Background and Purpose A few studies have observed a significant inverse correlation between cigarette smoking or lipid abnormalities and periventricular hyperintensities (PVHs) on T2-weighted magnetic resonance imaging (MRI) scans of the brain, which is surprising because smoking and hyperlipidemia are considered risk factors for cerebrovascular disease. We investigated the relation between smoking and lipid abnormalities and PVHs on T2-weighted MRIs.
Methods MRI scans were performed in 253 patients over the age of 40 years, and PVHs were assessed retrospectively by use of a five-point scale. Patients who were receiving medical treatment for hyperlipidemia were excluded. Serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides were determined in the fasting state by an automated enzymatic procedure. The low-density lipoprotein (LDL) cholesterol level was calculated by use of Friedewald’s equation. Age, sex, hypertensive status, antihypertensive treatment, presence or absence of diabetes mellitus, and history of stroke were included in the analysis.
Results Multiple linear regression analysis showed that age, hypertension, smoking, and antihypertensive treatment were significantly and independently correlated with the PVH score. The standard partial regression coefficients were .39 (P<.0001) for age, .33 (P<.0001) for hypertension, .16 (P=.0062) for smoking, and −.18 (P=.0124) for antihypertensive treatment. Hypercholesterolemia (total cholesterol level >220 mg/dL), HDL hypocholesterolemia (HDL cholesterol level <40 mg/dL), LDL hypercholesterolemia (LDL cholesterol level >130 mg/dL), hypertriglyceridemia (triglyceride level >150 mg/dL), sex, diabetes mellitus, and a history of stroke were not correlated with the PVH score.
Conclusions Cigarette smoking was a weak but significant positive predictor of the PVH score and was independent of age, hypertension, and antihypertensive treatment. Lipid abnormalities were not related to the PVH score.
Studies have shown that cerebrovascular risk factors such as aging, hypertension, and diabetes mellitus are associated with PVHs and other hyperintensities of the deep white matter detected on T2-weighted MRI scans of the brain. However, data on the relation between smoking and these foci are limited. Although most studies1 2 3 4 5 6 7 8 9 have found no significant correlation between smoking and white matter lesions, a few studies10 11 have reported significant inverse correlations, which is surprising because smoking is considered a risk factor for cerebrovascular disease and may be associated with the presence or progression of white matter lesions.
We retrospectively investigated the relation between smoking and lipid abnormalities and PVH. We previously found that age, hypertension, and antihypertensive treatment were correlated with the extent of PVHs.16 In the present study, we used multivariate analysis to examine the association between these variables, smoking and lipid abnormalities, and the extent of PVH.
Subjects and Methods
We reviewed the clinical records of patients who had undergone MRI scans of the brain between 1991 and 1994 and selected 253 patients who fulfilled the following conditions: (1) age ≥40 years; (2) complete clinical and laboratory data available, including urinalysis, complete blood count, fasting plasma glucose, HbA1c, fasting serum lipids, and blood chemistry tests for liver and kidney function in the fasting state; (3) availability of information on antihypertensive treatment; (4) a 75-g oral glucose tolerance test in subjects suspected of having diabetes mellitus; (5) no history of treatment for hyperlipidemia; (6) no history of multiple sclerosis, cerebral tumors, or leukodystrophy; and (7) MRI without artifacts and of sufficient quality to permit evaluation of the PVH grade. The study population consisted of 149 men and 104 women, aged 40 to 91 years (mean, 66.4 years). Diagnoses included cerebral infarction (n=111), transient ischemic attack (n=14), Parkinson’s disease (n=13), epilepsy (n=9), cerebral bleeding (n=9), and other conditions (n=97) such as neurosis, depression, headache, numbness, and dizziness.
Arterial blood pressure was measured with the patient seated. In most subjects, we used the blood pressure data obtained on the day of the MRI examination. If the MRI had been performed only in the acute stage of stroke, we used the blood pressure measured in the chronic stage (more than 1 month after the onset of stroke).
Hypertension was defined as a blood pressure of ≥160/95 mm Hg on any occasion. Patients receiving antihypertensive treatment were also classified as having hypertension. If a hypertensive patient had not received medical treatment or had a history of discontinuing medical treatment, that patient was classified as receiving no or irregular treatment. If a hypertensive patient regularly took antihypertensive medication, the patient was classified as receiving regular treatment.
Serum levels of Tch, HDL-C, and TGs were determined in the fasting state by use of an automated enzymatic procedure. The LDL-C level was calculated by use of Friedewald’s equation: LDL-C=Tch−(HDL-C)−(TG/5). Hypercholesterolemia was defined as a Tch level >220 mg/dL. Hypertriglyceridemia was defined as a TG level >150 mg/dL. HDL hypocholesterolemia was defined as a HDL-C level <40 mg/dL. LDL hypercholesterolemia was defined as a LDL-C level >130 mg/dL.
Data on cigarette smoking, including smoking duration (years), number of cigarettes smoked daily, and attempts to stop smoking, were obtained by use of questionnaires.
MRI was performed with a 1.0-T superconducting scanner (Shimadzu SMT100X). Spin-echo pulse sequences were used to generate both T1-weighted axial brain images (TR=400 ms, TE=15 ms, and NEX=3; or TR=500 ms, TE=20 ms, and NEX=3) and T2-weighted images (TR=3000 ms; TE=90 ms; NEX=1) with use of a 256×256 matrix. Scans were performed in the orbitomeatal plane with a multipolarization radiofrequency head coil. Sections were 8-mm thick and were separated by a 2-mm interscan gap; they began at the medullocervical cord junction and extended superiorly to the inner table of the skull.
We excluded punctate hyperintensities in the deep white matter from analysis. Images were read by an examiner without knowledge of the clinical data. We determined the PVH grade in all MRI sections using a previously described five-point scale16 : 0, absent; 1, caps only on anterior horns of the lateral ventricle at the level of the basal ganglia; 2, thin lining, smooth halo, or irregular PVH within the inner half of the white matter area at the level of the body of the lateral ventricle; 3, PVH extending into the outer half of the white matter area in any region around the lateral ventricle; and 4, PVH covering the entire white matter. An MRI study that yielded borderline results was automatically assigned to the lower grade.
We studied one MRI scan for each patient. If serial scans had been obtained, we analyzed the scan performed closest to the day on which laboratory tests were performed.
Data are presented as mean±SD. Differences in the PVH grade between two groups were analyzed by the Mann-Whitney U test. Differences among three groups were analyzed by the Kruskal-Wallis rank test. Spearman’s rank correlation was used to determine univariate correlation between the PVH grade and cerebrovascular risk factors. Multivariate linear regression analysis in a backward stepwise manner was used to estimate the independent effects of the predictor variables on the PVH grade. A probability value of <.05 was accepted as statistically significant.
In the group studied, there were 77 current smokers. Among them, the mean number of cigarettes smoked daily was 19.5 (range, 5 to 60), mean smoking duration was 41.1 years (range, 10 to 63), and mean number of cigarette-years was 809 (range, 50 to 2640). Among the 34 former smokers, the mean number of cigarettes smoked daily was 22.2 (range, 5 to 60), mean smoking duration was 31.6 years (range, 8 to 62), mean number of cigarette-years was 720 (range, 80 to 2580), and mean duration of abstinence from smoking was 14.5 years (range, 0.5 to 45). The frequency of current smoking, which decreased with age, was 45%, 38%, 41%, 15%, 12%, and 0% for subjects in their 40s, 50s, 60s, 70s, 80s, and 90s, respectively. Age (mean±SD) was 62.8±9.4 for current smokers, 67.1±9.9 for former smokers, and 68.2±10.6 for nonsmokers (Kruskal-Wallis rank test, P=.0002).
Age was positively correlated and blood pressures were weakly correlated with the PVH grade (Table 1⇓). Smoking duration was correlated with the PVH grade among current smokers (r=.359, P=.0018, n=77), but age was also strongly correlated with smoking duration (r=.829, P<.0001, n=77).
Univariate analysis showed that the PVH grade was higher in hypertensive subjects (2.3±0.7, n=125) than in normotensive subjects (2.0±0.6, n=128, P=.0001). The Kruskal-Wallis rank test showed a significant difference in the PVH grade among the three groups classified by hypertension and treatment. A history of stroke, that is, a history of cerebral infarction, cerebral bleeding, or transient ischemic attack, was significantly correlated with the PVH grade. None of the other variables showed a significant association with the PVH grade (Table 2⇓).
Multiple linear regression analysis showed that age, diastolic blood pressure, and smoking duration were significantly and independently correlated with the PVH score (Table 3⇓). Another multiple regression analysis showed that age, hypertension, antihypertensive treatment, and smoking were significantly and independently correlated with the PVH score (Table 4⇓).
This was not a population-based study. Subjects were selected from patients who visited the department of neurology. Therefore, 134 of 253 subjects were stroke patients, that is, they had experienced cerebral infarction, cerebral bleeding, or transient ischemic attack. Since the study population was biased, especially by the large number of stroke patients, the results were likely to be influenced by this bias. The chief aim of the present study was to examine the association between smoking and the extent of PVH. Smoking is a risk factor for stroke, and PVH is significantly associated with a history of stroke as shown in the present study; therefore, the role of smoking should be overstated by the large number of stroke patients in the study and should be falsely associated with the extent of PVH. To avoid any error caused by selection bias, a history of stroke was included in the multivariate analysis.
Multiple linear regression analysis showed a significant, positive correlation between smoking and the PVH grade that was independent of age, hypertension, and antihypertensive treatment. Although multiple linear regression analysis showed a positive correlation between smoking duration and the PVH grade, univariate analysis did not, probably because of the inverse correlation between age and the frequency of smokers and the positive correlation between age and the PVH grade. To the best of our knowledge, no previous studies have shown a positive correlation between smoking and PVH, but based on univariate analysis, Bots et al10 and van Swieten et al11 observed a significant inverse correlation between smoking and the presence of white matter lesions. They also found that subjects with white matter lesions were significantly older than those without lesions, which indicated that the effect of age should be eliminated when the association between smoking and white matter lesions is analyzed.
Van Swieten et al17 suggested that arteriolosclerosis is the primary pathogenetic factor in diffuse white matter lesions in the elderly. Arteriolosclerosis has been found to be associated with increasing age and hypertension,18 19 and these two variables were significant predictors of the PVH grade in the present study. However, studies have not shown a significant association between smoking and arteriolosclerosis. Reed et al20 reported that cigarette smoking is strongly associated with stroke, marginally associated with atherosclerosis in the large arteries of the circle of Willis, and not associated with atherosclerosis in the small arteries. In the present study, age, hypertension, smoking, and antihypertensive treatment were significantly and independently correlated with the PVH grade. The present results indicate that smoking is a weaker predictor of the PVH grade than age and hypertension. The weak association between smoking and PVH may be related to the weak correlation between arteriolosclerosis and smoking.
We did not find a significant association between lipid abnormalities and the PVH grade. We excluded from analysis patients who received medical treatment for hyperlipidemia, because we cannot classify each type of lipid abnormality from serum lipid level in a patient receiving medical treatment. This selection may produce lesser severity and shortened duration of lipid abnormalities among study populations, and these factors possibly obscured an association between lipid abnormalities and white matter lesions.
Although Manolio et al4 observed an inverse correlation between LDL-C and the extent of white matter lesions using multivariate analysis, and Streifer et al7 found an inverse correlation between hyperlipidemia and the degree of leukoaraiosis, other studies have not found a significant association between lipid abnormalities and white matter lesions. Murai et al21 reported that the HDL-C level and the ratio of HDL-C to LDL-C were significantly lower in patients with infarction of the cortical artery than in patients with infarction of the perforating artery, which suggests that lipoprotein abnormalities may have a stronger relation to cerebral atherosclerosis in large arteries than to arteriolosclerosis. Therefore, an association between the PVH grade and lipid abnormalities could not be significant. Reed et al20 reported that the serum level of cholesterol was strongly associated with atherosclerosis in the large arteries of the circle of Willis but not in small arteries, whereas the serum level of TGs was associated with atherosclerosis in the small arteries only. We did not find a significant association between cholesterol or TG levels and PVH in the present study. The mean TG level of the 28 subjects with hypertriglyceridemia was 222 mg/dL (maximal value, 378 mg/dL). It is possible that we found no association between hypertriglyceridemia and the PVH grade because our subjects had only mild hypertriglyceridemia.
Selected Abbreviations and Acronyms
|HDL-C||=||high-density lipoprotein cholesterol|
|LDL-C||=||low-density lipoprotein cholesterol|
|MRI||=||magnetic resonance imaging|
|NEX||=||number of excitations|
- Received October 30, 1995.
- Revision received January 17, 1996.
- Accepted January 17, 1996.
- Copyright © 1996 by American Heart Association
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