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Plasma Homocysteine Levels, Cerebrovascular Risk Factors, and Cerebral White Matter Changes (Leukoaraiosis) in Patients With Alzheimer Disease
Eva Hogervorst, PhD;
Helen Mendes Ribeiro, FRCR;
Andrew Molyneux, FRCR;
Marc Budge, FRACP;
A. David Smith, DPhil
Arch Neurol. 2002;59:787-793.
ABSTRACT
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Context The pathogenesis of leukoaraiosis on computed tomographic (CT) scanning
is unknown, but cerebrovascular risk factors for leukoaraiosis show overlap
with those for Alzheimer disease (AD).
Objective To investigate the contribution of cerebrovascular risk factors, in
particular plasma total homocysteine (tHcy), to leukoaraiosis in patients
with AD and controls.
Design Cross-sectional case-control study.
Setting Referral population to a hospital clinic and community volunteers from
the Oxfordshire region in England seen between July 1, 1988, and July 1, 2000.
Participants One hundred thirty-seven AD cases (104 confirmed post mortem) and 277
controls matched for age (mean ± SD, 73 ± 8 years) and sex.
Main Outcome Measures Cerebrovascular risk factors and leukoaraiosis on CT scans of cases
and controls; the odds ratio (OR) of having moderate to severe leukoaraiosis
with higher levels of plasma tHcy and cerebrovascular risk factors such as
age, sex, systolic blood pressure, smoking, diabetes mellitus, and apolipoprotein
E  4 genotype.
Results Leukoaraiosis was more prevalent in AD cases. For a 5-µmol/L increase
in tHcy levels, the OR for leukoaraiosis was 1.40 (95% confidence interval,
1.02-1.91) independent of other risk factors. The distribution pattern of
leukoaraiosis was more marked in the deep white matter than in the periventricular
area in individuals with elevated tHcy levels, particularly in patients with
AD.
Conclusions Higher tHcy levels are an independent risk factor for moderate to severe
leukoaraiosis in individuals with AD and of leukoaraiosis of the deep white
matter in particular. The nature of the relationship between tHcy levels and
leukoaraiosis in AD requires further longitudinal and intervention studies.
INTRODUCTION
LEUKOARAIOSIS,1 or white matter low attenuation,
on computed tomographic (CT) scanning is frequently found in patients with
cerebrovascular disease2 but has also been
associated with dementia severity in Alzheimer disease (AD).3-6
The pathogenesis of leukoaraiosis is probably multifactorial and, at present,
is poorly understood. Cerebrovascular risk factors associated with leukoaraiosis,
such as increased blood pressure (BP), diabetes mellitus, the presence of
the apolipoprotein E (APOE) 4 genotype, and
smoking are also considered to be risk factors for AD.2, 7-11
An increased plasma total homocysteine (tHcy) concentration is a known risk
factor for cerebrovascular disease,12 but moderately
elevated levels of tHcy were also associated with confirmed AD in the Oxford
Project to Investigate Memory and Ageing (OPTIMA).13
Other researchers14-17
have also found that tHcy levels were elevated in individuals with AD compared
with controls.
In the present study, we investigated the association between a variety
of cerebrovascular disease risk factors and leukoaraiosis in patients with
probable or definite AD and in control subjects from the OPTIMA cohort. In
particular, we wanted to test whether elevated levels of tHcy were associated
with leukoaraiosis and whether such an association was independent of other
cerebrovascular risk factors, such as older age, sex, systolic BP (SBP), the
presence of the APOE 4 allele, diabetes mellitus,
and smoking. Older age and hypertension are considered to be the most important
risk factors for leukoaraiosis.11 Although
most studies18-19 have found that
hypertension is a risk factor for leukoaraiosis in patients with AD, one study20 has found the opposite, that is, that lower SBP is
a risk factor. We therefore used SBP as a continuous variable. In a preliminary
study of 195 OPTIMA subjects, the presence of leukoaraiosis was positively
correlated with age, tHcy level, and SBP but not with smoking, vitamin B12 level, total cholesterol level, or the presence of the APOE 4 allele.21 Because cerebrovascular
risk factors are likely to be interrelated, the relative importance of the
individual cerebrovascular risk factors for AD or for leukoaraiosis remains
unclear.2, 8, 22 In
the present study, we used logistic regression to assess the relative contribution
of the individual risk factors to leukoaraiosis in a larger cohort of cases
with AD and controls.
PARTICIPANTS, MATERIALS, AND METHODS
PARTICIPANTS AND CLINICAL INVESTIGATIONS
The OPTIMA is a longitudinal study that started in 1988 and has since
recruited more than 600 elderly participants.13
Patients were usually referred to the OPTIMA by their family physician from
the Oxfordshire region because a dementia syndrome was suspected. Controls
were community-dwelling, self-caring volunteers who (1) were recruited through
lectures or general practices in the Oxfordshire region, (2) were without
objective cognitive impairment (Mini-Mental State Examination score >24) at
first assessment, and (3) were followed for 2 to 7 years to exclude the development
of cognitive dysfunction. Informed consent for all participants and ethical
approval was obtained before the study. All subjects had undergone extensive
medical examination at enrollment, including blood samples, brain scans (CT
or magnetic resonance imaging and single-photon emission CT) and measurements
of cognitive function (with the Cambridge Examination for
Mental Disorders of the Elderly,23 cognitive
section [CAMCOG], and Mini-Mental Status Examination). For the present study,
the first visit by each subject at which a CT scan had been obtained was selected.
We excluded 4 subjects who were younger than 50 years and 8 who had normal-pressure
hydrocephalus. We included 277 controls (35 confirmed post mortem) and 137
patients who had been diagnosed as having "probable" or "definite" AD according
to the National Institute of Neurological and Communicative Disorders and
Stroke and the Alzheimer's Disease and Related Disorders Association criteria.24 Of these, 104 were confirmed post mortem as probable
or definite AD according to the Consortium to Establish a Registry for Alzheimer's
Disease criteria.25 The interrater reliability
of the National Institute of Neurological and Communicative Disorders and
Stroke and the Alzheimer's Disease and Related Disorders Association clinical
criteria was found to be "substantial," and the accuracy and sensitivity of
these criteria (compared with histopathologic criteria) were high.26
LEUKOARAIOSIS
The CT scans were examined independently for leukoaraiosis by 2 radiologists
(H.M.R. and A.M.) who were masked to the clinical diagnosis. The CT scans
were rated for leukoaraiosis in the anterior frontal, posterior frontal, parietal,
and occipital brain areas. Within each area, leukoaraiosis was graded for
severity (ranging from 0 [none] to 3 [severe]) and extent (0 indicates none;
1, periventricular leukoaraiosis; 2, periventricular and deep white matter
leukoaraiosis; and 3, all the white matter involved). For CT examples demonstrating
these gradations, refer to our previous study.27
There was also a separate score for subjects in whom leukoaraiosis in the
deep white matter was more severe than periventricular leukoaraiosis (deep
white matter pattern of 1). These were compared with the other cases in whom
the extent of leukoaraiosis in any area was greater than 0 (none) but deep
white matter leukoaraiosis was not more severe than periventricular leukoaraiosis
(deep white matter pattern of 0). The interrater reliability (weighted  )
for these ratings was substantial on average (varying from 0.63-0.79 over
the different regions). The codes for severity and extent were multiplied
for the scores per area to give leukoaraiosis scores per area, which were
summed to obtain a total leukoaraiosis score.27
CEREBROVASCULAR RISK FACTORS
Plasma tHcy levels were measured in nonfasting samples obtained between
10 AM and noon that had been stored at –70°C by high-performance
liquid chromatography with fluorescence detection28
or by immunoassay with fluorescent polarization.29
Blood pressure was measured with the individual in the supine position. Diabetes
mellitus was coded as 0 (not present) or 1 (present but only if medication
[eg, insulin or other hypoglycemic agent] was prescribed). Smoking was coded
as 0 (never and past smokers) and 1 (current smokers). If the caregiver's
response deviated from the patient's response (in 14 instances), the answer
of the caregiver was used. Apolipoprotein E allele genotyping was performed
using standard methods30 and coded as 0 (no APOE 4 alleles present), 1
(1 APOE 4 allele present), and 2 (2 APOE 4
alleles present).
STATISTICAL ANALYSES
To describe potential differences in demographic and clinical variables
between groups, we performed  2analyses for categorical variables
and t tests (2-tailed, unpaired) for continuous variables
(Table 1).
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Table 1. Differences in Demographic and Clinical Variables Between
Cases and Controls*
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For the purpose of our logistic analyses (to assess which risk factors
predicted the combined severity and extent of leukoaraiosis), we performed
a mean split (mean total leukoaraiosis score was 2.98) and grouped subjects
as 0 (mean score or less, which was overall comparable to none to minimal
leukoaraiosis) vs 1 (which was comparable to moderate to severe leukoaraiosis).
Last, we looked at the association between the risk factors and the
pattern of the leukoaraiosis by comparing risk factors for subjects in whom
leukoaraiosis of the deep white matter was more severe than that of the periventricular
white matter (pattern of 1) to those who had leukoaraiosis but whose deep
white matter was not more affected than the periventricular area (deep white
matter pattern of 0). For these analyses, 2 analyses and logistic
regression were used. All analyses were performed using statistical software
(SPSS version 9.0 for Windows; SPSS Inc, Chicago, Ill) and significance was
set at P<.05.
RESULTS
CHARACTERISTICS OF THE SAMPLE
The demographic and clinical characteristics for the sample are displayed
in Table 1. Cases and controls
were similar in terms of age and sex. The CAMCOG and Mini-Mental State Examination
scores reflect the cognitive impairment and dementia severity of the cases.
RISK FACTORS FOR AD
There were approximately twice as many smokers and 3 times as many APOE 4 allele carriers in the AD group vs the control
group. Similar to our earlier findings, tHcy levels were higher in AD cases
compared with controls. Systolic BP was significantly lower in cases (P<.01), but there was no significant difference in DBP
(P>.16). There was also no significant difference
between groups in the percentage of participants with diabetes mellitus (P>.27).
CT SCAN DATA
As expected, overall extent (Table
2) and severity (Table 3)
of leukoaraiosis were greater in cases. The overall total leukoaraiosis score
(severity x extent) was also significantly higher in cases than in controls
(Table 1). Of cases, 78% had a
score that was higher than the overall mean total leukoaraiosis score (of
2.98) compared with 20% of the controls. There was only a small difference
in the number of cases who had periventricular leukoaraiosis only compared
with controls. However, cases were 3.5 times more likely than controls to
have a pattern in which leukoaraiosis of the deep white matter was more severe
than that of the periventricular area (Table 1).
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Table 2. Extent of Leukoaraiosis in Different Brain Areas in Cases
and Controls*
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Table 3. Severity of Leukoaraiosis in Different Brain Areas in Cases
and Controls*
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CORRELATIONS OF THE INDIVIDUAL CEREBROVASCULAR RISK FACTORS
Spearman rank correlations showed that, overall, total leukoaraiosis
was associated with the APOE 4 genotype (
= 0.12; P<.01), higher levels of tHcy ( =
0.24; P<.001), higher SBP ( = 0.13; P<.01), and being older ( = 0.43; P<.001). Having higher levels of tHcy, in turn, was associated with
a higher SBP ( = 0.17; P<.001), and both
were associated with older age (tHcy level: = 0.31; P<.001, SBP: = 0.15; P<.002).
There was also a trend for women to be more likely to have worse leukoaraiosis
( = 0.09; P = .06). Men, on the other hand,
were more likely to have higher levels of tHcy ( = -0.11; P<.02), possibly in part because smoking was associated
with having higher levels of tHcy ( = 0.14; P<.005),
and men were more likely to be smokers ( = -0.20; P<.02). Having diabetes mellitus was only associated with younger
age in this cohort ( = -0.11; P<.03).
RISK FACTORS FOR LEUKOARAIOSIS IN CASES AND CONTROLS
Table 4 shows that controls
with moderate to severe leukoaraiosis were on average 6 years older than those
who had no or minimal leukoaraiosis. Controls who had moderate to severe leukoaraiosis
were also more likely to have 2 APOE 4 alleles.
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Table 4. Vascular Risk Factors in Controls and Cases With or Without
Leukoaraiosis*
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Cases with moderate to severe leukoaraiosis were on average 9 years
older and had higher levels of tHcy than cases with no or with minimal leukoaraiosis.
In cases with no or minimal leukoaraiosis, the SBP was 8 mm Hg lower than
that of cases with moderate to severe leukoaraiosis, whereas there was no
difference between the SBP for the corresponding groups of controls. None
of the other factors were different (sex, presence of diabetes mellitus, smoking,
and DBP) for cases and controls having moderate to severe leukoaraiosis vs
those with no or minimal leukoaraiosis.
LOGISTIC REGRESSION ANALYSIS OF RISK FACTORS FOR LEUKOARAIOSIS
A summary of the logistic regression analyses is given in Table 5. Overall, the risk for moderate to severe leukoaraiosis
increased by a factor of almost 2 for a 5-µmol/L increase in tHcy levels.
This was independent of age (model 1) and diagnosis (model 2). The risk for
AD cases to have moderate to severe leukoaraiosis was more than 3 times higher
than for controls. When analyses were adjusted for the other cerebrovascular
risk factors (model 3), a 5-µmol/L increase in tHcy levels was associated
with a 40% increase in the risk for moderate to severe leukoaraiosis. None
of the other cerebrovascular risk factors had a significant independent association
with leukoaraiosis.
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Table 5. Summary of the Logistic Regression Analyses*
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We then stratified the analyses for diagnosis. For AD cases, the risk
of moderate to severe leukoaraiosis was a factor of 2 higher for every 5-µmol/L
increase in tHcy levels (odds ratio [OR], 2.01; 95% confidence interval [CI],
1.19-3.39; P<.01). Older age was an independent
risk factor in AD cases (OR, 1.16, 95% CI, 1.08-1.24; P<.001) and controls (OR, 1.12, 95% CI, 1.06-1.18; P<.001) for moderate to severe leukoaraiosis. None of the other
risk factors had a significant contribution to leukoaraiosis in these analyses.
Last, we investigated factors affecting the distribution pattern of
leukoaraiosis by entering all the risk factors simultaneously. Logistic regression
showed that for every 5-µmol/L increase in tHcy levels, the risk of
having a greater degree of deep white matter leukoaraiosis than of periventricular
leukoaraiosis was increased by 70% (OR, 1.70; 95% CI, 1.14-2.52; P = .009). This effect was independent of age (OR, 1.12; 95% CI, 1.05-1.18)
and diagnosis (OR, 3.35; 95% CI, 1.39-8.07). There was also a trend for smoking
to be a risk factor for deep white matter leukoaraiosis (P = .06). None of the other cerebrovascular risk factors had a significant
independent association. We stratified the analyses by diagnosis. For AD cases,
the risk of having deep white matter leukoaraiosis was higher with increased
tHcy levels: for every 5-µmol/L increase in tHcy the OR was 2.18 (95%
CI, 1.26-3.78; P<.01). In AD cases, smokers (OR,
3.87; 95% CI, 1.01-14.88; P<.05) and those who
were older (OR, 1.15; 95% CI, 1.06-1.26; P<.001)
also had increased risk. Older age showed a trend in controls (P = .08), but none of the other risk factors had a significant contribution.
COMMENT
We found that the risk for moderate to severe leukoaraiosis increased
40% for every 5-µmol/L increase in tHcy levels when controlling for
diagnosis and other cerebrovascular risk factors. In addition, moderate to
severe leukoaraiosis was more prevalent in older subjects and was 3 times
more common in AD cases than in age-matched controls. When analyses were stratified
by diagnosis, the risk for moderate to severe leukoaraiosis increased by a
factor of 2 for every 5-µmol/L increase in tHcy levels in cases. In
cases and controls, older age was independently associated with moderate to
severe leukoaraiosis. Leukoaraiosis in the deep white matter was more common
in cases than in controls. In cases, the risk for leukoaraiosis, which was
more profound in the deep white matter than in the periventricular areas,
was also increased by a factor of 2 with every 5-µmol/L increase in
tHcy levels, and, independently, was higher in smokers and in elderly individuals.
Other cerebrovascular disease risk factors, such as APOE 4 genotype, sex, SBP, and diabetes mellitus, did not have an
independent effect on leukoaraiosis in these analyses.
Several aspects of this study need to be discussed in more detail. First,
these data do not necessarily indicate that the association between tHcy and
leukoaraiosis is limited to patients with AD. The reason for not finding a
fitting model for quantified leukoaraiosis in controls may be related to a
floor effect in that there was too little leukoaraiosis, as assessed by CT,
in this group. Magnetic resonance imaging has been found to be more sensitive
for the radiologic detection of white matter changes in healthy elderly individuals.31 Thus, it is possible that with magnetic resonance
imaging, associations of leukoaraiosis with tHcy levels or other variables
would be found in controls.
A second, related point is that the tHcy level, leukoaraiosis, and all
other data were all taken from the subject's first visit, whereas the postmortem
confirmation of AD was from a later date. However, the interval from the first
visit to death was only 2 years on average. In addition, all the cases had
been diagnosed clinically at the first episode as probable AD. None of the
controls converted to the demented group over time, and there were no diagnoses
of dementia in our postmortem confirmed controls. An earlier study26 also showed a high specificity and positive predictive
value (both 92%) for the clinical probable AD diagnoses compared with Consortium
to Establish a Registry for Alzheimer's Disease histopathologic diagnoses
of AD.
A third point for discussion is that the total leukoaraiosis score was
used to assess the quantitative association with tHcy concentration and other
variables. This score was calculated from the extent and severity scores from
each region. It is conceivable that this score was not a good overall measure
(eg, if one patient scored "mild" severity in 3 areas, this would be similar
to "severe" in only one area). We checked post hoc whether this total score
was a valid reflection and found that the correlations between this score
and all the separate scores were high (>0.65).
There are several mechanisms through which tHcy could affect leukoaraiosis.
First, tHcy is thought to be associated with microvascular cerebral disease,
such as vascular endothelial dysfunction.32
Indeed, one study33 assumed that white matter
changes associated with elevated tHcy levels are due entirely to vascular
pathologic mechanisms. Second, tHcy could be a marker for hypomethylation,
which might affect the integrity of myelin.34
Alternatively, tHcy could have direct neurotoxic effects by acting as an N-methyl-D-aspartate agonist.35
In a recent study,36 an N-methyl-D-aspartate antagonist reduced leukoaraiosis in rats. We found
in cases that higher tHcy levels and smoking were independently associated
with having leukoaraiosis of the deep white matter that was more severe than
that of the periventricular area. Leukoaraiosis of the deep white matter may
have a different pathogenesis from that of periventricular white matter. Although
hyperintensity of the periventricular white matter on magnetic resonance imaging
was correlated with age and increasing ventricular dilation, hyperintensity
of the deep white matter was presumed to have ischemic origins in patients
with AD and Lewy body dementia.37 A perfusion
study38 of patients with AD also found that
deep white matter lesions were associated with reduced cerebral blood flow
in the hippocampal region. However, postmortem examination38
of one of their cases showed no ischemic changes in the deep white matter
lesions but instead showed severe loss of myelin and astrocytic gliosis. In
our cohort, a comparison of 10 cases with the lowest and 10 with the highest
total leukoaraiosis scores showed that leukoaraiosis was associated with white
matter pallor histopathologically but was not typical of severe small vessel
disease (Catherine Joachim, MD, unpublished observation, 2001). Which of these
mechanisms might be primarily responsible for the association among tHcy level,
smoking, and leukoaraiosis of the deep white matter remains to be investigated.
We found no association between the 4 allele of APOE and leukoaraiosis, although controls with moderate to severe leukoaraiosis
were more likely to be homozygous for 4 (2 subjects). Other studies39-42 also
did not find an association between APOE genotype
and the presence of leukoaraiosis in demented patients. The latter study42 suggested that having the APOE 4 allele could possibly modify the risk for acquiring dementia
but would not affect pathologic processes thereafter. Similarly, it has been
reported that having an APOE 4 allele combined
with leukoaraiosis rendered a greater risk for dementia (both AD and vascular
dementia), whereas each factor individually was not sufficient.41
In the present study, SBP was on average lower in AD cases than in controls,
but there was no difference for DBP. In addition, SBP was lower in AD cases
without leukoaraiosis (see also Blennow et al18
and Rezek et al19), but AD cases with leukoaraiosis
had SBP values similar to those of controls. The nature of the association
among SBP, AD, and leukoaraiosis is debated (see the beginning of this article)
and probably complex.43 A longitudinal study44 showed that 10 to 15 years before the onset of AD,
BP values were high in cases but then showed a decrease 1 to 2 years before
onset. Dysfunction in central BP autoregulatory mechanisms due to chronic
hypertension could lead to reduction of cerebral blood flow at BP levels considered
normal for normotensive subjects.2 Possibly,
cases with leukoaraiosis actually had a much higher SBP before a drop before
the onset of AD44 and the concomitant dysfunction
in BP autoregulatory mechanisms. Last, in our analyses, SBP was associated
with tHcy level and age but did not have an independent effect on leukoaraiosis
by itself. The possible interactive effects of the individual risk factors
should be investigated in more detail in a future study.
There was a trend for leukoaraiosis to be more severe in women, which
is similar to the findings of other investigators.45
However, men overall had higher levels of tHcy, the main risk factor studied
herein. When investigating the interaction between tHcy level and sex on leukoaraiosis
post hoc, we found that in men with AD, tHcy levels were not associated with
worse leukoaraiosis until levels were greater than 15 µmol/L (tHcy upper
tertile). For women, tHcy was associated with worse leukoaraiosis at lower
levels as well, possibly because older women have lower levels of sex hormones,
such as estradiol, which could counteract some of the detrimental effects
of tHcy on the brain.46
In summary, tHcy level is strongly and independently associated with
moderate to severe leukoaraiosis in patients with AD. In particular, leukoaraiosis
of the deep white matter was associated with high tHcy levels. Level of tHcy
is a potentially modifiable risk factor, and the presence of significant leukoaraiosis
is increasingly recognized as an important correlate of cerebrovascular events,
depression, cognitive decline, and dementia.47-49
Hence, more research is required to further elucidate this association.
AUTHOR INFORMATION
Accepted for publication January 22, 2002.
Author contributions: Study concept and design (Drs Budge and Smith); acquisition of data (Drs Ribeiro and Molyneux); analysis and interpretation of data (Dr Hogervorst); drafting of the manuscript (Dr Hogervorst); critical revision of the manuscript for important
intellectual content (Drs Hogervorst, Ribeiro, Molyneux,
Budge, and Smith); statistical expertise (Dr Hogervorst); obtained funding (Drs Budge and Smith); administrative,
technical, and material support (Drs Ribeiro and Molyneux); study supervision (Dr Smith).
This study was funded by the Blaschko Scholarship (Oxford, England)
(Dr Hogervorst) and by grants from Bristol-Myers Squibb (Princeton, NJ), the
Medical Research Council (Foresight Challenge) (London, England), and the
European Biomed (Brussels, Belgium). Dr Hogervorst is the Margaret Pelly Research
Fellow of Somerville College, Oxford.
We thank Helga Refsum, MD, Per Ueland, MD (Bergen, Norway), and Carole
Johnston (Oxford) for the homocysteine assays and all the patients and volunteers
and past and present members of the OPTIMA team for making this study possible,
in particular, Catherine Joachim, for her neuropathologic expertise.
Corresponding author and reprints: Eva Hogervorst, PhD, Oxford Project
To Investigate Memory and Ageing, Radcliffe Infirmary Trust, Oxford OX2 6HE,
England (e-mail: eva.hogervorst{at}pharm.ox.ac.uk).
From the Oxford Project to Investigate Memory and Ageing, Department
of Pharmacology, University of Oxford and Radcliffe Infirmary (Drs Hogervorst,
Budge, and Smith); the Department of Radiology, John Radcliffe Hospital (Dr
Ribeiro); and the Department of Neuroradiology, Radcliffe Infirmary (Dr Molyneux),
Oxford, England.
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