8; 95% CI, 2.59-24.69; p=0.001), in remission rate - between 30-minute vs. sham (odds ratio=4.40; 95% CI, 2.02-9.57; p=0.02) and vs. 20-minute (odds ratio=6.33; 95% CI, 2.85-14.10; p=0.003) groups. Two hypomania cases and one case of blood pressure elevation were detected in the 20-minute group. Among neuropsychological tests, only the change in Digit Span Backwards test showed a significant interaction between groups (TIME*GROUP; F(2, 65)=6,6, p=0.002); a greater improvement was observed in both active groups compared to sham (p<0.05). The change in BDNF level after the treatment did not show the significant difference between groups., Conclusions: tDCS of 20- or 30-minutes combined with sertraline are efficient for the treatment of mild and moderate depression; the effect of 30min stimulation exceeds the one obtained from 20min., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To study brain-derived neurotrophic factor (BDNF) content in aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG)., Methods: BDNF was studied in 57 patients with age-related cataract, 55 patients with POAG combined with cataract, and 29 healthy controls (one eye in each person). AH was sampled during cataract surgery., Results: The levels of BDNF in LF and BS did not differ in cataract patients and controls. The concentration of BDNF (pg/mL) in patients with POAG and cataract was lower than in cataract patients in AH (35.2 ± 14.2 vs. 54.6 ± 29.6, P < 0.001), LF (78.0 ± 25.1 vs. 116.2 ± 43.1, P < 0.001), and BS (19230 ± 5960 vs. 22440 ± 7580, P < 0.02), while the AH/LF ratio was similar (0.46 ± 0.18 vs. 0.48 ± 0.19). The AH level of BDNF declined in early POAG and relatively increased in the next stages of the disease, inversely correlating with visual field index (Pearson's correlation coefficient r = -0.404, P = 0.002) and average retinal nerve fiber layer thickness (r = -0.322, P = 0.018). BDNF contents in LF and BS were also the lowest in early POAG. BDNF in AH strongly correlated with its content in LF (r = 0.66, P < 0.000). A formula was suggested to calculate the AH concentration of BDNF basing on its content in LF., Conclusions: BDNF contents are decreased in AH, LF, and BS of patients with POAG demonstrating a significant decrease in the early POAG and relative increase in the next stages of the disease. A strong correlation exists between BDNF contents in AH and LF.

Aim: To investigate gender differences in biochemical characteristics in patients with nonpsychotic mental disorders, and to study their association with childhood trauma., Material and Methods: Women (n=308) and men (92) between 18 and 45 years of age, without serious somatic comorbidities, were examined. Laboratory evaluation included markers of hypothalamic-pituitary-adrenal axis activity (cortisol), hypothalamic-pituitary-thyroid system (TSH), proinflammatory cytokines (Il-1β and Il-6) and the brain derived neurotrophic factor (BDNF). All participants underwent psychometric testing, which included the Child Abuse and Trauma Scale (CATS), Beck and Hamilton depression scale (HAM-D) and Spielberger Anxiety Inventory (STAI). Correlations were studied between the biochemical parameters and total CATS scores and severity of depression and anxiety in subgroups of women and men with a depressive disorder., Results and Conclusion: The men and women in the total study population significantly differed by representation of the different diagnostic classes, which was reflected by differing levels of depressive and anxiety symptoms. The main finding was a correlation between the level of childhood trauma and morning serum cortisol levels in men with depressive disorder, which was absent in women.

Purpose: To study the ciliary neurotrophic factor (CNTF) concentration in the aqueous humor (AH), lacrimal fluid (LF), and blood serum (BS) in patients with age-related cataract and primary open-angle glaucoma (POAG)., Methods: CNTF concentrations were studied in 61 patients with age-related cataract, 55 patients with POAG combined with cataract, and 29 healthy controls (one eye in each person). Preliminary experiments permitted us to extend the minimum quantifiable value of the CNTF Quantikine enzyme-linked immunosorbent assay (ELISA) kit to 2.5 pg/ml., Results: The levels of CNTF in LF and BS did not differ in patients with cataract and controls. The CNTF concentration (pg/ml) in patients with POAG and cataract was lower than in patients with cataract (p<0.001) in AH (39.9±26.2 versus 57.2±25.6) and in LF (25.7±14.9 versus 39.9±18.0). The differences were not statistically significant for the CNTF level in BS (5.45±4.72 versus 5.96±4.92) and the AH/LF ratio (1.69±1.05 versus 1.58±0.70). In the patients with POAG, the AH level of CNTF correlated with the visual field index (Pearson's correlation coefficient r = 0.35, p = 0.01). A statistically significant decrease in the AH and LF concentrations of CNTF was observed in patients in all stages of POAG compared with the cataract group. This decrease was particularly prominent in patients with severe glaucoma. Compared to patients with combined early and moderate stages of disease patients with advanced glaucoma showed an insignificant reduction in the median CNTF concentration in AH and LF. The serum CNTF concentration did not show any dependence on the glaucoma stage. The CNTF concentration in the AH strongly correlated with the CNTF concentration in the LF (r=0.71, p<0.000). A formula was suggested to calculate the concentration of CNTF in AH based on the CNTF concentration in LF., Conclusions: The CNTF concentration is reduced in the AH and LF of patients with POAG, especially in those with severe visual field loss. The CNTF concentration in AH and LF showed a strong correlation, and this phenomenon opens up new options for a noninvasive estimation of the CNTF concentration in AH. The CNTF concentration established in the AH, LF, and BS of patients with age-related cataract can serve as normative data for persons older than 50 years old.

Background: Ascending thoracic aortic aneurysm (aTAA) is a heterogeneous group of disorders that involve impaired endothelial function. The nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) serves as an endothelial dysfunction marker. Thus, we investigated ADMA levels in patients with aTAA., Methods: Eighty-six patients with aTAA and 18 healthy individuals were enrolled. All patients underwent echocardiography. Plasma ADMA levels were measured using high-performance liquid chromatography., Results: ADMA levels were higher in aTAA patients than in control patients (p = 0.034). According to the multivariable regression model, higher ADMA levels were associated with ascending aortic diameter (p = 0.017), smoking (p = 0.016), and log-transformed estimated glomerular filtration rate (eGFR, p = 0.005)., Conclusion: This pilot study demonstrates an association of ADMA with ascending aortic dilatation; however, further studies are needed to investigate whether increased ADMA levels underlie aTAA development.

Though borderline psychiatric disorders (BPD) are quite common diseases, their pathogenesis remains obscure. Data from several groups and our previous results suggest that the pathological changes are typical not only for brain cells, but also for cells of the immune system. One of the evident illustrations of immune and nervous systems relationship in pathogenesis of mental diseases is the death of PBMC occurring in patients with depression. We have shown previously that activities of the caspases increase in some types of BPD. In this study, we have investigated caspase activities in PBMC of patients with BPD of different severity. It has been found that in severe depressive disorder activities of caspases were reduced either as compared to healthy controls or to patients with depression lesser severity. In contrast, in patients with severe anxiety activities of caspases were higher than in both control and patients with less severe forms of anxiety disorders. Thus, the study of caspase activity in PBMC makes it possible to differentiate between severe and mild forms of BPD.

The processes in the nervous and immune systems are closely interrelated. In particular, increased apoptosis was reported in lymphocytes of patients with depression. The aim of this study was to assess activities of proteases associated with cell death in lymphocytes of patient with personality disorders accompanied by depression and anxiety. In patients with personality disorders associated with organic brain dysfunction caspase activities were reduced in patients with depression and increased in patients with anxiety. The results may be useful for elucidation of pathogenetic mechanisms of personality disorders and in search of new biomarkers of these diseases.