Manifestations Of Cerebral Small Vessel Disease Research Articles

Abstract WMP85: Significance of Cerebral Small Vessel Disease in Acute Intracerebral Hemorrhage: The INTERACT2 Study

Background: Uncertainty exists over the significance of structural changes arising from cerebral small vessel disease (CSVD), including white matter lesions (WML), lacunes and atrophy, for outcome after acute intracerebral hemorrhage (ICH). We determined associations of CT markers of CSVD and outcomes among participants of the INTERACT2 study. Methods: We graded WML (van Swieten scale), brain atrophy (two linear measurements, frontal ratio [FR] and third ventricle Sylvian fissure distance [TSD]) and the presence of lacunes for 2069/2839 patients with available baseline brain CT (<6hr ICH onset) by three independent neurologists blind to clinical data. Results: WML and brain atrophy were independently associated with death or disability (modified Rankin Scale score 3-6) at 90 days: adjusted odds ratios for WML (grade 3 and 4 vs. 1), FR and TSD (most vs. least severe atrophy quartile) were 1.42 (95% confidence interval 1.02-0.98), 1.47 (1.08-1.99) and 1.64 (1.21-2.22), respectively (all P for trend <0.05). There was no association between lacunes or any CSVD biomarkers and absolute ICH growth, and no significant differences in the effects of intensive BP lowering in each subgroup of CSVD. Conclusions: CSVD manifestations of WML and brain atrophy have prognostic value in acute ICH but they do not appear to influence ICH growth. Intensive BP lowering provided similar treatment effects irrespective of degree of CSVD.

Significance of Haemodynamic and Haemostatic Factors in the Course of Different Manifestations of Cerebral Small Vessel Disease: The SHEF-CSVD Study-Study Rationale and Protocol.

Rationale. This paper describes the rationale and design of the SHEF-CSVD Study, which aims to determine the long-term clinical and radiological course of cerebral small vessel disease (CSVD) and to evaluate haemostatic and haemodynamic prognostic factors of the condition. Design. This single-centre, prospective, non-interventional cohort study will follow 150 consecutive patients with different clinical manifestations of CSVD (lacunar ischaemic stroke, vascular dementia, vascular parkinsonism or spontaneous deep, intracerebral haemorrhage) and 50 age- and sex-matched controls over a period of 24 months. The clinical and radiological course will be evaluated basing on a detailed neurological, neuropsychological and MRI examinations. Haemodynamic (cerebral vasoreactivity, 24 h blood pressure control) and haemostatic factors (markers of endothelial and platelet dysfunction, brachial artery flow-mediated dilatation test) will be determined. Discussion. The scheduled study will specifically address the issue of haemodynamic and haemostatic prognostic factors and their course over time in various clinical manifestations of CSVD. The findings may aid the development of prophylactic strategies and individualised treatment plans, which are critical during the early stages of the disease.

Inflammatory Proteins and the Severity of Dilated Virchow-Robin Spaces in the Elderly

Recent studies suggest dilated Virchow-Robin Spaces (dVRS) could be a manifestation of cerebral small-vessel disease, but little is known about their risk factors. As inflammation has been associated with other brain MRI findings, we investigated whether interleukin-6 and C-reactive protein were associated with the severity of dVRS in the eldery. dVRS were assessed in basal ganglia and white matter and rated on a severity scale. We found that elevated interleukin-6 levels were associated with higher severity of dVRS in basal ganglia, suggesting that inflammation might be associated with the burden of dVRS in the elderly.

Angiogenic T-Cells and Putative Endothelial Progenitor Cells in Hypertension-Related Cerebral Small Vessel Disease

Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3(+)/CD31(+)/CD184(+)) and putative EPC (CD31(+)/CD34(+)/CD45(-)/KDR(+)) by flow cytometry and determined EPC vitality by in vitro cluster formation. Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7(.)10(3)/mL versus 13±6(.)10(3)/mL [median±interquartile range]; P=0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25(.)10(9)/mL versus 0.78±0.50(.)10(9)/mL; P=0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012-0.627). Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Vascular inflammation in cerebral small vessel disease

Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD.

Plasma level of sICAM-1 is associated with the extent of white matter lesion among asymptomatic elderly subjects

Objective Inflammatory endothelial activation mediated by intercellular adhesion molecule-1 (ICAM-1) plays a role in the pathogenesis of large- and small-vessel disease. We explored the association between soluble ICAM-1 (sICAM-1) and white matter lesion (WML) as a manifestation of cerebral small-vessel disease. Methods One hundred and seventy-five elderly individuals aged ≥ 60 without neurological deficits were studied. Subcortical deep white matter hyperintensity (SDWMH) and periventricular hyperintensity (PVH) were rated separately. Lesions in each category were then divided into three groups (grade 0-I, grade II, grade III) according to the Fazekas scale. Results Plasma sICAM-1 levels were positively associated with grades of WML (for SDWMH: 297.4 ± 135.6 ng/mL in grade 0-I, 391.3 ± 145.5 ng/mL in grade II, and 450.2 ± 232.9 ng/mL in grade III, p < 0.001; for PVH: 282.5 ± 116.5 ng/mL in grade 0-I, 402.3 ± 160.4 ng/mL in grade II, and 428.1 ± 227.7 ng/mL in grade III, p < 0.001). Multivariate analysis showed higher sICAM-1 levels, age and hypertension were the independent risk factors associated with the presence and severity of WML. More than 4-fold increased risk of WML was observed in patients with the highest quartile of sICAM-1 (all WML OR = 4.694, 95% CI: 1.805–12.204; moderate WML OR = 4.618, 95% CI: 1.543–13.825; severe WML OR = 4.893, 95% CI: 1.236–19.368). Conclusion Increased plasma sICAM-1 suggests inflammatory process may be involved in the pathogenesis of WML.

Increased Aortic Pulse Wave Velocity Is Associated With Silent Cerebral Small-Vessel Disease in Hypertensive Patients

Aortic stiffness predicts an excess risk of stroke, supposedly via cerebral small-vessel disease. White matter hyperintensities, silent lacunar infarcts, and brain microbleeds, manifestations of cerebral small-vessel disease on neuroimaging, may precede overt cerebrovascular disease. Therefore, we assessed whether aortic stiffness is also related to such lesions. In 167 hypertensive patients (85 men) without a history of cardiovascular or cerebrovascular disease, a mean age of 51.8+/-13.1 years, and untreated office blood pressure levels of 169+/-25/104+/-12 mm Hg, we determined aortic pulse wave velocity and office and ambulatory 24-hour pulse pressure (off medication), as well as the volume of white matter hyperintensities and the presence of lacunar infarcts and microbleeds using brain MRI. Linear and logistic regression analyses were performed to assess the relationships between the arterial stiffness measures and brain lesions. Aortic stiffness and pulse pressure were significantly related to each of the brain lesions in univariate analyses (P<0.05). Multivariate analyses, adjusted for age, sex, brain volume, mean arterial pressure, and heart rate, showed that a higher pulse wave velocity was significantly associated with a greater volume of white matter hyperintensities (unstandardized regression coefficient: 0.041; 95% CI: 0.005 to 0.078; P<0.05) and the presence of lacunar infarcts (odds ratio [per SD increase in pulse wave velocity]: 1.78; 95% CI: 1.06 to 2.99; P<0.05) but not with microbleeds. The models for pulse pressure failed to reach statistical significance in multivariate analyses. In conclusion, aortic stiffness is independently associated with manifestations of cerebral small-vessel disease in hypertensive patients, linking systemic large- to cerebral small-artery disease.