From the Departments of Neurology (R.N., H.V.V., M.L.C.M.-S., M.B., J.H.,
R.A.C.R.) and Pathology (S.G. v D.), Leiden University Medical Center, Leiden,
Netherlands; Department of Neurology, Rijnland Hospital, Leiderdorp,
Netherlands (J.H.); and Department of Pathology and Laboratory Medicine,
Section of Neuropathology, University of California, Los Angeles Medical
Center (H.V.V.).
Methods—In a previous autopsy study we
semiquantitatively scored CAA-AM in 29 HCHWA-D patients. In the
present study we reviewed clinical charts and autopsy protocols of
these same patients. We investigated whether CAA-AM was associated with
age at death, number of cerebrovascular lesions, duration of clinical
illness, hypertension, and atherosclerosis.
Results—An association was found between CAA-AM and the number of
cerebrovascular lesions (P=0.009). The presence of
microaneurysmal degeneration was most strongly associated with
the number of cerebrovascular lesions (P<0.001). In
addition, we found an association between
atherosclerosis and the CAA-AM score
(P=0.047). Hypertension was not associated with
CAA-AM.
Conclusions—Our findings support previous reports suggesting an
important role of secondary microvascular degenerative changes in
CAA-associated cerebrovascular lesions and suggest an aggravating
effect of systemic atherosclerosis, but not
hypertension, on the evolution of CAA-AM. These findings may be of
relevance to understanding cerebrovascular complications of sporadic or
Alzheimer disease–associated CAA.
The tendency to CAA-associated intracerebral
hemorrhage may be increased by various secondary degenerative
or inflammatory changes of the vessel
wall.5 14 15 16 17 These changes, hereafter referred
to as CAA-associated microvasculopathy (CAA-AM), include
microaneurysms, fibrinoid necrosis, obliterative intimal
changes, perivascular lymphocytic infiltrates, and hyaline
thickening.3 5 16 18 19 The pathogenesis of
CAA-AM is not exactly known but is likely to result from the
replacement of the vascular media by amyloid, leading to
destruction of smooth muscle cells and weakening of the vessel wall.
Hypertension has been suggested as a risk factor for
CAA-AM,7 19 but this is not firmly
established.5 16 18 Other clinical risk factors
for the development of CAA-AM have not been described.
One of the problems in research on CAA is the
heterogeneity of the patients studied. This problem can
be minimized by studying patients with a genetically determined form of
CAA, such as hereditary cerebral hemorrhage with amyloidosis,
Dutch type (HCHWA-D). HCHWA-D is an autosomal dominant
disorder20 21 in which the genetic defect is a
single base mutation at codon 693 of the amyloid ß precursor protein
(ßPP) gene on chromosome 21.22 23 24 This results
invariably in excessive amyloid ß protein deposition in the media and
adventitia of arterioles and arteries in the
leptomeninges and in the cerebral and cerebellar cortex
of affected patients.25 Amyloid ß protein
deposits are also found in the cerebral cortical parenchyma. In
HCHWA-D, the formation of neurofibrillary tangles is minimal and
restricted to the oldest patients.26 Virtually
all affected patients develop intracerebral
hemorrhages and infarcts, and a substantial proportion of them
develop dementia.20 27 28
Recently, we described a high frequency of CAA-AM in patients with
HCHWA-D.17 In the present study we
hypothesize an association of the severity of CAA-AM with (1) the
number of cerebrovascular lesions, age at death, and duration of
clinical illness and (2) systemic vascular disease in the form of
hypertension and atherosclerosis. In addition, we
looked for a possible association of hypertension and
atherosclerosis with the total number of
cerebrovascular lesions, with the age at death, and with duration of
clinical illness of affected patients.
Hypertension was defined as a blood pressure repeatedly exceeding
95 mm Hg diastolic and/or 160 mm Hg
systolic29 or a history of use of
antihypertensive medication. Blood pressure measurements within 1 week
after the onset of stroke were disregarded.30
Pathological indications of hypertension were also investigated and
included cardiomegaly and ventricular
hypertrophy. Cardiomegaly was defined as a heart weight
above the 95th percentile, with sex, body weight, and body height taken
into account.31 Ventricular
hypertrophy was usually stated to be present or absent
in the autopsy protocol. If only left ventricular wall
thickness was stated in the autopsy protocol, ventricular
hypertrophy was defined as ventricular
thickness greater than 14 mm, independent of
sex.31 The presence of
atherosclerosis was most consistently
documented for the aorta, and aortic atherosclerosis
was therefore used as an indicator for the susceptibility of each
patient to develop atherosclerosis. The degree of
atherosclerosis of the aorta was rated in the autopsy
protocol as absent, slight (few atheromatous plaques),
moderate (moderate number of atheromatous plaques, some
confluent and some with ulceration), or severe (many confluent
atheromatous plaques with ulceration), based on the
experience of the pathologist performing the autopsy.
Assessment of CAA-AM was performed in each patient by one of the
investigators (H.V.V.), who was blinded for all the clinical and
pathological parameters (obviously except for
neuropathological changes). All available separate blocks of brain
tissue, a total of 15 to 30 blocks for each patient, were reviewed. The
precise localization from which each block originated was often not
certain, but all the major brain areas were
sampled,17 and regions affected by
hemorrhage or ischemia as well as unaffected areas were
included in the analysis. The methods and interobserver
reproducibility of the CAA-AM rating system have been
described.17 In short, the eight features of
CAA-AM affecting vessel walls that were scored comprised the following:
(1) hyalinization/fibrosis, (2) microaneurysms, (3) chronic
(perivascular lymphocytic) inflammation, (4) perivascular
multinucleated giant cells/granulomatous angiitis, (5)
macrophages/histiocytes within the vessel wall, (6)
vessel wall calcification, (7) fibrinoid necrosis, and (8) mural or
occlusive thrombi (Figure 1
We used Spearman correlation coefficients to assess the correlations
between the different parameters and ANOVA with CAA-AM
score as a grouping factor and age as a covariant to determine
the association between CAA-AM score and indicators of disease severity
corrected for age at death. Differences between hypertensive and
normotensive subjects and differences between absent or slight and
moderate or severe atherosclerosis were
analyzed with the Mann-Whitney U test. Differences
for age at death were analyzed with the unpaired t
test.
Pathological evidence of hypertension was found in 11 patients, 3 of
whom had clinically documented hypertension. Moderate/severe aortic
atherosclerosis was found in 4 patients (Table 1
CAA-AM scores were positively associated with the number of
cerebrovascular lesions (r=0.49, P=0.009) (Figure 2
After correction for age at death, patients with a CAA-AM score of 5 or
higher had more cerebrovascular lesions but not a longer duration of
clinical illness than patients with a CAA-AM score lower than 5 (Table 2
Of all individual histopathologic features of CAA-AM, the total number
of cerebrovascular lesions correlated most strongly with
microaneurysm formation (r=0.66,
P<0.001). After correction for age at death,
microaneurysm formation was still associated with a higher
number of cerebrovascular lesions (ANOVA with age at death as a
covariant: mean±SD, 4.5±1.3 cerebrovascular lesions in the
presence and 2.1±1.4 cerebrovascular lesions in the absence of
microaneurysms; P<0.001). Fibrinoid necrosis was
not significantly correlated with the number of cerebrovascular
lesions.
Hypertensive and normotensive patients had similar CAA-AM scores (Table 3
The four patients with moderate/severe aortic
atherosclerosis had an almost 2.5 times higher CAA-AM
score than the 17 patients with absent or slight
atherosclerosis, a difference that was statistically
significant (Table 3
Recently, we have characterized the frequency and severity of
microscopic features of CAA-AM in 29 autopsy cases of
HCHWA-D.17 We now demonstrate that in HCHWA-D
CAA-AM are associated with the number of cerebrovascular lesions,
duration of clinical illness, and age at death. It could be argued that
patients dying of their first cerebrovascular lesion did not survive
sufficiently long to develop CAA-AM. However, after correction for age
at death, the number of cerebrovascular lesions is still associated
with a higher CAA-AM score. In other words, patients with more severe
CAA-AM also develop a greater number of cerebrovascular lesions before
death than patients with less severe CAA-AM who die at the same age. It
is true that patients with low CAA-AM scores also developed at least
one stroke. This may mean that despite extensive brain sampling at
autopsy, secondary microvascular changes are missed, although they
appeared to be evenly distributed throughout the cerebral hemispheres
in most patients. Another possibility is that in addition to the
development of CAA-AM, CAA initiates other pathways that lead to
cerebrovascular complications. If the latter is the case, CAA-AM may
particularly play a role in the development of recurrent, smaller
cerebrovascular lesions because all patients who died from their first
cerebrovascular complication had low CAA-AM scores.
CAA-AM has previously been described in CAA patients with and without
hemorrhage.5 7 19 39 40
Hemorrhage in the presence of CAA has previously been
associated with cerebral microvascular fibrinoid necrosis in patients
with sporadic CAA, suggesting an important role for this particular
histopathologic feature of CAA-AM in the development of CAA-associated
hemorrhage.15 16 Other studies have
reported small hemorrhages adjacent to cerebral vessels with
hyalinization or microaneurysms.5 18 The
direct correlation between the number of cerebrovascular lesions and
the extent of CAA-AM found in this study confirms the earlier suggested
importance of CAA-AM in the development of CAA-associated
hemorrhage/infarct. In the present study of HCHWA-D, an
association of fibrinoid necrosis and the number of cerebrovascular
lesions was not found (despite extensive brain sampling), as has been
suggested in AD-associated or sporadic CAA.16
Although this microscopic finding was present in six of 29 autopsy
cases, the fibrinoid necrosis "score" did not correlate with any of
the other CAA-AM parameters, nor did it correlate with the
number of cerebrovascular lesions, age at death, or duration of
clinical illness. The CAA-AM type that most strongly correlated with
the number of cerebrovascular lesions was microaneurysm
formation, a microscopic finding also noted by Vonsattel et
al16 to be associated with severe sporadic
CAA.
Atherosclerosis has previously been associated with
AD41 and severe CAA.1
Recently it has been demonstrated that amyloid ß protein may be
internalized by smooth muscle cells via a receptor-mediated lipoprotein
pathway, which suggests that medial amyloid ß protein deposition in
CAA and subendothelial lipoprotein deposition in
atherosclerosis may share some common pathogenetic
mechanisms.42 This is in agreement with the
importance of apolipoprotein E genotype as a risk factor for
CAA.32 33 34 35 We have no evidence that the codon 693
mutation is associated with atherosclerosis. Our
results suggest that CAA-AM may be more severe in HCHWA-D patients who,
in addition to genetically determined CAA, also develop aortic
atherosclerosis. An association of
atherosclerosis with CAA-AM may possibly be explained
by common risk factors and/or common pathogenetic mechanisms. In a
previous study we observed histiocytes in the walls of
hyalinized CAA cerebral microvessels of HCHWA-D
patients17 ; histiocytes are a prominent
histological finding in arterial intimal
plaques characteristic of all stages of
atherosclerosis.43 Thrombus
formation is also seen in both HCHWA-D cerebral
microvasculature17 and overlying complicated
atherosclerotic lesions.43 Aortic
atherosclerosis was not significantly associated with
severity of symptoms (age at death, duration of clinical illness, or
number of cerebrovascular lesions). This may be due to ascertainment
problems or sample size.
We could not demonstrate an association of hypertension with the
severity of CAA-AM. This suggests that the microvasculopathy observed
in CAA may not be caused by hypertension and that hypertension may not
aggravate the formation of CAA-AM in HCHWA-D. This is in agreement with
previous reports for sporadic CAA,16 18 although
in other studies a relationship between hypertension and CAA-AM has
been suggested.7 19 Hypertension would be
expected to be associated with CAA-AM because it has been shown to be
associated with microvascular hyalinization, fibrinoid necrosis, and
microaneurysm formation in cerebral microvessels in patients
and animals without CAA.44 45 46 47 Of these changes,
the latter two have clearly been associated with
intracerebral
hemorrhage.45 48 49 Hypertension was also
not significantly associated with severity of symptoms in HCHWA-D
patients, which is in agreement with earlier
reports.4 5 16 18 38 39 However, it remains
possible that we could not identify a definitive association between
hypertension and CAA-AM or severity of symptoms because of the
unavoidable arbitrary classification of hypertension and ascertainment
problems in a retrospective study.
In conclusion, CAA-AM is a frequent pathological finding in patients
with HCHWA-D. The severity and extent of CAA-AM are associated with the
number of cerebrovascular lesions in a given patient;
microaneurysm formation especially appears to correlate with
the number of cerebrovascular lesions. Moderate or severe aortic
atherosclerosis may be associated with severe CAA-AM,
but we could not demonstrate an effect of aortic
atherosclerosis on age at death, duration of clinical
illness, or the number of cerebrovascular lesions. Hypertension was not
significantly associated with the evolution of CAA-AM or severity of
symptoms.
Received January 29, 1998;
revision received April 27, 1998;
accepted April 27, 1998.
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© 1998 American Heart Association, Inc.
Original Contributions
Microvasculopathy Is Associated With the Number of Cerebrovascular Lesions in Hereditary Cerebral Hemorrhage With Amyloidosis, Dutch Type
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—Microvascular
changes such as microaneurysms and fibrinoid necrosis have been
found in the presence of cerebral amyloid angiopathy (CAA). These
CAA-associated microvasculopathies (CAA-AM) may contribute to the
development of CAA-associated hemorrhages and/or infarcts,
hereafter referred to as "cerebrovascular lesions." Hereditary
cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D) is
an autosomal dominant form of CAA, in which the amyloid angiopathy is
pathologically and biochemically similar to sporadic CAA associated
with aging and Alzheimer disease. To determine the significance
of CAA-AM for CAA-associated cerebrovascular complications, we
investigated the association between CAA-AM and cerebrovascular lesions
in HCHWA-D patients.
Key Words: Alzheimer's disease • amyloid ß protein • cerebral amyloid angiopathy • cerebral aneurysm • cerebral hemorrhage
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Cerebral amyloid
angiopathy (CAA) is characterized by the presence of congophilic
fibrillar deposits in the media and adventitia of meningocortical
arteries and arterioles. The association of CAA with cerebral
hemorrhage is well established.1 2 3 4 5 CAA
is also recognized as one of the pathological hallmarks of
Alzheimer disease (AD).6 7 8 9 In AD,
Down's syndrome, and normal elderly subjects, the amyloid in CAA
consists of fibrillar amyloid ß protein. CAA may be associated with
dementia independent of the parenchymal lesions of
AD3 4 10 and has also been implicated as one of
the causes of multi-infarct dementia.11 12 13
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Each HCHWA-D patient from whom at least 15 blocks of autopsy
cerebral tissue were available in our brain bank was included in this
study. DNA analysis was performed in 13 patients, confirming
the point mutation in each of them. Of the other patients, 7 were
related in the first degree, 7 in the second degree, and 2 in the third
degree to a family member in whom the ßPP 693 mutation has been
confirmed by DNA analysis. All 29 patients showed typical
HCHWA-D neuropathology. The patients in whom no DNA
analysis was performed did not differ, either clinically or
neuropathologically, from patients in whom the diagnosis was confirmed
by DNA analysis. There is negligible room for doubt about the
presence of the ßPP 693 mutation in patients in whom no DNA
analysis was performed because of the unique neuropathological
features of HCHWA-D and the fact that those patients all come from
families with HCHWA-D, which has an autosomal dominant pattern of
inheritance. Clinical and autopsy information was obtained by chart and
autopsy protocol review. Because of the retrospective nature of the
study and the pathological features of old cerebral hemorrhages
and infarcts, a distinction between cerebral hemorrhage and
cerebral infarcts could not always be reliably made. For these reasons
we did not investigate each type of lesion separately but refer to both
of them as "cerebrovascular lesions." The number of cerebrovascular
lesions was defined as the number of visible cerebral
hemorrhages/infarcts documented by CT/MRI and/or described at
macroscopic pathological examination of the brain. Our
definition of a cerebrovascular lesion included lesions shown by
neuroimaging that were not described in the autopsy report because some
of those lesions were almost certainly "pathologically obscured" by
subsequent large hemorrhages. Some older and smaller lesions
diagnosed by neuroimaging during life were very likely to have been
overlooked at autopsy among numerous more recent and larger lesions.
Clinically diagnosed strokes not documented by neuroimaging and not
described in the autopsy protocol were not considered cerebrovascular
lesions in our analysis. This does not necessarily
mean, however, that in the course of those clinical episodes
cerebrovascular lesions did not develop. Neuroimaging was never
performed in some patients or performed many years after the clinical
event occurred in others. Older lesions may have been left undescribed
at autopsy (see above). The majority of cerebral
hemorrhages/infarcts were diagnosed clinically and by
neuroimaging as well as proven at autopsy. 
). Each
histological feature was scored as 0 (absent), 1
(present in 1 to 2 sections), 2 (present in 3 to 5 sections),
or 3 (present in 
6 sections), yielding a total CAA-AM score
ranging from 0 to 24 for each autopsy brain specimen.
View larger version (123K):
[in a new window]
Figure 1. Micrographs show examples of CAA-AM in HCHWA-D
patients. A, Microaneurysm in a meningeal vessel
from a patient with severe CAA. Arrowhead indicates intact component of
artery from which the aneurysm (indicated by arrows) is
presumed to have originated. Note fibrotic thickening of the
aneurysm wall, which (on immunohistochemistry with antibodies
against amyloid ß protein) was shown to contain negligible amyloid
ß protein (hematoxylin-eosin, magnification x175). B,
Cortical vessel demonstrating fibrinoid necrosis (hematoxylin-eosin,
magnification x175 ). C, Small artery with both a parenchymal (left)
and leptomeningeal component (subarachnoid space is on the
right); continuity between the two segments was demonstrated in a
parallel section. The meningeal segment shows extensive stenosing,
fibrosis/hyalinization, and scattered lymphocytes (large arrow) in the
vessel wall. The parenchymal component shows thrombosis, with
surrounding reactive astrocytes (small arrows) in the adjacent brain
parenchyma (periodic acid–Schiff stain, magnification x175).
D, Higher magnification of a congophilic vessel wall. A
multinucleated giant cell is seen immediately adjacent to the amyloid;
arrows highlight the giant cell and represent the junction
between the vessel wall amyloid and the giant cell (hematoxylin-eosin,
magnification x700).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Demographic, clinical, and pathological information and CAA-AM
scores for all patients are presented in Table 1. In all cases the first clinical
presentation of HCHWA-D was a stroke. Eleven patients
(patients 1 to 11, Table 1) died of their first stroke. Five patients
(patients 7 to 11, Table 1) showed evidence of an earlier (clinically
unnoticed) hemorrhage/infarct on CT/MRI and/or at autopsy.
Seventeen patients (patients 12 to 28, Table 1) died after more than
one stroke; in many of these patients imaging (CT/MRI) or autopsy
revealed one or more cerebral hemorrhages/infarcts in addition
to the clinically documented strokes. Only 1 patient (patient 29) did
not die of a stroke; rather, she experienced two strokes, became
severely demented and physically disabled, and died 4 years after the
last stroke from a pneumonia at the age of 81 years. Autopsy showed
multiple old cerebral infarcts and hemorrhages. Seven patients
were clinically diagnosed with one or more cerebral
hemorrhages/infarcts, which were not documented by neuroimaging
and not described in the autopsy protocol (Table 1 and Subjects and
Methods). If neuroimaging could clearly distinguish the type of lesion,
the large majority of cerebrovascular lesions were judged to be
cerebral hemorrhages. Clinical evidence of
hypertension was found in 7 patients (Table 1).
View this table:
[in a new window]
Table 1. Demographic, Clinical, and Pathological Information
and Extent of CAA-AM in HCHWA-D 
).
Macroscopic pathological examination of brain usually confirmed the
cerebrovascular lesions diagnosed clinically and/or with neuroimaging.
All lethal strokes were pathologically judged as major
hemorrhages. In 10 patients, one or more older macroscopic
cerebrovascular lesions were found that could not be related to
documented clinical signs and/or neuroimaging data (neuroimaging either
not performed or lesions not described). In most patients a lesion
defined by us as CAA-AM was present once or twice in some sections
but absent in others (see Subjects and Methods and Vinters et
al17 ). However, if CAA-AM was present in
every section (patients 16, 21, and 29), each section contained a
comparable frequency of CAA-AM lesions. The extent of histiocytic
infiltration, lymphocytic inflammation, hyalinization,
microaneurysm, and thrombus formation were all strongly
intercorrelated (r varying from 0.52 to 0.81 and
P from 0.000 to 0.004). Fibrinoid necrosis did not correlate
with the score of any other feature of CAA-AM. ), age at death
(r=0.50, P=0.006), and duration of clinical
illness (r=0.54, P=0.002). CAA-AM score was most
strongly associated with the number of cerebrovascular lesions combined
with the strokes that were proven only clinically (r=0.57,
P=0.002).
View larger version (15K):
[in a new window]
Figure 2. Association between CAA-AM and number of
cerebrovascular lesions. Spearman correlation coefficient is 0.49
(P=0.009). ). A CAA-AM score of 5 or higher was,
after correction for age at death, also associated with a greater
number of cerebrovascular lesions combined with the number of
exclusively clinically diagnosed strokes (mean±SD, 5.0±2.4 for a
CAA-AM score of 5 or more and 2.6±1.8 for a CAA-AM score lower than 5;
ANOVA, P=0.015).
View this table:
[in a new window]
Table 2. Association of CAA-AM With Indicators of
Disease Severity ). Patients with clinical and/or
pathological signs of hypertension had CAA-AM scores similar to those
of patients in whom none of these signs of hypertension was documented.
None of the three indicators for hypertension used was independently
associated with CAA-AM scores. Hypertension was also not associated
with age at death, disease duration, or the number of cerebrovascular
lesions (Table 3).
View this table:
[in a new window]
Table 3. Association of Hypertension and Atherosclerosis With
Disease Severity and CAA-AM in HCHWA-D ). There was no association found between
atherosclerosis and age at death, duration of clinical
illness, or the number of cerebrovascular lesions (Table 3).
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The cellular mechanisms by which CAA results in degeneration of
the cerebral microvessel wall and stroke are poorly understood.
Apolipoprotein E genotype has been implicated as a risk factor
for the development of CAA and CAA-associated hemorrhage in
sporadic CAA32 33 34 35 but not in
HCHWA-D.36 37 However, clinical or pathological
risk factors for the development of intracerebral
hemorrhage in CAA are not yet determined. Clinical and
pathological evidence of hypertension has been observed in 30% to 52%
of patients with CAA-associated cerebral
hemorrhage.2 3 Hypertension does not seem
to be an important factor in the development of
CAA4 5 18 38 but may increase the tendency toward
CAA-related hemorrhage or
infarcts.3 38
Selected Abbreviations and Acronyms
AD
=
Alzheimer disease
ßPP
=
amyloid ß precursor protein
CAA
=
cerebral amyloid angiopathy
CAA-AM
=
cerebral amyloid angiopathy–associated microvasculopathy
HCHWA-D
=
hereditary cerebral hemorrhage with amyloidosis, Dutch type
Acknowledgments
This study was supported by Internationale Stichting
Alzheimer Onderzoek (ISAO 96506) (Dr Natté). Dr Vinters'
tenure of the Visiting Chair in AD at Leiden University was supported
by Stichting Rotary Leerstoelen. Dr Vinters was further supported by US
Public Health Service grants P01 AG 12435 and P30 AG 10123. We
thank I. Hegeman-Kleinn and C. Welling-Graafland for technical
assistence.
Footnotes
Reprint requests to S.G. van Duinen, MD, PhD, Department of Pathology L1-Q, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, Netherlands.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Ellis RJ, Olichney JM, Thal LJ, Mirra SS, Morris
JC, Beekly D, Heyman A. Cerebral amyloid angiopathy in the brains of
patients with Alzheimer's disease: the CERAD experience, part
XV. Neurology. 1996;46:1592–1596.
4 is associated
with the presence and earlier onset of hemorrhage in cerebral
amyloid angiopathy. Stroke. 1996;27:1333–1337.4 and cerebral hemorrhage
associated with amyloid angiopathy. Ann Neurol. 1995;38:254–259.[Medline]
[Order article via Infotrieve]2 allele in hemorrhage due to cerebral amyloid
angiopathy. Ann Neurol. 1997;41:716–721.[Medline]
[Order article via Infotrieve]4 allele does not influence the
clinical expression of the amyloid precursor protein gene codon 693 or
692 mutations. Ann Neurol. 1994;36:434–437.[Medline]
[Order article via Infotrieve]
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