[Systemic inflammatory markers in age-associated cognitive impairment and Alzheimer's disease]. / Sistemnye vospalitel'nye markery pri vozrastnom kognitivnom snizhenii i bolezni Al'tsgeimera.

AIM: To determine a complex of immune markers reflecting various links of multicomponent inflammatory reactions in amnestic type of mild cognitive impairment (aMCI) in comparison with Alzheimer's disease (AD). MATERIAL AND METHODS: Sixty-seven patients with aMCI, aged 72 [63; 77] years, and 91 patients with Alzheimer's disease at the age of 74 [68; 79] years were examined. The aMCI was diagnosed according to the criteria of R.S. Petersen et al. (1999) and B. Dubois et al. (2014). The diagnosis of AD was established in accordance with the ICD-10 and NINCDS-ADRDA criteria. The degree of dementia severity was determined by clinical signs using the CDR (Clinical Dementia Rating) and the Mini Mental State Examination (MMSE) total score. The control group included 38 age- and sex-matched individuals. Immune and biochemical parameters were determined in blood plasma. The activity of LE and α1-PI was determined by spectrophotometric method. Concentrations of IL-6 and CRP were measured by enzyme immunoassay. RESULTS: AD was characterized by the significant decrease in LE activity (p<0.0001) and increase in the activity/levels of α1-PI, CRP and IL-6 (p<0.001; p<0.05; p<0.01, respectively) compared to controls. CDR and MMSE scores were correlated with the LE activity (r=-0.38, r=0.31, p<0.05), i.e. cognitive decline was associated with decreased activity of LE. aMCI was characterized by the significant increase in the activity/level of α1-PI and IL-6 (p<0.0001; p<0.01). In 30% of patients with aMCI, a spectrum of inflammatory markers, typical for patients with AD, was determined. CONCLUSION: Based on the results of comparative analysis of aMCI and AD, one can suggest that one third of patients with aMCI represents a group of ultra-high risk of AD. These patients need a dynamic follow-up with a regular assessment of the state of cognitive functions and possibly preventive therapy.

[The possibility of using immunological parameters for the evaluation of the clinical state of patients with childhood-onset schizophrenia].

OBJECTIVE: To compare clinical and immunological parameters in children with schizophrenia and to analyze the possibility of using them in the assessment of the pathological process activity. MATERIAL AND METHODS: We examined 62 patients, 39 boys and 23 girls, aged from 4 to 17 years, with childhood-onset schizophrenia. Mental state of the patients was assessed using a psychopathological method and with PANSS and CGI scales. The activity of leukocyte elastase (LE) and alpha(1)-proteinase inhibitor (α1-PI) was measured by spectrophotometric method. ELISA was used to determine the level of autoantibodies to neuroantigenes to S-100B and basic myelin protein. RESULTS AND CONCLUSION: The activation of innate immunity assessed by the activity of LE and α1-PI and adaptive immunity (levels of autoantibodies to neuroantigenes to S-100B and basic myelin protein) was identified. Significant correlations of the level of immune system activation with the severity of patient's state on СGI-S (r=0.64, p=0.000001) as well as scores on the PANSS negative symptom subscale (r=0.34, p=0.0077) were found. The results suggest the possibility of using these immunological parameters for the objectification of clinical state of children with schizophrenia.

[Clinical and immunological correlations in endogenous depression].

OBJECTIVE: To study the possibility of using immunological parameters for the evaluation of the activity of endogenous process in depression and quality of response to psychopharmacotherapy. MATERIAL AND METHODS: Authors examined 42 patients, aged 20-55 years, with the prevalence of anxiety (n = 22) or apathy (n = 20) in the clinical picture of depression. The following immunological parameters were measured in the blood of the patients: degranulation activity of leukocyte elastase (LE), functional activity of alpha-1-proteinase inhibitor (alpha-1-PI); the level of autoantibodies to neuroantigen S-100B and myelin basic protein. RESULTS AND CONCLUSION: The involvement of inflammatory and autoimmune responses in the pathophysiology of endogenous depression was confirmed. Depression associated with increased levels of autoantibodies to brain neuroantigens (an autoimmune component) had a more complicated structure and showed the tendency to prolonged course and resistance to the therapy. The results suggest that some immunological parameters may be used as markers of patient's clinical status and quality and completeness of psychopathological symptom reduction.

[The biological evaluation of depression severity: a novel method for the determination of platelet serotonin concentration].

OBJECTIVE: To develop a highly sensitive method for the determination of platelet-rich plasma serotonin concentration for every-day clinical practice. MATERIAL AND METHODS: The method was developed for determination of serotonin in plateled-rich plasma. Serotonin was determined using high performance liquid chromatography with fluorescent detection and hematologic analyzer. RESULTS AND CONCLUSION: In healthy people, concentrations of platelet serotonin were similar to those reported in literature: from 2.19 to 4.87 nmol/109 platelets. In patients with depression (n=30), platelet serotonin concentrations were lower (from 0.11 to 2.89 nmol/109 platelets) and correlated with the severity of depression. The method may be used in clinical purposes.

[Immunological monitoring of endogenous attack-like psychoses].

To analyze the possibility of using immunological parameters for the assessment of the activity of the process and prediction of the quality and completion of remission, we compared the dynamics of clinical and immunological parameters in 76 patients with endogenous attack-like psychoses during pharmacotherapy of a psychotic episode. Authors confirmed evidence for the activation of innate and adaptive immunity in the acute stage of psychosis as well as the correlation between immunological parameters (leukocyte elastase (LE) activity, alpha(1)-proteinase inhibitor (alpha(1)-PI), the level of autoantibodies to nerve growth factor (Aab-NGF)) and clinical symptoms assessed with the PANSS. The improvement of the clinical state assessed by the reduction in PANSS total score was noted in all patients though there were variations in the dynamics of immunological parameters. The increase of immunological parameters, along with the absence of changes at the discharge from the hospital, suggests that the remission was of low quality and the pathological process did not attenuate. Outpatient examination revealed the different dynamics of psychopathological disorders: stable state in 50% patients, moderate worsening of psychological state in 50% patients. Worsening of clinical symptoms after the discharge and in the outpatient stage was correlated with the elevation of the activity/level of immunological parameters. The changes in LE activity and Aab-NGF level precede the changes in mental state of patients in the following 1-2 months. These parameters may be used for monitoring of patients and prediction of quality and completion of remission.

[Inflammatory markers in schizophrenia in aged].

OBJECTIVE: To identify inflammatory markers in schizophrenia in aged. MATERIAL AND METHODS: The main group included 29 patients with schizophrenia, mean age 72.1 ± 6.9 years. A comparison group comprised 34 patients with Alzheimer's disease, mean age 73.4 ± 7.9 years. Seven plasma inflammatory indicators were determined. RESULTS: There was a significant increase in the activity/content of acute inflammation stage proteins: α1-proteinase inhibitor and C-reactive protein as well as anti-inflammatory interleukin-10 compared to the controls while the activity of other inflammatory molecules (leukocyte elastase, tumor necrosis factor alpha, interleukin-1 receptor antagonist) was not changed. No correlations between immunological parameters and clinical presentations were found. CONCLUSION: The results suggest that inflammation does not play a significant role in the remote stages of schizophrenia, in contrast to earlier stages of the disease, and the activity of the pathological process decreased in the late stages. These characteristics can reflect the body reactivity in elderly patients.

[Possibilities of the use of immunological indicators for the assessment of the risk of manifestation of endogenous psychoses in patients with nonpsychotic disorders of the juvenile age].

OBJECTIVE: To study parameters of innate and adaptive immunity in the blood serum of patients with nonpsychotic mental disorders and to classify them by risk of psychosis manifestation. MATERIAL AND METHODS: Authors studied 49 male patients, aged from 16 to 25 years, with nonpsychotic mental disorders corresponded to the premanifest stage of endogenous psychosis. The activity of leukocyte elastase (LE), functional activity of alpha-1-proteinase inhibitor (α1-PI) and the level of autoantibodies (aAB) to S-100 and basic myelin protein were measured. RESULTS: A significant increase in LE and α1-PI was found in patients compared to controls (p<0.001). The level of aAB to neuroantigens was similar in patients and controls. The increase in LE activity was positively correlated with HAM-D depressive symptoms and SOPS total scores (r=0.47, p=0.02). Correlations between α1-PI activity and scores on SOPS positive subscale (r= -0.61, p=0.002) and SOPS total scores (r= -0.43, p=0.04) were identified. After treatment, the improvement of patient's state assessed by SOPS and HAM-D was correlated with the decrease in LE activity in 80% (p<0.01). The further increase of LE activity in 20% may be considered as an indicator of low quality remission and risk of psychosis manifestation. CONCLUSION: Patients with nonpsychotic mental disorders with higher levels of inflammation markers may be attributed to high risk group.

[Membrane structure markers and the acetylcholinesterase activity of erythrocytes in patients with mild cognitive impairment].

Patients with the syndrome of MCI (n=22) and a control group (31 people without signs of mental and neurological diseases) were tested for the degree of hemolysis of erythrocytes (RBC), (membrane structure markers, acetylcholinesterase (AChE) activity in RBC), the level of lipid peroxidation (LPO) (content of malondialdehyde - MDA), microviscosity of surface areas of the membrane using two spin probes localized in the bulk lipids (s1) and in adjacent to the proteins regions of lipid bilayer (s2). There was no difference between the level of spontaneous hemolysis in the group with MCI and the control group which indicated the absence of changes in the mechanical resistance of the RBC membrane. Significant between- group differences were identified for s2 (the increase by >40% in MCI). A trend toward the increase in MDA level in MCI was found as well. There was a decrease by approx. 30% in the Vmax and Km for AChE reaction that indicated the changes in properties or amount of this enzyme. The value of Vmax/Km that determined the real activity of AChE was similar in both groups. No correlations between parameters of membrane structural-functional state that are characteristic of normalcy were noted in the patients with MCI. This finding demonstrated the changes in structural-functional regulation in RBC membrane in elderly people with MCI. Membrane structure status of erythrocytes in MCI holds a special position and differs both from normal ageing and developed Alzheimer's disease. The s1/s2 ratio is recommended as a membrane "marker"for identification of MCI.

[A multidiscipline clinical and biological approach to the study of psychotic types of autistic spectrum disorders in children].

The current problem of heterogeneity of psychotic types of autistic spectrum disorders (ASD) is reviewed. The authors present results of a multidiscipline psychopathological, pathopsychological, neurophysiological and immunological examination of 87 patients, aged from 3 to 14 years, with psychotic types of ASD: childhood psychosis (CP) and atypical childhood psychosis (ACP). Significant differences in clinical presentations of CP and ACP that were correlated with pathopsychological, neurophysiological and immunological disorders were found. These findings support different nosological entities of these types of ASD.

[Inflammatory markers in Alzheimer's disease and vascular dementia].

The following markers of inflammation: enzymatic activity of leukocyte elastase (LE), functional activity of alpha-1-proteinase inhibitor (α1-PI), levels of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured in the blood plasma of patients with Alzheimer's disease (AD) and vascular dementia (VD). The results confirm the presence of an inflammatory component in the pathogenesis of AD and VD. The high level of CRP may be considered as a marker of VD in the early stages of disease. There was an elevation of α1-PI activity in AD patients compared to age-matched controls. The α1-PI activity, levels of CRP and IL-6 increased with the severity of dementia while the LE activity significantly decreased compared to controls (p<0.01). In patients with AD, the IL-6 level was negatively correlated with MMSE scores (Spearman r = -0.46, p=0.0077) and, therefore, can be considered as a biological marker of the severity of the pathological process. Positive correlations between CRP and IL-6 may plausibly reflect an ability of IL-6 to induce the synthesis of CRP.

[Influence of high concentration of antibodies to NGF during early embryogenesis on formation of mice behavior in postnatal period].

In this work the influence of high concentration of antibodies to NGF on mouse's progeny has been investigated. During immunization with NGF the highest concentrations of antibodies were created in the first and third days of pregnancy (in different groups of animals). The dependence of abnormalities of mice postnatal development on level of antibodies to NGF at different stages of early embryogenesis has been established. Increasing of abnormalities in the formation of early behavioral acts and more clinically apparent anomalies in the somatic maturation in case of maximum of antibodies on day I of pregnancy has been showed. Immune responses to NGF during early embryogenesis of mice cause lag in the formation of behavioral acts. The latter are characterized by difficulties in sensor-motor coordination of the limbs and more clinically apparent in mice with a maximum of antibodies on day 1 of embryonic development. Infantilism in developing of contacts between progeny and mothers detected in mice with immune reactions may be a sign of serious mental dysontogenesis. The accelerated development of working memory established in mice with immune response to NGF requires further study of the development of cognitive abilities in these animals. The obtained results illustrate the important regulatory role of NGF at the early stages of development of the nervous system.

[Innate and adaptive immunity in children with psychotic forms of autism-spectrum disorders].

Leukocyte elastase (LE) activity, functional activity of alpha1-proteinase inhibitor, C-reactive protein, autoantibodies to nerve growth factor and to basic myelin protein have been studied in the blood serum of children with psychotic forms of autistic disorders - children psychosis (F84.02) and atypical children psychosis (F84.11). The activation of innate immunity (the increase in LE activity and acute phase proteins) was seen in children psychosis. The more severe mental disturbances, that are characteristic of endogenous atypical children psychosis, were accompanied by the activation of both innate and adaptive immunity ( the increase of the level of autoantibodies to neuroantigenes in the peripheral blood). Correlations between immunological and clinical parameters suggest the involvement of innate and adaptive immunity in the formation of autistic and cognitive disorders in children.

[The state of the immune system in endogenous mental diseases with pronounced affective disorders].

Parameters of innate and adaptive immunity were studied in the blood serum of 180 patients, aged 15-25 years, with different endogenous mental diseases with depressive and mania disorders in the clinical picture (affective psychoses (29 patients), schizoaffective psychoses (106 patients) , slow-progressive schizophrenia (23 patients) and intermittent-progressive schizophrenia (22 patients)). The activation of innate immunity (the increase in the degranulation activity of leukocyte elastase (LE) and functional activity of alpha-1-proteinase inhibitor (α1-PI) were found in all the diseases. The increase in disease severity (from affective disorders to intermittent-progressive schizophrenia) was correlated with the significant elevation of LE activity. The LE activity did not depend on the polarity and severity of affective pathology in each diagnostic group. The mean levels of autoantibodies to the nerve growth factor and the myelin basic protein did not differ from the control values in all the groups of patients.

[Pathogenetic characteristics of post stroke affective disorders].

Fifty patients with affective disorders developed after first cerebral stroke were studied. A spectrum of affective disorders included post-stroke depressions, generalized anxiety disorders, anxiety-depressive disorders and pseudo post-stroke depressions. Platelet serotonin (PS) levels were measured in these patients as well. The levels of PS at the first three days after stroke and their changes towards the 28th day are associated with the development of post-stroke affective disorders. The development of anxiety-depressive disorders in the acute period of stroke is related to the localization of brain lesion focus. The low levels of PS in patients at the first three days after stroke may be the risk factor of delayed affective disorders development.

[Dynamics of immunological and clinical parameters in the treatment of childhood schizophrenia].

A state of innate and adaptive immunity (leukocyte elastase (LE) activity, alpha(1)-proteinase inhibitor (alpha(1)-PI), the level of autoantibodies to nerve growth factor (Aab-NGF) and to basic myelin protein), have been studied in the blood serum of children with schizophrenia and compared to the changes of their clinical-psychopathological state. It has been shown that the exacerbation of schizophrenic process with early onset is accompanied by the activation of some parameters of innate immunity. But the higher activity of LE and alpha(1)-PI before the treatment cannot be considered as a predictive marker of therapeutic efficacy. At the same time, the decrease of LE activity during the treatment is a significant predictor of favorable therapeutic response. The unchanged level of Aab-NGF comparing to controls is also a favorable factor associated with therapeutic efficacy.

[Immunological reactions in different forms of mental disorders].

State of innate and adaptive immunity has been assessed by the indices of activity of leukocyte elastase, alpha1-proteinase inhibitor (alpha(1)-PI), level of C-reactive protein and autoantibodies to neuroantigens (nerve growth factor and basic myelin protein) in different forms of mentalopathology: schizophrenia-spectrum disorders, mental retardation with behavioral abnormalities, organic mental disorders, affective disorders, psychogenias (adaptation disorders), early alcoholism. The increase of activity or levels of all immunological parameters was characteristic of these diseases. However within each group were patients with different levels of immunity activation. A number of patients with significant immunity activation was higher in the groups of schizophrenia-spectrum disorders, early alcoholism, organic mental disorders, mental retardation with behavioral abnormalities and affective disorders. The lowest frequency of such cases was observed for psychogenias (adaptation disorders). These results give grounds to suggest that the extent of immunity activation depends as on severity of psychopathogy as well on individual peculiarities of immunological reactivity in response to a brain pathological process.

[MRI-parameters of frontal lobes in schizophrenia: correlations with the level of autoantibodies to nerve growth factor in the blood serum].

The relationship between MRI-parameters of frontal lobes and levels of autoantibodies to nerve growth factor (Aab-NGF) in the blood serum of patients with schizophrenia and their relatives was studied. The negative correlation between the Aab-NGF level and the total volume of frontal lobes (r= -0,59; p<0,01) was found in the group of patients. No significant correlations were found in the control groups of healthy subjects without family history of schizophrenia and relatives of patients. The authors concede that Aab-NGF may play a substantial role in the development of neuromorphological changes in schizophrenia.

[Correlations between clinical and immunological parameters in endogenous psychoses with a first episode at the juvenile age].

Sixty-seven patients, aged 16-25 years, with the first episode of endogenous psychosis (ICD-10 items F20.03, F20.23, F25) have been examined. Positive, negative and general psychopathological symptoms were assessed with the PANSS. Activities of leukocyte elastase (LE) and alpha1-proteinase inhibitor were used for measuring of innate immunity and the level of autoantibodies to nerve growth factor (Aab-NGF) was used for measuring of adaptive immunity. The manifestation of endogenous psychosis was accompanied by the activation of innate immunity, the level of activation was not related with the syndrome structure of episode (the prevalence of catatonic, hallucinatory-delusional or affective-delusional symptoms). The LE activity and dynamics of Aab-NGF during the treatment may be considered as prognostic markers of treatment effectiveness: the higher LE activity during the episode and decrease of Aab-NGF in the treatment process may predict a favorable therapeutic response.

[Changes of the level of serum antibodies to neuroantigens in patients with schizophrenia during the treatment].

The level of antibodies (AT) to neuroantigens (nerve growth factor and basic myelin protein) has been studied in the serum of 80 patients with schizophrenia, attack-like type, (ICD-10 items F20.01-02) during the treatment with psychotropic drugs. Therapeutic effectiveness has been measured clinically and with the PANSS. It has been shown that the autoimmune component is present during the acute episode of schizophrenia in about 30% of cases. No statistically significant differences have been found in the mean values of AT before and after the treatment however the dynamics of their changes has been closely related with the results of therapy: the decrease of AT level during the therapy is a predictive factor for good therapeutical remission; on the contrary, the increase of this level may be considered as an unfavorable prognostic factor.