Hyperhomocysteinemia as an independent risk factor for silent brain infarction N.K. Kim, PhD; B.O. Choi, MD, PhD; W.S. Jung, MD, PhD; Y.J. Choi, MD; and K.G. Choi, MD, PhD Abstract—Objective: To evaluate whether hyperhomocysteinemia is an independent risk factor for silent brain infarction (SBI), and to determine the relationship between homocysteine and folate in each type of methylenetetrahydrofolate reductase (MTHFR) polymorphism, in order to identify a way of reducing the risk for SBI. Methods: The authors enrolled 161 patients with SBI and 126 healthy people, checked their fasting homocysteine and folate levels, and analyzed for the MTHFR C677T polymorphism. Results: The mean plasma homocysteine level in patients with SBI (12.17  5.35 mol/L) was significantly higher than in normal healthy people (9.37  4.11 mol/L; p  0.05). By subgroup analysis, based on the classification of plasma homocysteine levels as high (11.77 mol/L), moderate (8.71 to 11.76 mol/L), and low (8.70 mol/L), the adjusted OR (AOR) of the high group for SBI was significantly greater than that of the low group (AOR, 4.78; 95% CI, 2.45 to 9.33). The homocysteine level showed a significant inverse correlation with folate level only in patients with SBI with the MTHFR 677TT genotype (p  0.05). Conclusions: This study demonstrates that hyperhomocysteinemia is an independent risk factor for SBI, and provides the possibility of reducing the risk for SBI in the MTHFR 677TT genotype by folate supplementation. NEUROLOGY 2003;61:1595–1599 Silent brain infarction (SBI) is defined as a cerebral infarction evident by brain imaging but without a clinical syndrome characterized by rapidly develop- ing clinical symptoms and signs of focal and at times global loss of brain function. 1 It is relatively common in the geriatric population with a prevalence of 10% to 40%, which gradually increases with age. 2-5 Al- though the clinical significance of SBI remains con- troversial, the presence of SBI has been suggested to indicate widespread vascular damage. 6 It has been reported that SBI greatly increase the risk for symp- tomatic cerebral infarctions. 7 The incidence of SBI has been reported to be 2.5 to 4.5 times 8,9 higher in hyperhomocysteinemia, which is an independent risk factor for vascular diseases, like cerebrovascular and cardiovascular diseases. 10,11 The results of prior studies show a strong associa- tion between the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and hyperhomocysteinemia. 12,13 In addition, some studies have indicated that it is possible to lower the concentration of plasma homocysteine (pHcy) by in- creasing folate intake. 14-17 Epidemiologic prospective studies have shown an inverse relationship between the dietary intake of folate and the risk of stroke. 18,19 However, no inverse correlation between homocysteine and folate levels has been determined in patients with SBI. We conducted this study to determine whether hyperhomocysteinemia is an independent risk factor of SBI and whether there is an association between homocysteine and folate for each type of MTHFR polymorphism. Patients and methods. Study population. The study popula- tion was composed of 161 patients with SBI (75 men, 86 women) and 126 control subjects (57 men, 69 women). The patients were enrolled from July 1, 2000, to January 31, 2003, in the neurology department at Ewha Womans University Hospital and Pundang CHA General Hospital by consecutive referral. A diagnosis of SBI was made by MRI examination and by agreement between two independent experienced neurologists. SBI was excluded when agreement was not reached. All patients underwent a brain MRI scan and electrocardiography. MR angiog- raphy was performed in 85%, echocardiography in 63%, transcra- nial Doppler in 22%, and four-vessel conventional cerebral angiography in 21% of cases. The criteria for SBI were as follows: spotted areas 3 mm in diameter or larger in areas supplied by deep perforating arteries showing high intensity in T2 and FLAIR images and low intensity in the T1 image; the absence of neuro- logic signs and symptoms that could have been explained by MRI lesions; no past history of clinical stroke, including TIA. Small punctate hyperintensities—1 to 2 mm in diameter—were more likely to represent dilated perivascular spaces and were not con- sidered in the present study. All examinations were performed using a 1.5-T superconduct- ing magnet system (Siemens Magnetom Symphony). The whole brain was scanned using a slice thickness of 7 mm and a 2-mm interslice gap, producing 16 axial images. The imaging protocol consisted of T2-weighted spin echo (repetition time/echo time [TR/ TE] = 3,700/90 msec), T1-weighted spin echo (TR/TE = 560/14 From the Department of Neurology and Ewha Medical Research Center (Drs. B.O. Choi, Y.J. Choi, and K.G. Choi), College of Medicine, Ewha Womans University, Seoul; Institute for Clinical Research (Dr. Kim), College of Medicine, Pochon CHA University, Sungnam; and Stroke Center (Dr. Jung), College of Oriental Medicine, Kyung Hee University, Seoul, South Korea. Supported by the Intramural Research Grant of Ewha Womans University. Received May 2, 2003. Accepted in final form August 13, 2003. Address correspondence and reprint requests to Dr. Byung-Ok Choi, Department of Neurology, Ewha Womans University, Dongdaemun Hospital, 70, Jongro 6-ga, Jongro-gu, Seoul, 110-783, South Korea; e-mail: bochoi@ewha.ac.kr Copyright © 2003 by AAN Enterprises, Inc. 1595