Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction

Abstract

Cerebral small vessel disease (SVD) causes focal lacunar infarction and more diffuse ischaemia, referred to as leukoaraiosis. Endothelial dysfunction has been proposed as a causal mechanism in the disease. Homocysteine is toxic to endothelium. We determined whether elevated homocysteine levels and the methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism are risk factors for SVD as a whole, and for two different SVD subtypes: isolated lacunar infarction and ischaemic leukoaraiosis. We also determined whether any association was mediated by endothelial dysfunction, as assessed by circulating endothelial markers. One hundred and seventy-two Caucasian patients with SVD and 172 community controls of similar age and sex were studied. Serum homocysteine measurement and MTHFR genotyping was performed. Levels of intercellular adhesion molecule 1 (ICAM1) and thrombomodulin were measured in a subgroup. Mean homocysteine levels were higher in SVD than controls [14.55 micromol/l [95% confidence interval (CI) 13.78-15.35] versus 12.01 micromol/l (95% CI 11.42-12.64), P < 0.0005]. Homocysteine was a stronger risk factor in those with ischaemic leukoaraiosis [12.92 (95% CI 4.40-37.98), P < 0.0005) per micromol increase in log homocysteine concentration (P < 0.0005)] in comparison with isolated lacunar infarction [4.22 (95% CI 1.29-13.73), P = 0.02] after controlling for both conventional risk factors and age. The MTHFR 677T allele was a risk factor only in the ischaemic leukoaraiosis group [odds ratio (OR) 2.02 (95% CI 1.31-3.1), P = 0.001]. Inclusion of the endothelial markers ICAM1 and thrombomodulin in a logistic regression model resulted in the association between homocysteine and SVD no longer being significant. In conclusion, hyperhomocysteinaemia is an independent risk factor for SVD, particularly ischaemic leukoaraiosis, and this effect may be mediated via endothelial dysfunction. Homocysteine-lowering therapy may be particularly effective in this subgroup.

Cognitive Disorders and Dementia in CKD

“…66 Elevated homocysteine levels are also associated with the number of WMLs and progressionpossibly through direct endothelial damage or stimulation of an endothelial inflammatory response. 65,67,68 Second, hyperhomocysteinemia could impair neuronal pathways because elevated homocysteine has a direct, neurotoxic effect by activating the N-methyl-D-aspartate receptor or by conversion into homocysteic acid, leading to cell death. 69 Furthermore, clinical studies show that elevated plasma homocysteine concentrations are associated with an increased risk for Alzheimer disease.…”

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].…”

Hyperhomocysteinemia, Oxidative Stress, and Cerebral Vascular Dysfunction

“…Some clinical observations support the concept that hyperhomocysteinemia produces inflammation and endothelial dysfunction in cerebral microvessels in humans. 20 Third, studies in CBS-deficient mice revealed that very modest hyperhomocysteinemia produces hypertrophy and altered mechanics in the cerebral microcirculation (Figure). 21 Increases in cross-sectional area of the vessel wall (hypertrophy) may have functional consequences because hypertrophy of vascular muscle can impair maximal vasodilator capacity.…”