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Dutch hereditary cerebral amyloid angiopathy Structural lesions and apolipoprotein E genotype.

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1995;32:134-13 5Brief Communication: Bornebroek et al:
HCHWA-D Lesions and APOE
Dutch Hereditary Cerebral
Amyloid Angiopathy:
Structural Lesions and
Apolipoprotein E Genotype
M. Bornebroek, MD,* J. Haan, M D , PhD,*I
S. G. Van Duinen, MD, PhD,$
M. L. C. Maat-Schieman, MD,”
M. A. Van Buchem, MD, PhD,$ E. Bakker, PhD,S
C. Van Broeckhoven, PhD,*#
and R. A. C. Roos, MD, PhD*
Hereditary cerebral hemorrhage with amyloidosis-Dutch
type is caused by a mutation at codon 693 of the p amyloid precursor protein gene. The disease is clinically characterized by strokes and dementia. In addition to cerebral
plaques, cerebral amyloid angiopathy is the pathological
hallmark. We investigated the correlation between radiological (white matter hyperintensities and focal lesions on
magnetic resonance images) and pathological lesions (cerebrovascular amyloid angiopathy and plaques) and the
apolipoprotein E genotype in patients with the disease.
Twenty-five patients were studied using magnetic resonance imaging, and brain tissue from 8 patients was studied histopathologically. Neither the white matter hyperintensity scores nor the number of focal lesions on
magnetic resonance images were associated with the presence of an ~4 allele. Nor was a correlation found between
the number and type of plaques and the apolipoprotein E
genotype. All patients had severe amyloid angiopathy in
all cortical areas investigated. This study showed that the
apolipoprotein E genotype does not modulate amyloidrelated structural lesions in hereditary cerebral hemorrhage with amyloidosis of the Dutch type.
Bornebroek M, Haan J, Van Duinen SG,
Maat-Schieman MLC, Van Buchem MA,
Bakker E, Van Broeckhoven C, Roos RAC.
Dutch hereditary cerebral amyloid angiopathy:
structural lesions and apolipoprorein E genotype.
Ann Neurol 1997;41:695-698
___From the Departments of *Neurology, $Pathology, $Diagnostic Radiology, and ?Human Genetics, Leiden University Hospital, Leiden;
?Department of Neurology, Rijnland Hospital, Leiderdorp, the
Netherlands; and #Laboratory o f Neurogenetics, Flanders Interuniversity for Biotechnology (VIB), Department of Biochemistry,
Born-Bunge Institute (BBS), University of Antwerp (UIA), Belgium.
Received Aug 28, 1996, and in revised form Oct 18. Accepted for
publication Oct 23, 1996.
Address correspondence to Dr Rornebroek, Department of Neurology, K5Q-97, Leiden University Hospital, P.O. Box 9600, 2300
RC Leiden, the Netherlands.
Copyright 0 1997 by the American Neurological Association
Hereditary cerebral hemorrhage with amyloidosisDutch type (HCHWA-D) is an autosomal dominant
disorder, caused by a mutation at codon 693 of the p
amyloid precursor protein (PPP) gen’e located o n chromosome 21 [ l ] . Cerebral AP amyloid angiopathy
(CAA) in leptomeningeal arteries and cortical arterioles
is the histopathological hallmark of HCHWA-D [2].
In addition, diffuse plaques, plaques with congophilia
and abnormal neurites, and cored plaques have been
found throughout the cortical gray nlatter [3].T h e disease is clinically characterized by strokes and dementia,
and the age at onset ranges from 40 to 65 years [4].
About one third of the patients die a.s a consequence of
their first stroke, whereas others survive for many years
and have recurrent strokes. Dementia often develops
after the first stroke, but in some c:ases it may be the
first symptom of HCHWA-D. The underlying causes
of the phenotypic differences between HCHWA-D patients are nor known.
T h e ~4 allele of the apolipoprotein E gene (apoE,
protein; APOE, gene) is a genetic risk factor for Alzheimer’s disease (AD) [5]. T h e presence of an APOE
~4 allele appears to reduce the age at onset of AD, a
reduction that is probably more marked if subjects are
homozygous for this allele. T h e presence of an APOE
~2 allele, on the other hand, may have a protective effect for AD. Histopathologically, in AD the presence
of one or two APOE ~4 alleles is associated with increased and the ~2 allele with decreased plaque density
[5, 61. CAA and CAA-related hemorrhages are also
more frequent and severe in APOE €4 allele carriers
with AD or sporadic CAA [7, 81.
In H C H W A - D , clinical features, such as age at onset, age at death, occurrence of dementia, and the
number of strokes, are not influenced by the APOE €2
or ~4 allele [9, I 01. However, these clinical parameters
may not be the most valid measures of disease severity.
T h e severity of the disease might be more accurately
reflected by structural lesions such as CAA and
plaques. It is difficult to quantity CAA postmortem,
but it cannot be measured in vivo. Focal lesions reflect
scars of old strokes and more recent hemorrhages including those that produce no clinical symptoms.
Thus, the number of focal lesions could be an indicator of CAA severity in vivo. White matter hyperintensities (WMHs) on magnetic resonance images (MFUs)
of HCHWA-D patients are a first sign of the disease
and are chronically progressive. W M H s are the result
of hypoperfusion of the deep white matter due to stenosis of the long perforating arterioles caused by amyloid angiopathy. They can, therefore, also be an index
of CAA severity [ 1I]. Another indication of disease severity in HCHWA-D may be the type and the number
of A@ plaques in the parenchyma.
In the present study, we investigated the structural
lesions ( W M H s and focal lesions o n MRI and CAA
696 Annals of Neurology Vol 41
No 5
May 1997
and plaques in brain tissue) in H C H W A - D patients, in
relation to the APOE genotype.
Patients and Methods
A total of 31 HCHWA-D patients were studied: 23 with
MRI, 6 by histopathological investigation, and 2 by both
modalities. In all patients, the diagnosis of HCHWA-D was
made by detection of the PPP codon 693 mutation [I].
APOE genotype was determined as described previously [?I.
MRI was performed in 25 mutation carriers (12 men, 13
women; age range, 40-69 years; mean, 52 years). Eighteen
had had one or more strokes, while 7 were presymptomatic
and had not yet had a stroke. Fourteen of the patients had
developed dementia as assessed by neuropsychological examination [ 121. One patient had non-insulin-dependent diabetes mellitus and 2 had hypertension.
MRI was performed on a 1.5-T machine. T 1 - , T 2 - , and
proton densiryweighted images were obtained in the axial
plane. The number of focal lesions (scars of old hemorrhages,
infarctions) was counted and WMHs were scored with a
semiquantitative rating scale based on the one designed by
Scheltens and colleagues [13]. This scale (ranging from 0 to
24) provides a WMH score related to the size and the number of foci in four regions (frontal, temporal, parietal, and
occipital). All scans were analyzed by two radiologists unaware of the clinical symptoms and APOE genotype.
CAA and A P plaques were studied in the brains of 8
HCHWA-D patients (6 men, 2 women). The age of these
patients at death ranged from 42 to 81 years. All had had
one or more strokes and 4 had dementia.
Formaldehyde-fixed and paraffin-embedded tissue of frontal, parietal, and temporal regions of the cerebral cortex was
stained with a Bodian methenamine silver stain [14].In each
6-p,m-thick, nontangential section including all layers of the
cortex, an area of 3.14 mm2 was selected as representing an
average number of plaques. Amyloid angiopathy was rated
semiquantitatively in each section of the cortex as described
[15]. Two observers (S. G. V. D. and M.L. C. M-S.), independently and unaware of the APOE genotype, scored the
CAA and counted the number of plaques without coarse
neuritic changes (diffuse plaques) and the number of plaques
with neuritic changes (other plaques) in these areas.
WMH scores and the number of focal lesions in ~4 carriers
and noncarriers were subjected to multivariate regression
analyses to control for the effect of age.
Of the 25 mutation carriers investigated using MRI,
12 were €4 carriers and 13 had no €4 allele. Distribution of APOE genotype was as follows: ~ 2 1 ~ n3 =
, 1;
€ 2 1 ~ 4n,
2; € 3 1 ~ 3n, = 12; ~ 3 1 ~ n4 ,= 7; € 4 1 ~ 4 ,
n = 3 . Distribution of the APOE genotype and mean
WMH score and number of focal lesions are given in
Table 1. T h e sum score of WMHs did not differ significantly ( p = 0.518) between €4 carriers (mean,
19.5; range, 14-24) and noncarriers (mean, 19.6;
range, 14-24) and was, as expected, significantly cor=I
Table 1. Distribution o f APOE Genotype dnd MRI
Abnormalities in 25 HCHWA-D Patients
No. of Age
Patients (yr)
WMH Score"
No. of Focal
19.7 (14-24)
20.0 (19-21)
20.0 (15-24)
20.7 (14-24)
1.5 (0-5)
5.0 (2-8)
0.8 (0-2)
2.1 (1-5)
"Mean (range).
HCHWA-D = hereditary cerebral hemorrhage with amyloidosisDutch type; WMH = white matter hyperintensiry.
related with age ( p = 0.034) on multivariate analysis
[16]. The sum score of WMHs in patients homozygous for ~4 (n = 3) did not differ from that in patients
heterozygous for ~4 or non-&4 carriers. In patients with
an ~4 allele, the mean number of focal lesions was 1.8
(range, 0-8) and in patients without an ~4 allele 1.6
(range, 0-5). The number of focal lesions was not associated with the presence or absence of an ~4 allele
( p = 0.514) or with age ( p = 0.26) in multivariate
analyses. The MRI of the patient with an &2/&3genotype did not demonstrate less severe WMHs (score, 22)
or a smaller number of focal lesions (3 focal lesions)
than did MRIs of patients without the ~2 allele.
Distribution of the APOE genotype in the 8
HCHWA-D brains studied was as follows: ~ 2 1 ~n3 =
2; ~ 3 1 ~ n3 ,= 3; € 3 1 ~ 4 n, = 3. All 8 brains investigated had severe amyloid angiopathy in all cortical areas (>20 affected vesselslarea). This makes modulation
by APOE genotype impossible to detect, but unlikely.
The number and type of plaques are provided in Table
2 together with APOE genotype and age at death. The
mean number of plaques in a cortical area did not difTable 2. Distribution of the APOE Genotype and
Plaques in 8 HCHWA-D Patients
Age at
carriers 58
No. of Diffuse
No. of Othet
2611 5110
19.5/25.0/25.0 8.3/12.4/6.6
HCHWA-D = hereditary cerebral hemorrhage with amyloidosis-Dutch
type; - = parts of frontal lobe were not available.
fer benveen patients with an €4 allele and those without an ~4 allele. The ~2 allele was not associated with
a lower number of plaques. In 3 patients, other plaques
were found: 1 had an € 3 1 ~ 4 1
, had an €31~3,and 1
had an € 2 1 ~ 3genotype.
The ~4 allele frequency (50%) in the investigated
group of HCHWA-D patients was higher than that in
the general Dutch population (30%), confirming the
finding in our earlier study [3]. The higher €4 allele
frequency can be explained, as all patients are members
of a few large families with a common ancestor. In this
study, we showed that the APOE genotype did not
correlate with the structural lesions, as visualized by
MRI, or with CAA and plaques in the brains of
HCHWA-D patients. These findings extend those of
our earlier studies, which showed no correlation of the
APOE genotype with clinical parameters, such as age at
onset, age at death, occurrence of dementia, and number of strokes "9, 101.
In sporadic CAA as well as in familial and sporadic
AD, the APOE genotype is a strong predictor of the
clinical expression of the disease and the development
of structural lesions, including vascular lesions. The ~4
allele is associated with larger numbers of plaques,
more severe CAA, and the occurrence of hemorrhages
in a dose-dependent manner [6, 171. In addition, there
are indications that vascular lesions (multiple infarcts,
WMHs, hemorrhagic infarcts) in AD are associated
with the ~4 allele 181. Moreover, in patients with vascular dementia without AD pathology, a significantly
higher frequency of the ~4 allele, compared to normal,
is reported [I&].However, the results of studies are inconsistent; a few failed to demonstrate a significant
correlation between the APOE genotype and the burden of the amyloid pathology [13]. These findings indicate that the APOE genotype not only influences
neuronal pathology, but also can probably modulate
vascular changes. In this study of HCHWA-D patients, we found no association between APOE and
amyloid-related structural lesions.
In AD patients with PPP 670/671 and PPP 717
mutations there was no obvious effect of the APOE
genotype on AP accumulation in the brain, although
the number of patients studied was too small to allow
a definite conclusion [2O]. The age at onset, however,
does seem to be influenced by the APOE genotype, ~4
leading to earlier onset ages [20].
We previously suggested two possible explanations
for the lack of influence of APOE genotype on clinical
features of HCHWA-D [9, lo]. First of all, clinical
features may be an invalid measure of disease severity
because superimposed external factors, at least partially,
influence these clinical symptoms. In the present study,
we minimized the influence of external factors by mea-
Brief Communication: Bornebroek et al: HCHWA-D Lesions and APOE
suring structural lesions. Second, it is possible that
apoE has a lower binding affinity for AP when the
codon 693 mutation is present, and therefore may not
influence AP deposition. This study did not, however,
investigate the binding affinity of apoE for AP.
15. Ellis RJ, Olichney JM, Thal LJ, et al. Cerebral amyloid angi-
Financial support was provided by the “Dutch Organisation for Scientific Research ( N W O M.B. project 903.52.124).
We thank Mrs S. de Bruine (Department of Diagnostic Radiology)
for scoring the MRIs and Mr R. Brand (Department of Medical
Statistics, Leiden University) for assistance with the statistical analyses.
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Two paragraphs were omitted from “Mitochondria1
Function in Muscle from Elderly Athletes” by Brierley
and colleagues (Ann Neurol 1997;41:1 14-1 16) The
first two paragraphs under Discussion should read as
In physically fit, health adults, respiratory chain
function did not deteriorate with age. W e recently
reported the same in a large group of sedentary subjects in whom physical activity was carefully controlled [91. This study is the first to use strict subject
selection criteria similar to the SENIEUR protocol
of immunological aging research [ 151 and studied a
unique group of humans-athletes-a
model choice
for determining true aging within skeletal muscle.
Our two studies cast doubt on the significance of
initial reports that respiratory chain function declines dramatically with age in humans [6-81. The
SENIEUR protocol was developed because many
immunological changes seen with age are not due to
age but are secondary to disease. In these earlier
studies, many factors were uncontrolled, and it is
likely that altered physical activity and disease are
responsible. If mitochondria are involved in aging, it
has to be through a more subtle mechanism than a
global decline in respiratory function.
Reference 15 is:
Ligthart GJ, Coberand JX, Fourniers C , et a]. Admission criteria for immunogerontological studies in
man: the SENIEUR protocol. Mech Ageing Dev
1984;28:47-5 5 .
The publisher apologizes for the error.
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dutch, structure, lesions, apolipoprotein, amyloid, hereditary, genotypes, cerebral, angiopathy
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