[A role of altered inflammation-related gene expression in cerebral small vessel disease with cognitive impairment]. / Rol' izmeneniya ekspressii genov, assotsiirovannykh s vospaleniem, pri tserebral'noi mikroangiopatii s kognitivnymi rasstroistvami.

OBJECTIVE: To identify the role of changes in the expression of inflammation-related genes in cerebral microangiopathy/cerebral small vessel disease (cSVD). MATERIAL AND METHODS: Forty-four cSVD patients (mean age 61.4±9.2) and 11 controls (mean age 57.3±9.7) were studied. Gene expression was assessed on an individual NanoString nCounter panel of 58 inflammation-related genes and 4 reference genes. A set of genes was generated based on converging results of complete genome-wide association studies (GWAS) in cSVD and Alzheimer's disease (AD) and circulating markers associated with vascular wall and Brain lesions in cSVD. RNA was isolated from blood leukocytes and analyzed with the nCounter Analysis System, followed by analysis in nSolver 4.0. Results were verified by real-time PCR. RESULTS: CSVD patients had a significant decrease in BIN1 (log2FC=-1.272; p=0.039) and VEGFA (log2FC=-1.441; p=0.038) expression compared to controls, which showed predictive ability for cSVD. The cut-off for BIN1 expression was 5.76 a.u. (sensitivity 73%; specificity 75%) and the cut-off for VEGFA expression was 9.27 a.u. (sensitivity 64%; specificity 86%). Reduced expression of VEGFA (p=0.011), VEGFC (p=0.017), CD2AP (p=0.044) was associated with cognitive impairment (CI). There was a significant direct correlation between VEGFC expression and the scores on the Montreal Cognitive Assessment test and between BIN1 and VEGFC expression and delayed memory. CONCLUSION: The possible prediction of cSVD by reduced expression levels of BIN1, VEGFA and the association of clinically significant CI with reduced VEGFA and VEGFC expression indicate their importance in the development and progression of the disease. The established importance of these genes in the pathogenesis of AD suggests that similar changes in their expression profile in cSVD may be one of the conditions for the comorbidity of the two pathologies.

[Nitric oxide availability in cerebral microangiopathy]. / Dostupnost' oksida azota pri tserebral'noi mikroangiopatii.

OBJECTIVE: To develop a test of individual nitric oxide (NO) availability based on changes in erythrocyte rheological properties after incubation with a NO donor and to evaluate the role of these disorders in brain damage and development of cognitive impairment (CI) in cerebral small vessel disease (cSVD). MATERIAL AND METHODS: In 73 cSVD patients (48 (65.8%) women, mean age 60.1±6.5), the rheological properties of erythrocytes before and after incubation with 10 µmol/L L-arginine-NO donor were evaluated using a laser-optical rotating cell analyzer, and the blood-brain barrier (BBB) permeability by MRI-T1 dynamic contrast. RESULTS: Among the studied parameters of erythrocyte rheological properties, the best characteristic by ROC analysis was the rate of erythrocyte disaggregation (y-dis) after incubation with L-arginine (area under the curve 0.733 (0.609-0.856), sensitivity 67%, specificity 79%). Patients with a y-dis threshold >113 sec-1 had more severe CI, arterial hypertension, white matter lesions, and increased BBB permeability in gray matter and normal-appearing white matter. CONCLUSION: The prolonged rate of erythrocyte disaggregation in cSVD patients after incubation with L-arginine indicates the risk for disease progression due to decreased NO bioavailability/disruption of the functional L-arginine-eNOS-NO system. This test can be used to assess individual NO bioavailability and potentially identify indications for modifying therapy with NO donors such as L-arginine. Clinical trials are needed to standardize and evaluate the efficacy of NO donor therapy in patients with cSVD and CI.

[Pharmacotherapy in post-stroke rehabilitation]. / Farmakoterapiya v postinsul'tnoi reabilitatsii.

The article presents data on the conditions of use and efficacy of botulinum toxin preparations, oral muscle relaxants, selective serotonin reuptake inhibitors, acetylcholinesterase inhibitors and a glutamatergic transmission modulator in post-stroke neurorehabilitation, and provides recommendations for their rational and safe use. The clinical efficacy of Mexidol, which has a polymodal effect on a wide range of post-stroke disorders, especially in long-term sequential therapy, is discussed. A complex use of post-stroke rehabilitation methods with the determination of individual tactics based on the clinical picture of the patient and the defined rehabilitation goals is recommended. The inclusion of Mexidol in the complex therapy of patients with stroke consequences for tasks related to improving motor, affective and cognitive functions and self-care and quality of life looks promising. It is necessary to continue high-quality clinical studies to assess the pharmaceuticals efficacy in relation to post-stroke disorders.

Daily blood pressure profile and blood-brain barrier permeability in patients with cerebral small vessel disease.

Cerebral small vessel disease (CSVD) plays an important role in cognitive impairment, stroke, disability, and death. Hypertension is the main risk factor for CSVD. The use of antihypertensive therapy has not resulted in the expected decrease in CSVD complications, which may be related to the underestimation of significance of daily blood pressure profile for blood-brain barrier (BBB) permeability. 53 patients with CSVD of varying severity (mean age 60.08 ± 6.8 years, 69.8% women, subjects with treated long-standing hypertension vs. normotensive subjects - 84.8% vs. 15.2%) and 17 healthy volunteers underwent ambulatory blood pressure monitoring (ABPM) and MRI, including T1-weighted dynamic contrast-enhanced magnetic resonance imaging for assessing BBB permeability. Most of ABPM parameters in CSVD patients did not differ from controls, but were associated with the severity of white matter hyperintensity (WMH) and the total CSVD score. BBB permeability in normal-appearing white matter (NAWM) and grey matter (GM) was significantly higher in CSVD patients, and the severity of BBB permeability remained similar in patients with different stages of WMH. Among BBB permeability parameters, the area under the curve, corresponding to an increase in the contrast transit time in NAWM, had the greatest number of correlations with deviations of ABPM parameters. BBB permeability in CSVD is a universal mechanism of NAWM and GM damage associated with a slight increase in ABPM parameters. It is obvious that the treatment of hypertension in patients with not severe WMH should be more aggressive and carried out under the control of ABPM.

White matter hyperintensity in different migraine subtypes.

The diagnostic value of white matter hyperintensities (WMH) in different types of migraineare unknown. To evaluate the WMH pattern of different subtypes in migraine patients with no vascular risk factors. 92 migraine patients (73 females, mean age 34.6 ± 8.9; 61 episodic migraine, 31 chronic migraine, 36 migraine with aura, 56 migraine without aura) without vascular risk factors underwent brain MRI (3 T). We also included a matched healthy control group with no migraine (n = 24). The prevalence of WMH in different types of migraine was similar and ranged from 38.7 to 44.4%; the control group showed no WMH at all. Lesions were located within frontal, parietal and temporal lobes (in order of decreasing incidence) in juxtacortical and/or deep white matter. WMH appeared as round or slightly elongated foci with a median size of 2.5 mm [1.5; 3]. Total number, size and prevalence of WMH by lobes and white matter regions were similar between groups, and no interaction with age or sex was found. The number of lesions within the frontal lobe juxtacortical white matter correlated with the age of patients (r = 0.331, p = 0.001) and the duration since migraine onset (r = 0.264, p = 0.012). Patients with different migraine subtypes and without vascular risk factors are characterized by a similar pattern of WMH in the absence of subclinical infarctions or microbleedings. Therefore, WMH have no relevant prognostic value regarding the course of migraine and vascular complications. WMH pattern may be used to differentiate migraine as a primary disorder and other disorders with migraine-like headache and WMH.

[Clustering of diagnostic MRI signs of cerebral microangiopathy and its relationship with markers of inflammation and angiogenesis]. / Klasterizatsiya diagnosticheskikh MRT-priznakov tserebral'noi mikroangiopatii i ee svyaz' s markerami vospaleniya i angiogeneza.

OBJECTIVE: To perform cluster analysis of MRI signs of cerebral microangiopathy (small vessel disease, SVD) and to clarify the relationship between the isolated groups and circulating markers of inflammation and angiogenesis. MATERIAL AND METHODS: The identification of groups of MRI signs (MRI types) using cluster hierarchical agglomerative analysis and iterative algorithm of k-means and assessment of their relationship with serum concentrations of tumor necrosis factor-α (TNF-α), transforming growth factor-ß1 (TGF-ß1), vascular endothelial growth factor-A (VEGF-A), hypoxia-inducible factor 1-α (HIF1-α) determined by ELISA were performed in 96 patients with SVD (STRIVE, 2013) (65 women, average age 60.91±6.57 years). RESULTS: Cluster analysis of MRI signs identified two MRI types of SVD with Fazekas grade 3 of white matter hyperintensity (WMH). MRI type 1 (n=18; 6 women, mean age 59.1±6.8 years) and MRI type 2 (n=22, 15 f., mean age 63.5±6.2 years) did not differ by age, sex, severity of hypertension, presence of other risk factors. MRI type 1 had a statistically significantly more pronounced WMH in the periventricular regions, multiple lacunes and microbleeds, atrophy, severe cognitive impairment and gait disorders compared with MRI type 2. Its formation was associated with a decrease in VEGF-A level. MRI type 2 had the significantly more pronounced juxtacortical WMH, white matter lacunes, in the absence of microbleeds and atrophy, and less severe clinical manifestations compared with MRI type 1. Its formation was associated with an increase in TNF-α level. CONCLUSION: Clustering of diagnostic MRI signs into MRI types of SVD with significant differences in the severity of clinical manifestations suggests the pathogenetic heterogeneity of age-related SVD. The relationship of MRI types with circulating markers of different mechanisms of vascular wall and brain damage indicates the dominant role of depletion of angiogenesis in the formation of MRI type 1 and increased inflammation in the formation of MRI type 2. Further studies are needed to clarify the criteria and diagnostic value of differentiation of MRI types of SVD, and also their mechanisms with the definition of pathogenetically justified prevention and treatment of various forms of SVD.

[Cognitive disorders in the middle-aged population and cerebrovascular risk factors]. / Kognitivnye narusheniia u lits srednego vozrasta i faktory riska tserebrovaskuliarnykh zabolevanii.

AIM: To study the frequency of subjective and objective cognitive disorders in the middle-aged population and their associations with main and additional cerebrovascular risk factors. MATERIAL AND METHODS: The authors examined 169 men and 239 women aged 40-59 years. Medical history study, blood tests, electrocardiography, brachiocephalic and common femoral arteries scan, echocardiography, magnetic resonance imaging of the brain (MRI) were performed. Luria and Munsterberg tests were done to assess cognitive dysfunction. Affective disorders were assessed by the Hospital scale of anxiety and depression. RESULTS AND CONCLUSION: Absence of subjective (SCI) and/or objective (OCI) cognitive impairments was found in 26,5%; 10% had purely SCI, more than 35,7% of complaints were accompanied by deviations in neuropsychological test results (OCI+), over 25% had only OCI-. The average age of patients with OCI+ was higher than in the control group. In women, the frequency of SCI was twice as high and OCI less frequent as in men. Absence of cognitive impairment and SCI were observed more frequently in individuals with higher education. The prevalence of multiple white matter lesions (WML) in MRI was 36%. Multiple WML and atherosclerosis of major arteries were more common in OCI+ group (47%). Mild affective disorders were more frequent in the studied groups. Anxiety disorders were more common than depressive ones. The amount of patients with affective disorders was highest in OCI+. Therefore, SCI is a common phenomenon among people aged 40-60 years. The use of simple neuropsychological tests in screening examination allows to identify individuals who are most appropriate for active search for vascular risk factors. Anxiety and depressive disorders cause a significant proportion of SCI among middle-aged people and are an important additional target for therapeutic measures.

Hypertension and Cerebral Microangiopathy (Cerebral Small Vessel Disease): Genetic and Epigenetic Aspects of Their Relationship.

Hypertension (HT) and its cerebral complications are extremely vexing medical and social problems. Despite the obvious association between hypertension and the clinical and neuroimaging features of cerebral microangiopathy (CMA) (also known as cerebral small vessel disease), the causal links between them remain ambiguous. Besides, antihypertensive therapy as the only way to manage these patients does not always prevent brain damage. Knowledge about the key factors and mechanisms involved in HT and CMA development is important for predicting the risk of cerebral complications and developing new approaches to their prevention and treatment. At present, genome-wide association studies and other approaches are used to investigate the common hereditary mechanisms of HT and CMA development, which will explain a large number of CMA cases not associated with hypertension, lack of a correlation between HT severity and the degree of cerebral injury, and failure of antihypertensive therapy to prevent CMA progression. Epigenetic markers likely play a modulating role in the development of these diseases.

[Biomarkers and mechanisms of early vascular damage]. / Biomarkery i mekhanizmy rannego povrezhdeniia sosudistoi stenki.

AIM: To assess the association of classic vascular risk factors, indicators of cerebral arteries wall damage and stress induction, and their role in early vascular and brain damage in middle age subjects without vascular events. MATERIAL AND METHODS: 87 patients were evaluated (49 women, 38 men, mean age 51.2±6.5). The following vascular risk factors were assessed: hypertension, diabetes, total cholesterol and low density lipoproteins levels, obesity and smoking. Patients underwent ultrasound of neck arteries, brain MRI and laboratory testing of blood parameters, probably associated with vascular wall damage: CRP, TNF-α, sICAM-1, sVCAM, HIF1-α, NO, VAP-1, VEGF-A, VEGF-C, sVEGF-R1, sVEGF-R2, TGF-ß1, general antioxidant status. RESULTS AND CONCLUSION: Mediating role of stress parameters in risk factors formation, initiation and maintenance of mechanisms of vascular damage was demonstrated. Hypercortisolemia suggested the association with age, atheromatosis, local inflammatory reactions via the TGF-ß1-HIF-1-VEGF family, systemic inflammation response via CRP, and elevated epinephrine levels were associated with TNF-α-mediated systemic inflammation. The association of TNF-α and MRI signs of cerebral small vessel disease (SVD) in non-hypertensive patients may indicate that TNF-α-mediated inflammation and increased permeability of vessel wall is an independent cause and potential biomarker of early small vessel damage. Influence of hypertension on age-dependent SVD is probably maintained by local vascular wall damage mechanisms via the TGF-ß1-HIF-1-VEGF family. However, hypertension heterogeneity and association of early cerebral vessels damage with various protective reactions require further clarification of the conditions for using these parameters as possible biomarkers of early SVD.

[ANTIPLATELET AND ANTI-ISCHEMIC EFFECTS OF MEMANTINE AND 5-HYDROXYADAMANTAN-2-ONE IN PATIENTS WITH CEREBROVASCULAR PATHOLOGY AND IN EXPERIMENTS].

It was investigated the effect of two adamantane derivatives, memantine and 5-hydroxyadamantan-2-one (5-HA), in patients with cerebrovascular disorders. In vitro studies showed that 5-HA, unlike memantine, exhibited antiplatelet activity. Experiments showed that memantine reduced cerebral blood flow in the brain cortex of intact rats and those under conditions of transient global ischemia, whereas 5-HA only selectively improved blood flow in ischemic brain and was superior to the reference drug nimodipine. The obtained data indicate the leading role of the GABA-ergic (rather than glutamatergic mechanisms) in implementation of the anti-ischemic cerebrovascular activity.

[Venous thromboembolism in patients with Guillain-Barre syndrome].

OBJECTIVE: To perform an in-depth prospective analysis of the prevalence, risk factors, specific characteristics of venous thromboembolism (VTE) and the dynamics of venous thrombosis during the treatment with low-molecular-weight heparin (LMWH) in patients with different forms and severity of Guillain-Barre syndrome (GBS) admitted to an intensive care unit (ICU). MATERIAL AND METHODS: Prevalence, risk factors and course of VTE were analyzed for the first time in 65 ICU inpatients with various forms and severity of GBS. Neurological status was evaluated at baseline and in dynamics, duplex scanning of veins of the legsin the system of inferior vena cava was performed. RESULTS AND CONCLUSION: Despite the preventive using of LMWH, a half of patients with GBS, regardless of the form of the disease during the progression of neurological symptoms, have VTE (deep vein thrombosis--52%, pulmonary embolism--15%). Significant risk factors include: severe disease course requiring artificial ventilation, bed rest for more than 3 days, infectious complications, the presence of the catheter in the central vein, age over 40 years. Venous thrombosis in the system of inferior vena cava in patients with GBS does not differ from that in other critical illnesses suggesting that this pathological process is universal. Preventive measures for this category of patients is insufficient and requires a search for other prevention strategies.

[Prevention of venous thromboembolism in the acute stroke]. / Profilaktika venoznykh tromboémbolicheskikh oslozhnenii v ostroi stadii insul'ta.

OBJECTIVE: To assess the effectiveness of preventive measures to reduce VTE rates among patients with severe stroke in intensive care unit (ICU). MATERIAL AND METHODS: The efficacy and safety of previously developed protocol for VTE prevention was assessed in 378 stroke patients in the ICU who received different levels of preventive measures. Subjects were distributed into three groups. We assessed neurological status of all patients on admission and in the course of stroke, and performed ultrasound scanning of lower limb veins for groups II and III. RESULTS: The rate of VTE events remained high regardless of the level of preventive measures. However, we observed a changing nature of PE from massive to nonmassive without increasing the rate of hemorrhagic complications while the strict protocol of VTE prevention with mandatory use of low molecular weight heparins was applied, including patients with hemorrhagic stroke. CONCLUSION: The use of the proposed protocol of VTE prevention in routine care for patients with stroke in ICU is safe and may significantly reduce the incidence of fatal pulmonary embolism.

[STROKE: INCIDENCE AND RISK FACTORS FOR VENOUS THROMBOEMBOLIC COMPLICATIONS IN INTENSIVE CARE UNIT].

AIM: To study the evidence of venous thromboembolic complications (VTE (acute venous thrombosis (DVT) and pulmonary embolism (PE)) at the background of modern prevention for different characteristics and localization of stroke, as well as defining the role of the main clinical risk factors in the pathogenesis for ITE in stroke patients in intensive care unit. MATERIAL AND METHODS: The study included 123 patients with different types, localization and severity of stroke. All patients received standard prophylaxis VTE with low molecular weight heparin (LMWH). Neurological status, the severity of the general condition, the main clinical risk factors of stroke were assessed when income and in dynamics. There was planned duplex scanning of the veins of the inferior vena cava performed. RESULTS AND DISCUSSION: In spite of the application of modern preventive measures VTE, their frequency remains high accounting for 56%. All patients have a place DVT, in 26% of pulmonary embolism occurs. Groups at highest risk of VTE are patients with stroke more than 8 points of NIHSS, who are ventilated and assessed infection-inflammatory disorders, especially pulmonary. This group is considered to be at the highest risk of VTE. Modern preventive strategy for them is not sufficient and needs for the search of other preventive approaches.