(Stroke. 2001;32:1116.)
© 2001 American Heart Association, Inc.
Original Contributions |
Elevated Plasma Homocysteine Levels and Risk of Silent Brain Infarction in Elderly People
From the Department of Geriatric Medicine (T.M., H.A., M. Morikawa, H.S.), Tohoku University School of Medicine, Sendai, Japan; the Center for Emotional and Behavioral Disorders (T.Y., H.Y.), Hizen National Hospital, Saga, Japan; the Second Department of Internal Medicine (H.Y.), Kyushu University, Fukuoka, Japan; Research and Development (M. Miura, S. Hashimoto), Mitsubishi Kagaku Bio-Clinical Laboratories Inc, Tokyo, Japan; the Department of Psychiatry (S. Higuchi, S.M.), Kurihama National Hospital, Kanagawa, Japan; and the Department of Cardiology (A.K.), Sendai City Medical Center, Sendai, Miyagi, Japan.
Correspondence to Dr Hiroyuki Arai, Department of Geriatric Medicine, Tohoku University School of Medicine, Sendai, Miyagi, 980-8574, Japan. E-mail h-ara{at}mail.cc.tohoku.ac.jp
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Background and Purpose—Silent brain infarction (SBI) on MRI is common in elderly people, and recent studies have demonstrated that SBI increases the risk of progression to clinically apparent stroke and cognitive decline. Therefore, an early and accurate detection of SBI and a search for potential treatable risk factors may have a significant impact on public health.
Methods—Community-dwelling
elderly people aged 
66 years who participated in the present
study (n=153) underwent brain MRI and standardized physical and
neuropsychological examinations as well as blood biochemistry
determinations, including total plasma homocysteine (pHcy), renal
function, vitamin status, and polymorphisms of the
methylenetetrahydrofolate reductase
gene.
Results—SBI was
found in 24.8% of the participants. In the univariate
analysis, the pHcy levels in subjects with SBI (13.6±4.1
µmol/L) were significantly higher
(P=0.0004) than those in
subjects without SBI (11.0±3.3 µmol/L). When pHcy levels were
stratified into high (15.1 mmol/L), moderate (11.6 to 15.0
mmol/L), and low (
11.5 mmol/L) groups, age
(P<0.0001), male sex
(P<0.0001), the habits of
cigarette smoking (P<0.0001)
and of alcohol consumption
(P=0.0002), and folate levels
(P=0.01) were significantly
associated with an elevation of pHcy levels. The elevated pHcy levels
were significantly associated with SBI after individual adjustment for
age, sex, hypertension, renal function, and the habits of smoking and
alcohol consumption.
Conclusions—pHcy level is associated with age and nutritional and other lifestyle factors, and it contributes to a risk for SBI.
Key Words: homocyst(e)ine • lacunar infarction • magnetic resonance imaging • risk factors
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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According to a clinicopathological study by Fisher,1 88 (77.2%) of 114 patients with at least 1 lacunar stroke lesion were free of either clinical history of stroke or a neurological deficit during life. Most of these lacunar lesions were reported to be located in deep brain structures, including basal ganglia, pons, and subcortical white matter. Moreover, recent advances in neuroimaging techniques have enabled us to detect the presence and extent of silent brain infarction (SBI) more accurately and easily. Indeed, because high-resolution MRI has become widely used as a part of routine examination of the brain in Japan, SBI has become a more recognizable condition that draws unique attention as an important prodromal stage or as a risk for progression into symptomatic stroke and cognitive impairment in the elderly population. Hougaku et al2 detected SBI in 49 (42%) of 117 elderly people in outpatient clinical settings who had at least 1 stroke risk factor but did not have a history of clinical stroke. Shinkawa et al3 found SBI in 125 (12.9%) of 966 subjects who had undergone autopsy in a community-based study at Hisayama. Furthermore, Kobayashi et al4 demonstrated in a prospective study that elderly subjects with SBI were 10 times more likely to develop clinical stroke than were those without SBI. The Cardiovascular Health Study demonstrated a strong association between SBI and impaired cognition.5 Although it is well documented that many conditions, including age, hypertension, atrial fibrillation, and hypercoagulability, confer a strong risk of SBI,3 4 5 6 7 subjects without such traditional risk factors occasionally develop SBI. Therefore, it is likely that there may be other undefined risk factors that might operate in the pathogenesis of SBI.
For the past decade, mildly elevated plasma homocysteine (pHcy) levels have been recognized as a risk factor for a number of occlusive vascular diseases (see review8 and citations herein for more details). Furthermore, recent studies have demonstrated that elevated pHcy levels are also associated with Alzheimer’s disease, with no apparent macroscopic lesions, suggesting that pHcy-induced microvascular lesions may play a role in the pathogenesis of Alzheimer’s disease.9 Although the homozygous state of a common mutation (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene is reported to be responsible for the thermolabile phenotype and is associated with decreased MTHFR activity and elevated pHcy levels,10 little is known regarding the confounding caused by factors associated with hyperhomocysteinemia, and its relevance to SBI has never been studied. In the present study, we conducted a population-based, cross-sectional, case-control analysis of SBI to test the hypothesis that an elevated pHcy increases a risk for SBI. We also analyzed vitamin status and other lifestyle profiles that might be potentially related to pHcy levels.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects
We examined 153 community-dwelling elderly people (30 men and 123 women, aged 76.7±5.3 years, range 66 to 88 years) who were living in the rural community of Sefuri Village, Saga, Japan. All participants were healthy volunteers and were living independently at home without apparent history of stroke and dementia. Informed consent was given by each participant, and our study protocol was approved by the ethical review committee at Tohoku University School of Medicine. All participants underwent standardized physical and neuropsychological examinations. Cognitive functions were assessed and evaluated by Mini-Mental State Examination. Those who had cardioembolic risk factors, including atrial fibrillation, valvular heart disease, and myocardial infarction, were excluded. Subjects were diagnosed as having hypertension if there was a history of blood pressure recordings >160/95 mm Hg or if the subject was being treated by antihypertensive drugs. Habitual alcohol consumption was considered present if there was a history of alcohol intake for
5
days a week. MRI was performed on a 1.0-T superconducting magnet.
Transverse T1-weighted, T2-weighted, and fluid-attenuated inversion
recovery (FLAIR) images were obtained with a slice thickness of 8
mm. The diagnosis of SBI was made as follows: (1) spotty areas 3
mm in diameter showing high intensity in the T2 and FLAIR images and
low intensity in the T1
image,11 (2) lack of
neurological signs and/or symptoms that can be explained by the MRI
lesions, and (3) no medical history of clinical stroke. Very small
punctate hyperintensity lesions (1 to 2 mm in diameter) were more
likely to represent dilated perivascular spaces and were not
considered in the present study. MRI findings were evaluated by 2
independent researchers in a blinded manner. The diagnosis of SBI was
made when the researchers agreed with each other. Those participants
without evidence of SBI on MRI were selected as controls. All other
details have been described in our earlier
report.12
Total pHcy, Blood Biochemistry, and Genotyping
of MTHFR Alleles
Peripheral blood samples were taken
in the morning after the subjects had fasted for at least 12 hours.
After centrifugation at 2000 rpm for 15 minutes, plasma
samples were kept at -20°C until analysis. Predicted
creatinine clearance was calculated as an index of renal
function according to the formula described by Cockcroft and
Gault.13 Total pHcy levels
were measured by a sensitive enzyme conversion
immunoassay.14 Serum vitamin
B12 and folate levels were determined by use of
a chemiluminescence assay. Subjects who showed extremely high levels of
vitamin B12 (>1500 pg/mL) or folate (>20
ng/mL) were excluded from subsequent statistical analysis.
Genomic DNA was extracted from peripheral leukocytes by a
DNA extraction kit (DNA Extractor WB kit, Wako Chemicals). The C677T
polymorphisms of the MTHFR gene were determined according to the
methods described by Frosst et
al10 in a blind manner of
diagnosis.
Statistical Analysis
Statistical analyses were carried out with
the SPSS software package, version 10.0. Logistic regression models
were used to estimate the odds ratio (95% CI) of SBI for tertiles of
pHcy levels, ie, 11.5, 11.6 to 15.0, and 15.1 mmol/L, to
assess the relation of pHcy levels to other relevant risk factors of
SBI. Two dummy variables representing higher pHcy
groups (11.6 to 15.0 and 15.1) were compared with the lower pHcy
group (11.5).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Of the 153 eligible subjects, 38 (24.8%) met the criteria for a diagnosis of SBI. Most lesions were <10 mm in diameter and were usually located in subcortical white matter or basal ganglia. The mean±SD of the Mini-Mental State Examination score was 28.5±3.4 points in the SBI-negative group and 25.9±3.8 points in the SBI-positive group (P<0.001). Table 1
showed distribution of clinical or other
characteristics according to the presence or absence of SBI. This
univariate analysis demonstrated that the pHcy
levels in the SBI group were significantly higher than those in the
group without SBI (13.6±4.1 versus 11.0±3.3 µmol/L,
P=0.0004). Furthermore, male
sex (P<0.0001), age
(P=0.0004), hypertension
(P=0.0046), habits of smoking
(P<0.0001) and alcohol
consumption (P=0.0003), and
folate (P=0.012) and vitamin
B12
(P=0.014) levels were also
significantly associated with SBI. By contrast, there was no
significant association between SBI and diabetes mellitus, body mass
index, packed cell volume, total cholesterol levels, HDL
cholesterol levels, and MTHFR polymorphism in the
univariate analysis.
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As shown in
Table 2, when pHcy levels were stratified into high
(15.1 mmol/L), moderate (11.6 to 15.0 mmol/L), and low
(11.5 mmol/L) groups, age
(P<0.0001), male sex
(P<0.0001), habits of
cigarette smoking (P<0.0001)
and alcohol consumption
(P=0.0002), and folate levels
(P=0.01) were significantly
associated with elevation of pHcy levels. Blood pressure tended to be
higher as pHcy levels increased, but it did not reach a statistical
significance (P=0.06). The pHcy
levels did not differ significantly between different MTHFR
genotypes (data not shown). Vitamin B12
and folate levels did not differ significantly between different MTHFR
genotypes (data not shown). As shown in
{Table 3, the odds ratio (95% CI) of SBI was 4.5 (1.5
to 13.5) in the high group and 2.8 (1.1 to 7.0) in the moderate group
compared with the low group after adjustment for age
(P=0.01, model A). After
adjustment for sex, the odds ratio (95% CI) was 4.7 (1.6 to 13.8) in
the high group and 2.6 (1.0 to 6.6) in the moderate group
(P=0.01, model B). Furthermore,
after adjustment for hypertension and renal function, the odds ratio
(95% CI) was 6.0 (2.1 to 16.9) in the high group and 3.2 (1.3 to 8.1)
in the moderate group (P=0.001,
model C). Finally, after adjustment for current habits of smoking and
alcohol consumption, the odds ratio (95% CI) was 4.5 (1.5 to 13.3) in
the high group and 2.3 (0.9 to 6.1) in the moderate group
(P=0.02, model
D).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The prevalence of SBI was 38 (24.8%) of 153 in the present study. The prevalence was similar to that (28%) reported in a population-based study of 3647 living men and women aged
65 years who underwent MRI in the Cardiovascular
Health Study,5 whereas it was
higher than that (12.9%) reported in a community-based autopsy
series.3 The prevalence of SBI
may vary with different age, underlying risk factors, imaging
techniques, and research
protocols.2 3 4 5
The strengths of the present study are as follows: We have examined
MRI abnormalities of SBI and compared them with a number of
variables, including age, sex, disease status, and lifestyle
profiles as well as pHcy levels and other biochemical determinations of
renal function and vitamin status. We have found that mild
hyperhomocysteinemia is associated with an increased a risk for
SBI after age, sex, hypertension, renal function, and habits of
smoking/alcohol consumption were controlled individually. There was a
graded relationship between pHcy levels and the risk of SBI without an
obvious threshold level. Despite a small sample size in the present study, the present results confirmed earlier reports that age, serum creatinine level, and a lifestyle profile characterized by an excessive alcohol consumption and low vitamin intake strongly contribute to the elevation of pHcy levels.15 16 By contrast, we found no association between the MTHFR polymorphism and pHcy levels and between the MTHFR polymorphism and SBI. These findings are in agreement with other recent studies that the MTHFR polymorphism does not appear to be associated with an increased risk of stroke or other vascular diseases.17 18 The exact reason for the negative association is unclear at the present time. One possibility may be that decreased and thermolabile MTHFR activity can be well counteracted by an adequate intake of dietary vitamins in the majority of the homozygous subjects, thus leading to unremarkable pHcy levels as a function of the MTHFR polymorphism. Alternatively, it can be argued that there remains a possibility of interactions with other potentially important genes, such as the G20210A prothrombin gene mutation19 (authors’ unpublished data). It is not known whether extracranial large arteries or intracranial microvessels are more susceptible to pHcy levels. Hougaku et al2 demonstrated that asymptomatic carotid lesions were closely related to the appearance of SBI. In contrast, Faßbender et al20 described surprisingly high concentrations of pHcy in patients with cerebral microangiopathy but not in patients with cerebral large-vessel disease.
Regardless of the sites and mechanism by which elevated pHcy generates or promotes atherosclerosis, the present study indicates that mild hyperhomocysteinemia can be treatable and normalized irrespective of the MTHFR genotype by either an adequate supplementation of vitamins or an appropriate intervention of lifestyle or a combination of both in elderly people. Indeed, a dietary supplementation with a moderate dose of folate is reported to reduce pHcy levels.21 22 Furthermore, Petersen and Spence23 have demonstrated that a cocktail of folate, vitamin B6, and vitamin B12 that was aimed at lowering pHcy levels attenuates the progression of carotid plaque area in patients with mild to moderate hyperhomocysteinemia. Although most of the subjects examined in the present study were cognitively normal and did not reach levels that fulfill the criteria for the diagnosis of dementia, the presence of SBI appeared to have a mild effect on cognitive function. Therefore, a reduction of pHcy levels may have a significant impact in reducing the risk of SBI and preventing the progression into clinical stroke, vascular dementia, or both. Prospective randomized trials assessing the effectiveness of homocysteine-lowering therapy in patients with SBI are needed.
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Acknowledgments |
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We are grateful to Dr Uemura K. for critical review of the manuscript. The authors also express special thanks to Sefuri Village residents who made our research possible.
Received August 14, 2000; revision received October 17, 2000; accepted December 15, 2000.
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W.T. Longstreth Jr, C. Dulberg, T. A. Manolio, M. R. Lewis, N. J. Beauchamp Jr, D. O'Leary, J. Carr, and C. D. Furberg Incidence, Manifestations, and Predictors of Brain Infarcts Defined by Serial Cranial Magnetic Resonance Imaging in the Elderly: The Cardiovascular Health Study Stroke, October 1, 2002; 33(10): 2376 - 2382. [Abstract] [Full Text] [PDF]
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P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
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C. R. M. Rieder, D. Fricke, H. X. Wang, A. Wahlin, H. Basun, J. Fastbom, B. Winblad, and L. Fratiglioni Vitamin B12 and folate in relation to the development of Alzheimer's disease Neurology, November 13, 2001; 57(9): 1742 - 1743. [Full Text] [PDF]
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