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Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction.
Brain. 2004 Jan; 127(Pt 1):212-9.B

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.

Authors+Show Affiliations

Department of Clinical Neurosciences, St George's Hospital Medical School, London SW17 ORE, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

14607791

Citation

Hassan, Ahamad, et al. "Homocysteine Is a Risk Factor for Cerebral Small Vessel Disease, Acting Via Endothelial Dysfunction." Brain : a Journal of Neurology, vol. 127, no. Pt 1, 2004, pp. 212-9.
Hassan A, Hunt BJ, O'Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004;127(Pt 1):212-9.
Hassan, A., Hunt, B. J., O'Sullivan, M., Bell, R., D'Souza, R., Jeffery, S., Bamford, J. M., & Markus, H. S. (2004). Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain : a Journal of Neurology, 127(Pt 1), 212-9.
Hassan A, et al. Homocysteine Is a Risk Factor for Cerebral Small Vessel Disease, Acting Via Endothelial Dysfunction. Brain. 2004;127(Pt 1):212-9. PubMed PMID: 14607791.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. AU - Hassan,Ahamad, AU - Hunt,Beverley J, AU - O'Sullivan,Michael, AU - Bell,Rachel, AU - D'Souza,Reuben, AU - Jeffery,Steve, AU - Bamford,John M, AU - Markus,Hugh S, Y1 - 2003/11/07/ PY - 2003/11/11/pubmed PY - 2004/3/11/medline PY - 2003/11/11/entrez SP - 212 EP - 9 JF - Brain : a journal of neurology JO - Brain VL - 127 IS - Pt 1 N2 - 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. SN - 0006-8950 UR - https://www.unboundmedicine.com/medline/citation/14607791/Homocysteine_is_a_risk_factor_for_cerebral_small_vessel_disease_acting_via_endothelial_dysfunction_ L2 - https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awh023 DB - PRIME DP - Unbound Medicine ER -