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(Stroke. 1996;27:2043-2047.)
© 1996 American Heart Association, Inc.

Articles

Magnetic Resonance Imaging White Matter Hyperintensities in Clinically Normal Elderly Individuals

Correlations With Plasma Concentrations of Naturally Occurring Antioxidants

R. Schmidt, MD; M. Hayn, PhD; F. Fazekas, MD; P. Kapeller, MD H. Esterbauer, PhD

the Departments of Neurology (R.S., F.F., P.K.), MRI-Center (R.S., F.F., P.K.), Institute of Biochemistry (M.H., H.E.), Karl-Franzens University Graz (Austria).

Correspondence to Reinhold Schmidt, MD, Department of Neurology, Karl-Franzens University Graz, Auenbruggerplatz 22, A-8036 Graz, Austria.

	Abstract

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Background and Purpose White matter hyperintensities are a common magnetic resonance imaging (MRI) observation in the elderly. They are believed to represent a subclinical form of ischemic brain damage, but the underlying pathophysiological mechanisms are still incompletely understood. We postulated that oxidative mechanisms may favor the development of these changes and therefore correlated their presence and extent with the plasma concentrations of 10 naturally occurring antioxidants.

Methods We studied 355 clinically normal volunteers 45 to 75 years of age who were randomly selected from the official community register. A 1.5-T MRI of the brain and measurements of the plasma concentrations of antioxidants including zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, alpha- and beta-carotene, retinol, gamma- and alpha-tocopherol, as well as ascorbate were performed in all study participants. White matter hyperintensities were graded as punctate, beginning confluent, and confluent abnormalities.

Results Punctate, beginning confluent, and confluent white matter abnormalities occurred in 101 (28.5%), 44 (12.4%), and 14 (3.9%) individuals, respectively. Study participants with white matter damage were significantly older and had a higher frequency of arterial hypertension and cardiac disease but lower serum concentrations of total cholesterol. The plasma levels of lycopene and alpha-tocopherol were significantly lower in subjects with early confluent and confluent white matter hyperintensities, while individuals with punctate foci had an antioxidant status similar to those with normal MRI scans. Alpha-tocopherol was the only antioxidant that remained significantly and inversely related to the presence of beginning confluent and confluent white matter changes after adjustment for the between-group differences in age, arterial hypertension, cardiac disease, and cholesterol. The adjusted odds ratio for early confluent and confluent white matter abnormalities was 3.70 (95% CI, 1.69 to 8.10) in the lowest compared with the highest quartile of the alpha-tocopherol concentration. The odds ratio increased to 7.11 (95% CI, 1.63 to 22.84) when quintiles of the alpha-tocopherol level were compared.

Conclusions These data do not prove a causal relation, but they provide evidence of an association between low plasma concentrations of vitamin E and a higher risk of cerebral white matter disease in elderly normal subjects.

Key Words: magnetic resonance imaging • white matter • aging • oxidants • neuroprotection

	Introduction

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Magnetic resonance imaging (MRI) white matter hyperintensities (WMH) occur in 50% of elderly persons without associated clinical symptoms.¹ Pathological studies demonstrated widening of perivascular spaces, perivascular demyelination, or lacunar lesions in the presence of small-vessel disease as their morphological substrate.^{2 3 4} Therefore, these changes were thought to represent an early subclinical form of subcortical atherosclerotic encephalopathy.¹ Most previous studies on their clinical correlates found a strong association of WMH with aging,^{5 6 7 8 9} but it has remained undetermined as to which additional vascular risk factors contribute to their evolution. Hypertension has been considered most often.^{5 9 10 11} However, there are also studies that suggested cardiac disease,^{5 7 8} diabetes mellitus,⁶ or hypercholesterolemia⁹ as their predictors. Some investigations even failed to detect any association of WMH with conventional cerebrovascular risk factors.¹² This inconsistency in results prompted many authors to assume that other age-related causative factors may play an important role in the pathogenesis of white matter abnormalities in the elderly.¹ One of them may be oxygen radical formation and lipid peroxidation, which has been shown to increase with advancing age¹³ and may be excessive during cerebral ischemia.¹⁴ Protection against oxygen radicals and lipid peroxidation is provided by a complex interplay of antioxidants^{15 16} and, if free radical scavengers contribute to the development of WMH, their plasma levels should be inversely related to the extent of such changes. This study for the first time evaluates the relationship between WMH and the plasma concentrations of 10 natural antioxidants in a large cohort of community-dwelling elderly normal subjects.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Subjects and Design
Individuals 45 to 75 years of age and stratified by sex and 5-year age groups were randomly selected from the official register of residents of the city of Graz, Austria. They received a written invitation to participate in the Austrian Stroke Prevention Study (ASPS), a single-center prospective follow-up study in our community. The study has been approved by the Medical Ethics Committee of the Karl-Franzens University of Graz. Written informed consent was obtained from all study participants. The rationale and design of the ASPS have been described previously.¹⁷ Briefly, the objective of the study was to examine the frequency of cerebrovascular risk factors and their effects on cerebral morphology and function in the normal elderly. The response rate of the ASPS was 28%. This relatively low rate of response might have been caused by the fact that in our country, insurance companies cover risk factor screening in asymptomatic individuals. Therefore, many of those invited probably rather chose to consult their physicians than to participate in a research program. Yet, a random sample of 200 nonresponders were interviewed by phone and did not differ from responders in terms of age, sex, educational level, and history of major risk factors for stroke. The inclusion criteria for the study were no history of neuropsychiatric and severe general disease and a normal neurological exam. Overall, 1998 individuals fulfilled these inclusion criteria. All study participants underwent a structured clinical interview, a physical and neurological examination, three blood pressure readings, ECG and echocardiography, as well as laboratory testing including a blood cell count and a complete blood chemistry panel. Directly after finishing, the study protocol subjects were contacted at random to participate in the additional neuroimaging study including brain MRI. From a total of 402 individuals so far invited, 363 agreed to participate. Because of claustrophobia occurring in 6 attendees during the examination and technical problems with our MRI equipment in 2 subjects, we ultimately included 355 individuals in the current study.

Vascular Risk Factors
Diagnosis of vascular risk factors relied on the individual's history and appropriate laboratory findings. Arterial hypertension was considered present if a subject had a history of arterial hypertension with repeated blood pressure readings >160/95 mm Hg or if the readings at examination exceeded this limit. Diabetes mellitus was coded present if a subject was treated for diabetes at the time of the examination or if the fasting blood glucose level at examination was >140 mg/dL. Cardiac disease was assumed to be present if there was evidence of cardiac abnormalities known to be a source for cerebral embolism,¹⁸ evidence of coronary heart disease according to the Rose questionnaire¹⁹ or appropriate ECG findings (Minnesota code I: 1 to 3, IV: 1 to 3, or V: 1 to 2), or if an individual presented signs of left ventricular hypertrophy on echocardiogram or ECG (Minnesota code III: 1, or IV: 1 to 3). Study participants were defined as smokers if they currently smoked more than 10 cigarettes per day. The plasma levels of total cholesterol, trigycerides, and HDL cholesterol were determined in all subjects.

Magnetic Resonance Imaging
MRI was performed on 1.5-T superconducting magnets (Gyroscan S 15 or ACS, Philips) with the use of a spin-echo technique. Sagittal T₁-weighted images (TR/TE 600/30 ms) and transverse T₂-weighted scans (TR/TE 2500/30, 60 ms) were obtained with a slice thickness of 5 mm. All scans were reviewed by one of us (F.F.) without knowledge of the participant's laboratory data. WMH were specified and graded according to our scheme^{7 20} into 0, absent; 1, punctate; 2, beginning confluent; and 3, confluent. Adhering to a recent publication demonstrating irregular periventricular hyperintensities to be ischemic in etiology, we also considered this type of abnormality as grade 3 WMH.⁴ Minimal periventricular signal hyperintensities in the form of caps and "pencil-thin" lining were disregarded as available data do not indicate an association of these findings with cerebrovascular disease.^{4 21} Lacunar infarctions were coded separately, but their rare occurrence precluded a meaningful statistical analysis. There were no individuals with thromboembolic brain infarcts.

Laboratory Assays
Total cholesterol and triglycerides were determined with the use of commercially available kits (Unit-Kit III Roche, Hoffmann-La-Roche). HDL cholesterol was measured with the Tdx REA Cholesterol assay (Abbott).

Blood sampling for antioxidant measurements was performed according to the protocol of the MONICA study.²² Briefly, 10 mL of blood was collected into EDTA-containing plastic tubes and centrifuged. Two 2-mL plasma samples were transferred to Eppendorf tubes and a third 0.5-mL plasma sample was pipetted into plastic tubes containing 0.5 mL of 10% aqueous metaphosphoric acid. The tubes were promptly frozen and stored at -70°C. The time between blood sampling and the start of freezing of plasma and acidified plasma varied between 45 minutes and 2 hours. Storage until analysis varied from 1 month to 2 years. For measurements of lipophilic antioxidants, the deep-frozen plasma tubes were thawed and extracted within 30 minutes after thawing. Into 10-mL Pyrex tubes 0.4 mL plasma, 0.4 mL H₂O (vortexed), 0.8 mL ethanol with 0.1% butylated hydroxytoluene (vortexed 10 seconds), and 2 mL hexane (stored over bidistilled water containing 20 µmol/L EDTA) were successively pipetted. After vortexing for 1 minute, this mixture was centrifuged. A volume of 1.2 mL of the upper hexane phase was transferred into brown crimp vials and dried in a speed-vac for 10 minutes at room temperature. The residue was dissolved in 0.3 mL ethanol/ethyl acetate 10/1, and 20 µL was injected into the HPLC (Lichrospher 100 RP18, 5 µm, 125x4 mm). Separation was performed in isocratic mode with a mixture of acetonitrile/methanol/ethanol/H₂O: 50/60/20/2 containing 0.01% ammonium acetate (1.2 mL/min). The effluent was monitored with two detectors in series, a UV-vis detector set to 450 nm for detection of carotenoids and a fluorescence detector set initially to 325/500 nm for detection of retinol and after 3.8 minutes to 292/335 nm for detection of tocopherols.

For measurements of ascorbate, the deep-frozen tubes with the metaphosphoric acid plasma were thawed and centrifuged at 9000 rpm. A volume of 0.1 mL of the supernatant was mixed with 0.4 mL HPLC-eluant, centrifuged, and injected by the autosampler into the HPLC (Lichrosphere 100 RP18, 5 µm, 250x4 mm). The HPLC-eluant was prepared by adding 4.3 mL of 70% perchloric acid and 100 mg EDTA to 1 L of bidistilled water. Flow rate was 1 mL/min. The effluent was monitored with an electrochemical detector set to +0.6V against an Ag/AgCl reference electrode filled with 3 mol/L LiCl. Peak quantification was done with at least two standard mixtures of ascorbic acid. The time between thawing and HPLC separation did not exceed 3 hours.

Statistical Analysis
We used the Statistical Package for Social Sciences (SPSS/PC+) for data analysis. The Mantel-Haenszel test and trend test were used to evaluate linear associations between WMH grading and risk factors for stroke. Pearson's correlation coefficients were calculated to assess the relationship between plasma levels of antioxidants and risk factors. Differences of antioxidant concentrations among WMH categories were evaluated by one-way ANOVA and ANCOVA adjusted for potentially confounding factors. Additionally, logistic regression was used to investigate the associations between WMH and antioxidant status. Each antioxidant was included separately in a multiple logistic regression with all the risk factors and the season of blood sampling. The vitamin concentrations were expressed as categorial variables^{1 2 3 4} according to the quartile whose limits included the results. The odds ratios were calculated as the exponential of the three coefficients that resulted, and the exponential of the confidence intervals of these coefficients were the confidence intervals of the odds ratios (95% CI). Respective analyses for quintiles of antioxidant concentration also were performed.

	Results

Top Abstract Introduction Methods Results Discussion References

 
A total of 159 (44.8%) individuals had WMH. There were 101 (28.5%) subjects with grade 1, 44 (12.4%) with grade 2, and 14 (3.9%) with grade 3 abnormalities. As can be seen from Table 1, the extent of WMH was significantly associated with age, arterial hypertension, and cardiac disease. A significant inverse relationship existed between the WMH grading and total cholesterol.

View this table: [in this window] [in a new window]   Table 1. Vascular Risk Factors and White Matter Hyperintensity Grading

Table 2 gives the means and standard deviations of the various antioxidant plasma levels and their quartile distributions. Significant seasonal variations were noted for cryptoxanthin and lycopene but not for any other antioxidant including gamma- and alpha-tocopherol, retinol, and ascorbate. The highest concentrations for cryptoxanthin were noted in February, the lowest in October, with a difference of 58% (P=.0005). The plasma levels of lycopene were highest in September and lowest in January, with a difference of 57% (P=.001). For the other antioxidants, seasonal differences ranged from 9% for canthaxanthin to 49% for alpha-carotene.

View this table: [in this window] [in a new window]   Table 2. Plasma Antioxidant Concentrations: Mean, SD, and Percentile Values

The comparison of antioxidant concentrations among the four WMH grades yielded significant differences for lycopene and alpha-tocopherol (Table 3). These differences can be attributed to the lower antioxidant levels of study participants with grades 2 and 3 WMH, since subjects with grade 1 WMH had similar antioxidant concentrations as individuals without white matter changes. When ANCOVA was used to correct for the variations in age, arterial hypertension, cardiac disease, and cholesterol among the WMH groups, the difference for alpha-tocopherol remained statistically significant (P=.016). Pearson's correlations between the lycopene and alpha-tocopherol concentrations with age, arterial hypertension, cardiac disease, and total cholesterol yielded significant associations for lycopene with age (r=-.16; P=.002) and total cholesterol (r=.21; P=.0003). Alpha-tocopherol correlated significantly with total cholesterol (r=.53; P=.0001).

View this table: [in this window] [in a new window]   Table 3. Plasma Antioxidant Concentrations and White Matter Hyperintensity Grading

The odds ratios for grade 2 and 3 WMH relative to the highest quartile of the distribution of plasma antioxidant concentrations are shown in Table 4. In the lowest quartiles of the lycopene and alpha-tocopherol level, the odds ratios increased to 3.73 and 3.87, with the overall trends being significant. After adjustment for age, sex, season of blood sampling, hypertension, diabetes, cardiac disease, current smoking, total serum cholesterol, HDL cholesterol, and triglycerides, only alpha-tocopherol maintained a significant inverse relationship between quartiles of serum concentration and grades 2 and 3 WMH (P=.048). The adjusted odds ratio was 3.70 (90% CI, 1.69 to 8.10) in the lowest compared with the highest quartile of the alpha-tocopherol concentration. When comparing the lowest (<23.5 µmol/L) with the highest (>36.2 µmol/L) quintile of the alpha-tocopherol level, the adjusted odds ratio for grades 2 and 3 WMH increased to 7.11 (95% CI, 1.63 to 22.84).

View this table: [in this window] [in a new window]   Table 4. Odds Ratio for Grades 2 and 3 White Matter Hyperintensities by Quartiles of Plasma Antioxidant Concentrations

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The ranges of plasma antioxidant levels demonstrated in this population-based study of elderly normal subjects were similar to those reported from the pooled serum analyses of 3480 participants of various previous studies including the Third National Health and Nutrition Examination Survey.²³ The magnitude of seasonal variations were also comparable to those reported in a previous study among healthy volunteers.²⁴ Relatively high standard deviations of almost all antioxidants, which most likely resulted from widely differing dietary uptake of study participants, make nonsignificant results difficult to interpret.

We found low plasma concentrations of alpha-tocopherol and lycopene to be related to a higher extent of MRI white matter abnormalities. Alpha-tocopherol was the only antioxidant for which this association remained significant after adjustment for possible confounders such as age, vascular risk factors, and seasonal trends. Although it cannot be excluded with certainty at this point that low alpha-tocopherol levels are only the epiphenomenon of WMH development such as atherogenesis-related inflammatory processes, there is evidence that a lack of protection against oxidative processes may indeed be causally related to the evolution of such brain changes. Numerous studies using ¹³³Xe CBF measurements, Xe-enhanced CT, and PET indicate that incidental WMH in elderly persons occur in the presence of hypoperfusion and ischemia,^{1 7 25} a condition known to result in a strong increase of oxygen radical production that may ultimately exceed the scavenging potential of essential antioxidants, particularly when their tissue levels are low.²⁶ The sources of the primary radicals can be xanthine-oxidase, NADPH-oxidase, auto-oxidizing catecholamines, damaged mitochondria, and others.²⁷ Iron ions, released at lower pH in ischemic tissue, can potentiate the initial injury and trigger secondary degenerative processes via lipid peroxidation–mediated membrane degradation.¹⁴ In such a scenario, the high concentration of ascorbate in the brain, which is about 10-fold higher than in plasma, may have a deleterious effect as iron/ascorbate amplifies such secondary damage.²⁸ In this context, it is of interest that in the present investigation the highest plasma concentrations of ascorbate were seen in the subset of individuals with the most extensive WMH (see Table 3). Moreover, it has been described that alpha-tocopherol deficiency and products evolving from lipid peroxidation have prothrombotic consequences that may increase the risk for thromboembolic events.²⁶ As to whether a prothrombotic state actually contributes to the genesis of WMH is yet unclear. It is noteworthy that low levels of alpha-tocopherol were also found to favor the formation of oxidatively modified LDL, which, according to a popular theory, could play an important role in the initiation and progression of atherosclerosis.^{15 29} In fact, several authors described small-vessel disease as the underlying cause of WMH,^{2 3 4} and their extent was found to increase with increasing arteriolar vessel wall thickness.³⁰

In the present study, the indirect association of the alpha-tocopherol level existed only with early confluent and confluent (grades 2 and 3) but not with punctate (grade 1) WMH. This is not surprising when considering that the pathological correlate of more extensive WMH consistently represents true ischemic lesions comprising larger areas of demyelination with variable loss of fibers and commonly microcystic infarctions, whereas the substrates of minimal WMH include a plethora of parenchymal changes that are only partly related to ischemia.^{2 3 4} Frequent nonischemic histopathological findings associated with punctate white matter foci are enlarged spaces around arterioles and venules with subtle alterations in the myelin content of shrunken tissue or even ganglion cell heterotopia.³¹

In line with our findings, there is accumulating evidence from animal studies and epidemiological investigations suggesting that suboptimal plasma levels of alpha-tocopherol and perhaps other natural antioxidants increase the relative risk for cardiovascular disease and cerebral ischemia.^{32 33} The optimal target values for the major antioxidants are >30 µmol/L for alpha-tocopherol, >50 µmol/L for ascorbate, >0.4 µmol/L for beta-carotene, and >2.5 µmol/L for retinol.¹⁶ Overall, the mean antioxidant concentrations of our study population are well within this optimal range and closely resemble those reported in previous investigations.^{23 34} The present study demonstrated that subjects with an alpha-tocopherol level <23.5 µmol/L (lowest quintile) are at the highest risk to develop WMH.

Lycopene was the second antioxidant that tended to be negatively related with WMH occurrence on MRI. This association deserves further evaluation, as little known about the role of this micronutrient in the genesis of vascular disease in general and cerebral ischemia in particular. Biochemical studies have demonstrated that lycopene is one of the most potent scavengers of singlet oxygen.³⁵

	Acknowledgments

 
This study was supported by "Jubilaumsfonds der Osterreichischen Nationalbank" (Project #4484). The authors thank Karin Gollner for excellent technical assistance.

Received May 30, 1996; revision received July 31, 1996; accepted July 31, 1996.

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