Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis

Abstract

Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P <or= 0.006). The ischaemic leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of leukoaraiosis (P <or= 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.

Blood Biomarkers of Ischemic Stroke

“…One study of 116 patients found CRP to be significantly higher in patients with large vessel compared to small vessel ischemic strokes [43]. Lacunar stroke has also been shown to have higher levels of thrombomodulin, ICAM-1, tissue factor, and homocysteine compare to controls, though it is unclear whether this is different compared to other stroke subtypes [44,45]. Progression of white matter hyperintensities on MRI which may reflect small vessel disease has been associated with a higher plasma level of intercellular adhesion molecule (ICAM) [46].…”

Relation of Brain Natriuretic Peptide Levels to Cognitive Dysfunction in Adults >55 Years of Age With Cardiovascular Disease

“…15 In turn, endothelial abnormalities have recently been linked to cerebrovascular disease and reduced cognitive function. 9,16,17 Further research is needed to clarify the relation between BNP and these possible mechanisms.There are several limitations of the present study. Although BNP levels were significantly related to cognitive performance in the current sample, further examination in larger and more diverse samples would strengthen the generalizability of the findings.…”

“…15 In turn, endothelial abnormalities have recently been linked to cerebrovascular disease and reduced cognitive function. 9,16,17 Further research is needed to clarify the relation between BNP and these possible mechanisms.…”

Blood pressure and vascular cognitive impairment: the debate continues

“…As arterial narrowing increases, it leads to a decline in the perfusion of the capillary bed, which can result in discrete regions of lacunar infarction and/or more diffuse ischaemic changes in the periventricular and deep white matter called leukoaraiosis. 13 Chronic hypertension also predisposes to impaired blood brain barrier function, with endothelial cell retraction, increased vascular permeability and greater susceptibility to white matter injury for relatively small insults. The potential for white matter injury is further increased by the blood supply to the periventricular and deep white matter being dependent on end-arteries lacking appropriate anastamoses, thus creating an arterial watershed zone.…”

“…11,13 Second only to age, hypertension has been shown to the most important risk factor for small vessel disease [3][4][5][6] and a complex and dynamic relationship between BP and cerebral function is being revealed; high BP may initially accelerate arteriosclerotic change and impair cerebral autoregulation with adverse effects on cognition but high BP may be required for adequate perfusion when arteries are diseased and cerebral autoregulation is impaired. Uncertainty surrounds the appropriate level of BP for optimum cognitive performance and the desirability of lowering of BP beyond a certain level in patients with established cerebral small vessel disease continues to be a subject of much debate.…”