(Stroke. 1997;28:951-956.)
© 1997 American Heart Association, Inc.
Articles |
Apolipoprotein E Polymorphism and Silent Microangiopathy-Related Cerebral Damage
Results of the Austrian Stroke Prevention Study
From the Departments of Neurology (R.S., F.F., K.N., P.K.) and Internal Medicine (M.S., V.W.), the Institute of Medical Biochemistry (H.S., G.M.K.), and the MRI Center (R.S., F.F., P.K.), Karl-Franzens University Graz, Austria.
Correspondence to Reinhold Schmidt, MD, Department of Neurology, Karl-Franzens University Graz, Auenbruggerplatz 22, A-8036 Graz, Austria. E-mail reinhold.schmidt{at}kfunigraz.ac.at
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Abstract |
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Background and Purpose Microangiopathy-related cerebral damage (MARCD) includes white matter abnormalities and lacunar infarctions and represents a common MRI observation in subjects above 50 years of age. The risk factors of such brain abnormalities are not fully determined. The goal of this study was to determine whether the genetic heterogeneity of apolipoprotein E (apoE) contributes to the occurrence of MARCD.
Methods Brain MRI (1.5 T) was performed in 280 individuals (ages 50 to 75 years) without neuropsychiatric disease randomly selected from the official register of residents of the city of Graz, Austria. All study participants underwent apoE genotyping, carotid Doppler sonography, electrocardiography, echocardiography, and a complete blood chemistry panel. MARCD was defined as evidence of early confluent and confluent white matter hyperintensities or lacunes. Carotid atherosclerosis was graded on a five-point scale ranging from not present (0) to complete occlusion (5).
Results MARCD occurred in 61 individuals (21%). The
distribution of apoE genotypes differed significantly between
subjects with and without MARCD (P=.036). Subjects with such
findings more commonly had the 
2/3 genotype (24.6%
versus 10%) at similar frequencies of genotypes containing the
4 allele. The 2/3 genotype was associated with
lower levels of total cholesterol (P=.0009), LDL
cholesterol (P=.00001), and apolipoprotein B
(P=.00001). Also, there was a nonsignificant trend toward
less cardiac disease. Other major vascular risk factors and carotid
abnormalities were similar among the various genotypes.
Multiple logistic regression analysis created a model of
significant MARCD predictors, including age (odds ratio [OR], 1.1 per
year), hypertension (OR, 3.4), and the apoE 2/3 genotype
(OR, 3.0).
Conclusions These data suggest an association between the
apoE 2/3 genotype and MARCD despite favorable effects on
the lipid profile and cardiac disease.
Key Words: apolipoproteins • lacunar infarction • magnetic resonance imaging • stroke prevention • white matter
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Apolipoprotein E acts as a ligand for the "remnant" (apoE) and the LDL (apoB/E) receptor and plays a crucial role in maintaining plasma cholesterol homeostasis. It is a polymorphic protein, with apoE
2, 3, and 4 as common isoforms. The catabolism of
lipoproteins appears to be modulated by the apoE and apoB/E receptor
affinity of apoE. ApoE 2 binds defectively, resulting in receptor
upregulation and subsequent decrease of plasma cholesterol.
ApoE 4, by contrast, is associated with increasing
cholesterol levels because this isoform accelerates hepatic
remnant uptake by apoE receptors, thereby downregulating the number of
apoB/E receptors.1
Previous work has indicated that the apoE 4 allele is associated
with early development of coronary heart disease and
arteriosclerosis.2 There exist only
three investigations on the importance of the apoE polymorphism for
the evolution of cerebral ischemia.3 4 5 All of them
suggested some role of the genetic heterogeneity of
apoE for the occurrence of strokes, but it remained undetermined which
genotype carries the highest risk. Two studies observed high
frequencies of the 4 allele along with a low frequency of the
3 allele in stroke patients.3 4 Couderc et
al,5 however, found that it was the 2 allele that
may be associated with higher cerebrovascular morbidity at younger
ages. These authors suggested a potentiation of other risk factors,
including diabetes, hypertension, and obesity, in the presence of the
2 allele as a possible mechanism. In light of these results, we
conducted the present investigation to determine whether the apoE
polymorphism may also be involved in the development of MARCD,
which is a common MRI observation in the elderly and includes white
matter abnormalities and lacunar lesions.6 The
predisposing factors of clinically silent MARCD are widely unknown.
However, their exploration may hold important preventive implications,
since MARCD probably identifies a group of individuals at high risk for
clinically overt cerebrovascular disease.7 8
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subjects and Design
Individuals aged 50 to 75 years 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, 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 Austrian Stroke Prevention Study have been previously described.9 Briefly, the objective of the study is to examine the frequency of cerebrovascular risk factors and their effects on cerebral morphology and function in the normal elderly population. The inclusion criteria for the study were no history of neuropsychiatric disease (including previous cerebrovascular disease and dementia) and a normal neurological examination. From a total of 8193 individuals invited between September 1991 and March 1994, a sample of 2794 subjects agreed to participate, with 1998 individuals fulfilling the inclusion criteria. All study participants underwent a structured clinical interview, physical and neurological examinations, three blood pressure readings, ECG, and echocardiography, as well as laboratory testing including blood cell count and a complete blood chemistry panel. Every fourth study participant was then invited to enter phase II of the Austrian Stroke Prevention Study, which included MRI, Doppler sonography, single-photon emission CT, and neuropsychological testing. Mini-Mental State Examination (MMSE)10 and Mattis' Dementia Rating Scale (MDRS)11 scores were obtained from all study participants. Since 1993, we also performed apoE genotyping in all phase II attendees. The current study cohort consists of those 280 individuals consecutively selected since 1993 who underwent both brain MRI and apoE genotyping. All but four study participants had MMSE and MDRS scores above 24 and 137, respectively, the cutoff points thought to be indicative of dementia.10 11
Vascular Risk Factors
Diagnosis of vascular risk factors was based on the
individual's history and appropriate laboratory
findings.12 Arterial hypertension was
considered present if a subject had a history of
arterial hypertension with repeated blood pressure readings
above 160/95 mm Hg or if the readings at examination exceeded
this limit. Diabetes mellitus was coded as present if a subject was
being treated for diabetes at the time of the examination or if the
fasting blood glucose level at examination exceeded 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,13 evidence of coronary heart disease
according to the Rose questionnaire14 or appropriate ECG
findings15 (Minnesota codes 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 codes III: 1 or IV: 1 to 3). Study participants were
asked if they ever smoked and if they currently smoked.
Laboratory Measurements
A lipid status including the level of
triglycerides, total cholesterol, and LDL and
HDL cholesterol, as well as lipoprotein(a), was determined
for each study participant. Thirty minutes after
venipuncture, the coagulated blood samples were
centrifuged at 1600g for 10 minutes, and the serum
was transferred to plastic tubes and analyzed within 4 hours.
Trigycerides and total cholesterol were enzymatically
determined using commercially available kits (Uni-Kit III "Roche"
and MA-Kit 100 "Roche," Hoffman-La Roche). HDL
cholesterol was measured by the use of the TDx REA
cholesterol assay (Abbott). LDL cholesterol was
calculated by the equation of Friedewald. The lipoprotein(a)
concentration was determined by the electroimmunodiffusion method using
a reagent kit containing monospecific anti-lipoprotein(a) antiserum and
the Rapidophor M3 equipment (Immuno AG). The levels of apoB and apoA-I
were assessed by an immunoturbidometric method utilizing polyclonal
antibodies and a laser nephelometer (Behringwerke AG). The plasma
fibrinogen concentration of study participants was measured according
to the Clauss method using the prescription and reagents of
Behringwerke AG.
ApoE Genotyping
High-molecular-weight DNA was extracted from
peripheral whole blood using Qiagen genomic tips. ApoE
genotyping was done according to the method of Hixson and
Vernier.16 A 244-bp-long fragment of the apoE gene was
amplified using the two oligonucleotide primers F6
(5'-TAA GCT TGG CAC GGC TGT CCA AGG A-3') and F4 (5'-ACA GAA TTC GCC
CCG GCC TGG TAC AC-3'). PCR was performed on 0.8 µg of genomic DNA in
a buffer containing 10 mmol/L Tris (pH 8.3), 50 mmol/L KCl,
1.5 mmol/L MgCl2, 10% DMSO, 0.2 mmol/L of each dNTP, 800
ng/µL of each primer, and 2 U of DynaZyime II DNA polymerase
(Finnzymes Oy) in a final volume of 50 µL. After 5 minutes at 94°C,
amplification was carried out in 30 cycles, each consisting of 1 minute
at 94°C, 1 minute at 60°C, and 2 minutes at 72°C. A final step of
elongation was performed at 72°C for 10 minutes. Amplification was
assessed by electrophoresis of 5 mL of the PCR product on 1.5%
agarose gel stained with ethidium bromide. The PCR products (15 mL)
were digested with 20 U of Cfo1 (Promega Corp) in the supplied buffer
over 3 hours at 37°C. After digestion, samples were electrophoresed
on 20% nondenaturating polyacrylamide gel for 1.5 hours at 180
V. Gels were stained with ethidium bromide (1.0 µg/mL) and
photographed under UV transillumination. The most common 3
allele is cut by Cfo1 at codon 158, the 4 allele is cut
twice by the addition of a second restriction site at position 112, and
the less frequent 2 allele lacks either recognition site. The
restriction enzyme digestion results in DNA fragments characteristic of
the different alleles. The 2 allele results in fragments 91
and 83 bp long; the 3 allele in fragments 91, 48, and 35 bp
long; and the 4 allele in fragments 72, 48, and 35 bp long. The
38-bp fragment is common in all alleles. Fragments smaller than 35
bp are no longer precisely seen on the gel. The six different
genotypes can be easily determined by the banding pattern of
the allele-specific fragments.
Carotid Duplex Scanning
Color-coded equipment (Diasonics, VingMed CFM 750) was used to
determine atherosclerotic vessel-wall abnormalities of the carotid
arteries. All B-mode and Doppler data were transferred to a
Macintosh personal computer for processing and storage on optical
disks. The imaging protocol involved scanning of both CCA and ICA in
multiple longitudinal and transverse planes and has been previously
described.9 The examinations were performed by one
experienced physician. Image quality was assessed and graded as good
(CCA and ICA clearly visible and ICA detectable over a distance of >2
cm), fair (CCA and ICA sufficiently visible and ICA detectable over a
distance of at least 2 cm), and poor (CCA and ICA insufficiently
visible or ICA detectable over a distance of <2 cm). Three
examinations were of poor quality and were excluded from further
analysis. Measurements of maximal plaque diameter were done in
longitudinal planes, and the extent of atherosclerosis
was graded according to the most severe visible changes in the CCA and
ICA as 0, normal; 1, vessel-wall thickening (>1 mm); 2, minimal
plaque (<2 mm); 3, moderate plaque (2 to 3 mm); 4, severe
plaque (>3 mm); and 5, lumen completely obstructed.
Magnetic Resonance Imaging
MRI was performed on 1.5-T superconducting magnets (Gyroscan S
15 and ACS, Philips) using proton-density and T2-weighted (repetition
time [TR], 2000 to 2500 ms; echo time [TE], 30 to 90 ms) sequences
in the transverse orientation. T1-weighted images (TR, 600 ms; TE, 30
ms) were generated in the sagittal plane. Slice thickness was 5
mm, and the matrix size used was 128x256 pixels. All scans were read
by an experienced investigator without knowledge of the clinical and
laboratory data. The scans were evaluated for WMH and lacunar lesions.
WMH were graded according to our scheme as absent, punctate, early
confluent, and confluent.17 Assessment of intrarater
variability yielded a value of 
=0.9 for WMH grading.18
Caps and periventricular lining were disregarded as they
probably represent normal anatomic variants.19 20
Lacunes were focal lesions involving the basal ganglia, the internal
capsule, the thalamus, or brain stem not exceeding a maximum diameter
of 10 mm. Punctate WMH were not included in the definition of
MARCD because these foci represent a plethora of minimal
cerebral abnormalities that cannot unequivocally be attributed to
cerebral ischemia according to histopathologic
correlations.19
Statistical Analysis
We used the Statistical Package for Social Sciences (SPSS/PC+)
for data analysis. Categorical variables among the
different apoE genotypes were compared by
2 test. Assumption of normal distribution for
continuous variables was tested by Kolmogorov-Smirnov statistics.
Comparisons of continuous variables were done with Student's
t test and one-way ANOVA. Multiple logistic regression was
used to assess the relative contribution of apoE genotypes and
vascular risk factors in the presence of MARCD. We
simultaneously entered age; presence of
arterial hypertension, diabetes mellitus, and cardiac
disease; plasma fibrinogen levels; and the apoE genotypes to
create a model of significant MARCD predictors. The selection of
variables other than the apoE genotypes followed a recent
study of Pantoni and Garcia,21 which reviewed previous MRI
studies on risk factors for leukoaraiosis. Odds ratios and 95%
confidence intervals were calculated from the ß coefficients and
their standard errors.
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Results |
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The allele frequencies calculated from the genotypes of the 280 study participants were 0.076, 0.81, and 0.11 for the
2,
3, and 4 allele, respectively. The 2/3, 3/3,
2/4, 3/4, and 4/4 genotypes were noted in 37
(13.2%), 184 (65.7%), 6 (2.1%), 51 (18.2%), and 2 (0.7%) subjects,
respectively. MARCD occurred in a total of 61 study participants
(21.8%). Early confluent and confluent WMH were seen in 49 (17.5%)
and lacunes in 15 (5.4%) individuals. There were 3 subjects (1.1%)
with both types of ischemic brain changes. As can be seen from
Table 1
, subjects with MARCD were older and more
commonly suffered from arterial hypertension than their
counterparts without such brain abnormalities. The frequency of MARCD
varied significantly among participants depending on their apoE
genotype (Table 2). MARCD was twice as commonly
encountered in individuals with the 2/3 than in those with the
3/3 or 3/4 genotype. The small number of subjects
carrying the 2/4 and 4/4 alleles precluded meaningful
statistical analyses of these subsets. One of the 6 individuals
with the 2/4 genotype had lacunar lesions, and 1 of the 2
homozygotes for 4 had confluent WMH. The comparison of demographics,
vascular risk factors, and duplex scanning results among apoE
genotypes is shown in Table 3. As can be seen
from this table, the 2/3 genotype was associated with
significantly lower serum concentrations of total
cholesterol, LDL cholesterol, and apoB. This
group also tended to have less cardiac disease. There were no
between-group differences for duplex scanning results. Overall,
atherosclerotic plaques were noted in 19 (52.8%), 103 (56.6%), and 32
(62.7%) subjects with the 2/3, 3/3, and 3/4
genotypes, respectively (P=.62). When multiple
logistic regression was used to assess the relative contribution of the
apoE 2/3, 3/3, and 3/4 genotypes on MARCD
occurrence, the apoE 2/3 genotype was found to be
significantly and independently associated with these cerebral
abnormalities in addition to age and arterial hypertension
(Table 4). No other putative risk factors were found to
be significantly related to such brain abnormalities.
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Discussion |
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In our study population, the frequencies of apoE alleles were consistent with expected rates in white populations.22 23 This also applied for the rate of early confluent and confluent white matter changes, the most common type of MARCD in current investigation. The Cardiovascular Health Study assessed white matter abnormalities in 3301 elderly subjects and found early confluent and confluent lesions in 14.2% of study participants.24 This is close to the 17.5% rate that we observed. We confirm previous investigations demonstrating that MARCD occurs with advancing age and arterial hypertension.6 17 25 26 27 28 29 The association between such brain abnormalities and presence of the apoE
2 allele is a novel
finding. Histopathologic studies demonstrated that early confluent and confluent white matter abnormalities represent areas of perivascular demyelination, mild to moderate loss of fibers, and gliosis.30 31 32 They commonly contain central lacunes.33 34 Several groups of researchers reported that these changes are associated with arteriolosclerosis,30 31 32 35 with one study describing a strong correlation between vessel-wall thickness and extent of white matter abnormalities, as would be expected if small-vessel disease is involved in the etiology of such lesions.36 The common pathogenetic mechanism and the histological similarities between more extensive WMHs and lacunes prompted us to compile the two types of abnormalities for analysis in the present investigation. Punctate foci in the white matter were not considered because they were seen to include a plethora of parenchymal changes that commonly do not relate to ischemia. Nonischemic histopathologic findings associated with punctate white matter foci are enlarged spaces around arterioles but also around venules.19 30 32 In some cases, even ganglion-cell heterotopia was noted.19
The mechanisms leading to an association between the apoE 2
allele and MARCD are unclear. One of three studies3 4 5
on the role of apoE in stroke also more commonly encountered 2
carriers in patients than in control subjects.5 The
authors suggested potentiation of other cerebrovascular risk factors
rather than a direct deleterious effect of the apoE2 isoform to be the
cause for their observation. In the present study, we show that the
presence of the apoE 2 allele favorably influenced the lipid
profile of study participants and lowered the frequency of cardiac
disease without affecting the rate of arterial hypertension
and diabetes mellitus. Therefore, mechanisms other than risk
factor–dependent ones must be responsible for the increase of MARCD in
elderly persons carrying the 2 allele. Even though we did not
find any association between extracranial carotid
atherosclerosis and the apoE polymorphism, one
cannot exclude that apoE2 exerts a selective atherogenetic effect on
intracranial small vessels. A direct atherogenetic role of apoE2 has
been suggested by previous investigations, showing an
overrepresentation of this isoform associated with lower-limb
atheromatosis in the absence of
dyslipidemia.37 Another explanation for the
higher prevalence of MARCD in individuals with the 2/3
genotype might be 2-related impairment of repair mechanisms,
particularly of remyelination processes. Immunohistochemical studies in
rats have shown that apoE is synthesized and secreted in greatly
elevated amounts during selective demyelination and remyelination,
suggesting that this lipoprotein has a vital function during normal and
pathological turnover of myelin cholesterol in the central
nervous system.38 39 40 41 We know from postmortem studies that
ischemia-related demyelination represents the most
common histopathologic substrate of the type of MRI changes seen in our
study participants.25 26 27 A reparative potential of apoE in
demyelinating diseases is also emphasized by observations in patients
with multiple sclerosis, who have significant apoE elevations in their
cerebrospinal fluid during clinical remission when remyelination
occurs.42 ApoE is thought to participate in the storage of
lipids produced by neuronal damage and in the reutilization of the
stored lipids during regeneration.43 44 It transports
myelin and cell debris lipids to macrophages and probably also
to myelin-producing oligodendrocytes in the vicinity of the
injury.44 Binding of apoE to specific receptors that have
been detected on the surface of macrophages and
oligodendrocytes is essential for these processes.45 Since
apoE 2 binds defectively to these receptors, it may inhibit repair
mechanisms, which ultimately may result in more extensive parenchymal
damage after cerebral ischemia.
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Selected Abbreviations and Acronyms |
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Received October 29, 1996; revision received February 10, 1997; accepted February 25, 1997.
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