[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.

[Controlled arterial hypertension and blood-brain barrier damage in patients with age-related cerebral small vessel disease and cognitive impairments]. / Kontroliruemaya arterial'naya gipertenziya i povrezhdenie gematoentsefalicheskogo bar'era u bol'nykh s vozrastzavisimoi tserebral'noi mikroangiopatiei i kognitivnymi narusheniyami.

OBJECTIVE: To evaluate the relationship between blood pressure (BP) profile and blood-brain barrier (BBB) permeability in age-related cerebral microangiopathy (CMA) in patients with- and without controlled arterial hypertension (AH). MATERIAL AND METHODS: 24-hour ambulatory BP monitoring (ABPM), brain MRI, including T1-weighted dynamic contrast images, were performed in 53 patients with CMA (age 60.1±6.8, women 69.8%, controlled hypertension/normal BP 84.8%/15.2%) and 17 healthy volunteers. RESULTS: ABPM showed good control of AH with most of the assessed parameters associated with the severity of white matter hyperintensity (WMH). The permeability of the BBB in normal-appearing white matter (NAWM) and gray matter in patients with CMA was significantly higher than in the control group and was associated with ABPM parameters. The permeability of the BBB in WMH decreased with an increase in its severity. CONCLUSION: BBB permeability is a universal mechanism of NAWM and gray matter damage that supports the progression of WMH in CMA patients with controlled AH and without AH. The relationship of increased BBB permeability with slight deviations of ABPM can be explained by common mechanisms of their development due to endothelial dysfunction due to CMA and also points to the utility of more aggressive AH treatment. It is advisable to study the effect of antihypertensive and vascular drugs on BBB permeability with a view to their potential use in CMA.

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.

[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.

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.