Cerebral Hemorrhage With Biopsy-Proved

Amyloid Angiopathy
William H. Yong, MD; Marie E. Robert, MD; Diana Lenard Secor, MS;
Theodore J. Kleikamp, MD; Harry V. Vinters, MD

\s=b\ Clinical, radiological, and immunohistochemical findings in brain biopsy specimens
from six patients with cerebral amyloid angiopathy\p=m-\associated intracerebral hemorrhage were reviewed. Acute clinical presentations included headache, nausea and
vomiting, loss of consciousness, and focal
neurological deficits such as hemiplegia and
blindness. Transient schemic attacks experienced by one patient and referable to one
hemisphere did not indicate impending hemorrhage in that region. Computed tomographic scans revealed acute, irregular, superficial, lobar hemorrhage with occasional
ring enhancement. Immunohistochemical
studies were performed on biopsy specimens using primary antibodies against portions of the Alzheimer A4 (\g=b\-)peptide or \g=g\ x=req-\
trace peptide (the vascular amyloid protein in

f~^ erebral amyloid angiopathy (CAA)

is characterized by the accumula¬
tion of amyloid in the media and adventitia of medium and small arteries, arterioles, and occasionally veins.1,2 It is
responsible for up to 10% of primary,
nontraumatic brain hemorrhages or 1%
of all strokes.3 Cerebral amyloid angio¬
pathy commonly occurs in otherwise
healthy and nondemented persons with¬
out cerebral hemorrhage or infarcts.2
The amyloid in most patients with CAA
Accepted for publication August 1, 1991.
From the Department of Pathology (Drs Yong,

Robert, and Vinters and Ms Secor) and Brain Research Institute (Dr Vinters), UCLA School of
Medicine; and Department of Neurology, St Vincent Hospital and Medical Center, Portland, Ore
(Dr Kleikamp).
Reprint requests to Department of Pathology

(Neuropathology), CHS 18-170, UCLA School of
Medicine, Los Angeles, CA 90024-1732 (Dr
Vinters).

patients with hereditary cerebral hemorrhage with amyloidosis\p=m-\Icelandictype). In all
patients, anti-A4 and anti\p=m-\\g=g\-trace labeled cerebral microvessels. Immunoreactive senile

plaques were few compared with the numbers of stained microvessels. Reactive astro-

cytes in some patients were labeled by both
antiserum samples, suggesting uptake or
production of these proteins by the astrocytes. This study demonstrates the heterogeneous clinical and radiological features of
cerebral amyloid angiopathy\p=m-\relatedbrain
hemorrhage and the value of anti-A4 and
anti\p=m-\\g=g\-trace immunohistochemical study of
biopsy material from patients with suspected
cerebral amyloid angiopathy\p=m-\relatedintraparenchymal bleeding.
{Arch Neurol. 1992;49:51-58)

is virtually identical biochemically to
that found in patients with Alzheimer's
disease (AD) senile or neuritic plaques,
both lesions containing the Alzheimer
A4 or ß-peptide. '~6 Cerebral amyloid an¬
giopathy occurs in over 90% of brains
from patients with AD or senile demen¬
tia of the Alzheimer type (SDAT).6
Thus, understanding the pathophysiological nature of CAA may provide in¬
sights into AD and SD AT7 Cerebral
amyloid angiopathy appears to increase
in extent and severity with age.2 There
are associations between CAA and syn¬
dromes of familial cerebral hemor¬
rhage,8,9 Down's syndrome,1" isolated
cerebral vasculitis,1112 leukoencephalopathy,13" and cerebrovascular malfor¬

mations.1516 Traditionally, CAA has

been diagnosed by staining tissue sec¬
tions with Congo red and viewing them
under polarized light. Recently, im-

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munohistochemical staining with pri¬
mary monoclonal or polyclonal antibod¬
ies to the Alzheimer A4 peptide and to a
peptide related to y-trace or cystatin C
(a protease inhibitor that composes the
microvascular amyloid in hereditary
Icelandic
cerebral
hemorrhage
[HCHWA-I]) has been shown to localize
amyloid in microvessel walls in brain
tissue from appropriate patients.1718 In
this study, we examine the efficacy of
immunohistochemical methods in de¬
tecting CAA in brain biopsy specimens
from six patients with peripheral lobar
cerebral hemorrhages. Clinical and ra¬
diological features of the patients are

emphasized.

SUBJECTS AND METHODS

The charts of six patients who ranged in
age from 54 to 86 years were reviewed with
respect to clinical presentation, age, sex, his¬
tory of hypertension and smoking or other
risk factors for vascular disease, dementia,
neurological and psychiatric symptoms, im¬
aging studies, surgical procedures, treat¬
ment, and outcome. Two of the patients
(cases 1 and 4) were seen and treated at St
Vincent Hospital and Medical Center, Port¬
land, Ore, and four (cases 2, 3, 5, and 6) were
followed up at the UCLA Medical Center.
Initial diagnosis of CAA in biopsy material
(available from all patients) was by Congo
red staining of paraffin sections and examina¬
tion with polarization microscopy. Immuno¬

histochemical (immunoperoxidase) staining
of tissues was carried out utilizing primary
polyclonal antibodies raised against synthet¬
ic peptides representing a 28-amino-acid
fragment from the Alzheimer A4 (ß-) pep¬
tide19,20 or an 18-amino-acid fragment from a
y-trace-like protein initially isolated from ce¬
rebral microvessels of patients with
HCHWA-I.17,21,22 The immunocytochemical
method involved formic acid pretreatment of
brain tissue sections to improve immunola-

'

beling" and a standard avidin-biotin-peroxidase technique for visualization of immunoreactivity. Control sections from all patients
were treated with serum samples preabsorbed with the immunogen to which the
antibody was raised as a measure of antibody
labeling specificity. Sections of AD brain
with widespread parenchymal and microvascular A4 amyloid were immunolabeled with
anti-A4, while paraffin-embedded brain tis¬
sue from patients with HCHWA-I was
stained with anti-y-trace antibody to serve

positive controls and ensure consistent
levels of staining in each run.

Table 1. -Clinical Features of Spontaneous Cerebral Hemorrhage
in Six Patients With CAA*
Location of

Patient

No./Age, HTN/ Dementia
y/Sex Smoker at Onset
1/54/M

?/ +

No

Clinical
Presentation
Loss of con¬

sciousness

(h/oTIAs, R
hemiparesis 1
y?)

Subsequent
Symptoms
Seizures,
dementia,

depression,
blindness,
obtundation

as

2/58/F

Confusion, diffi¬ Memory loss,
culty walking,
irritability,
urinary incon¬
depression,
tinence, apha¬
paranoia
sia, HA, N/V
(h/o depres¬
sion, 38 y)
L hemiparesis,
Seizures, apha¬
HA, N/V, pro¬
sia, L hemi¬
gressive leth¬
paresis, L
argy (h/o
paresthesias

REPORT OF CASES

Table 1 summarizes the clinical features of
all patients, and Table 2 summarizes the histologieal features of the cerebral biopsy spec¬
imens; relevant details of both are presented
below.
CASE 1.—A 54-year-old white man with a
questionable history of mild hypertension
and a two- to three-pack per day smoking
history presented with loss of consciousness
in 1984. In the previous year, he had com¬
plaints of numbness in the right hand and
occasional episodes of dropping objects from
that hand. At that time, a conrouted tomo¬
graphic (CT) scan of the head was negative,
but electroencephalography (EEG) showed
excessive synchronous 2- to 3-Hz slow-wave
activity. He was started on a regimen of
phenytoin sodium, 400 mg/d. He remained
asymptomatic for 4 months and then had an
episode of aphasia followed by a tonoclonic
seizure. Magnetic resonance imaging (MRI)
immediately before this episode demonstrat¬
ed multiple regions in the periventricular and
centrum semiovale regions bilaterally, con¬
sistent with plaques of multiple sclerosis.
Neuropsychological testing was consistent
with organic dementia and depression. In
1987, his symptoms worsened, and MRI re¬
vealed additional small foci of probable demyelination involving the brain stem. The
j)atient then suffered acute confusion and
blindness. Computed tomography revealed a
large hemorrhage in the right occipital and
posterior parietal regions with mass effect.
Cerebral arteriography failed to demon¬
strate an arteriovenous malformation
(AVM) but showed mild atheromatous
change of the cerebral vessels. He showed
mild clinical improvement and in mid-1987
underwent a right temporal lobe biopsy that
revealed CAA.
Postoperatively, the patient was obtunded, and a CT scan demonstrated edema but
no new hemorrhage. Dexamethasone sodium
phosphate was administered, with clinical
improvement. In late 1987, a CT scan re¬
vealed an additional left-sided occijjital lucency. Magnetic resonance imaging in April
1988 revealed multiple serpiginous channels
with high signal intensity in the temporal
region, suggestive of an AVM. In retrospect,
and since an angiogram 1 year earlier had not
shown AVM, this area may have represented
acute hemorrhage in a gyral pattern. His
condition improved slightly until October
1988, when his vision and ability to carry out
activities of daily living deteriorated. Com¬
puted tomographic and MRI scans in Novem¬
ber 1988 demonstrated a right-sided parieto-

3/60/F

Hemorrhages
(Onset/
Surgical
Procedures
Subsequent)
L, R periventric- R temporal
ular/R occipibiopsy
toparietal
R
tem¬
(X2),
poral, L occip¬
ital, R hemi¬
sphere
L frontal biopsy
L, R frontal/
none

R frontal/

R frontal evacu¬
ation of he¬

none

matoma

TIAs with R

hemiparesis
7 y, L hemi¬

Yes

paresis 6 mo)
R frontal, L
HA, confusion,
Confusion, L
ataxia, L hohemiparesis, L cerebellar/L
monymous
paresthesia,
occipital, R
cerebellar
hemianopsia,
memory loss,
L hemiplegia
irritability
(h/o carotid
and peripheral

R frontal biopsy

vascular dis¬

No

5/82/F

ease)
HA, slurred

No change

speech, R
hemiparesis,

L occipital/

L occipital evac¬
uation of he¬

none

matoma

obtundation
6/86/M

No

L hemiparesis,
R parieto-occipi- R parieto-occipiMalaise, N/V,
L homonyataxia, obtun¬
totemporal/
totemporal
mous hemian¬
none
evacuation of
dation, L

hematoma
hemiparesis
opsia
*CAA indicates cerebral amyoid angiopathy; HTN, hypertension; TIA, transient ischemie attack; h/o, history
of; HA, headache; and N/V, nausea and vomiting. Ages are age at onset of first hemorrhage. The periventricular lucencies in patient 1 probably represented infarcted and demyelinated areas.

Table 2.—Immunohistochemical and Microscopic Features
of Hemorrhagic Brain Tissue Associated With CAA*

Staining of

Staining of

Cerebral Microvessels
Case
No.

Congo
Red

Senile Plaques

Anti-7Anti-A4

Trace

Staining of
Astrocytes

Anti-7-

Anti-7-

Anti-A4

Trace

Anti-A4

Trace

CNA

CNA

CNA

CNA

CNA

CNA

*CAA indicates cerebral amyoid angiopathy; CNA, cannot assess. With the minimal amount of brain tissue
sometimes available, ¡mmunolabeled sections did not always contain reactive astrocytes or senile plaques, and
It was therefore not possible to comment on their immunolabeling properties.

occipital hemorrhage (Fig 1, top and center).
Magnetic resonance imaging in April 1989
showed maturation of the parieto-oceijrital
hemorrhage. Following 1 month of increas¬
ing dementia in May 1989, the patient be¬
came acutely unresponsive, and a CT scan
demonstrated an extensive, multilobar right

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hemispheric hemorrhage with substantial
subarachnoid spread (Fig 1, bottom). An
EEG obtained during obtundation revealed
marked abnormalities in the right hemi¬
sphere consisting of focal slowing over the
right frontotemporal regions superimposed
on generalized bilateral slowing. He suffered

Fig 2. —Patient 2. Left, Enhanced computed tomographic scan of a low-density, ring-enhancing,
superficial left frontal lobe lesion. Right, Computed tomographic scan with contrast of a simulta¬
neous hemorrhage in the right frontal lobe. An area of ring enhancement is visible with a central
region of mixed density.

recurrent grand mal seizures refractory to
phenytoin and died 2 months later.
Autopsy (restricted to the brain) revealed

mild atherosclerosis except for a large basilar
artery plaque. The frontal lobes bilaterally

Fig 1. —Patient 1. Top, This T2-weighted mag¬
netic resonance imaging (MRI) image (repeti¬
tion/echo times, 2800/80 ms) demonstrates a
serpiginous lobar lesion of high signal intensity,
representing hemorrhage in the right occipital
region (November 9, 1988). Center, A sagittal
T'-weighted MRI image (600/20 ms) of the right
occipital lesion (same date) demonstrates an
area of high signal Intensity (indicating a chron¬
ic or subacute hemorrhage) surrounding a cen¬
tral region of lesser Intensity. Bottom, Com¬
puted tomographic scan without contrast of a
multilobar right cerebral hemorrhage (May 17,
1989) demonstrating delineation of superior
gyri probably secondary to subarachnoid
Involvement.

demonstrated recent hemorrhage. A recent
3-cm encapsulated hematoma was located at
the left frontotemporal junction. There was
bilateral cortical loss in the temporal regions,
with a resorbed hemorrhagic lesion on the
left. The right parieto-occipital region re¬
vealed a resorbed hemorrhagic cortical le¬
sion that extended to the ventricles. A re¬
sorbed 2-cm hemorrhagic lesion was noted to
the left of the splenium of the corpus callo¬
sum. The ventricular system was dilated,
especially the temporal horns of the lateral
ventricles. A "degenerative vasculopathy"
with extensive amyloid deposition in cere¬
bral cortical leptomeningeal microvessels
was noted. Bilateral infarcts were noted, as
were multiple old and acute microinfarcts of
the cerebellar cortex. Senile plaques were
not as prominent as amyloidotic microvessels
in the neocortex.
CASE 2.—A 58-year-old normotensive
black woman with a 44-pack per year history
of smoking presented in 1984 with a 2- to 3week history of progressive confusion, diffi¬
culty walking, and incontinence. Beginning
at the age of 20 years, she had experienced
episodes of depression requiring prolonged
hospitalization. Treatments had included
electroconvulsive therapy and antipsychotic
medications. She subsequently received the
diagnosis of bipolar disorder with psychotic
features and was also thought to have a
mixed personality disorder. In the 2 years
before the most recent admission, she had
undergone increasing numbers of hospitalizations for major depressive episodes. Two
weeks before admission, gait and speech dif¬
ficulties developed. Two days before admis¬
sion, the patient had nausea, vomiting, and
urinary incontinence. On the day before hos-

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pitalization, a headache developed. A CT
scan of the brain with contrast revealed ringenhancing lesions, one in each frontal lobe,
that were thought to be consistent with ma¬
lignant neoplasia (Fig 2). Results of a leftsided frontal craniectomy with ultrasoundguided needle biopsy revealed CAA, gliosis,
and hemorrhage, but no evidence of malig¬
nant neoplasia. A follow-up CT scan revealed
resolving lesions consistent with prior hema¬
tomas. She continued to have episodes of
depression and experienced increased mem¬
ory loss and irritability. Three years postoperatively, an EEG demonstrated intermit¬
tent, generalized theta wave and
polymorphic delta wave activity consistent
with encephalopathy (toxic, metabolic, or de¬
generative) in the left anterior region. The
EEG changes were not thought to be attrib¬
utable to resolving hematomas.
CASE 3.—A 60-year-old normotensive
white woman with a 25-pack per year smok¬
ing history presented with a 12-hour history
of left-sided hemiparesis in 1988. She had a 9year history of transient ischemie attacks
(TIAs). During the first 7 years, she had had
three TIAs characterized by right-sided fa¬
cial and extremity paresthesias and weak¬
ness. The first two TIAs had also included an

expressive aphasia. Computed tomographic
scanning of the brain was repeatedly normal,
as was a carotid artery duplex scan. Six
months before admission, she suffered a TIA
characterized by left-sided facial and ex¬
tremity paresthesias and weakness, and pos¬
sibly a seizure. Both CT and MRI scans were
normal. On the day before admission, a head¬
ache and episodes of vomiting developed. In

the 12 hours before admission, left-sided
weakness developed as before, but she also
demonstrated a rapidly progressing lethargy
that culminated in a somnolent though painarousable state. A CT scan of the brain re¬
vealed a right frontal lobe hematoma (Fig 3),
which was evacuated. The biopsy material

revealed CAA. Follow-up CT scans revealed
no further hemorrhage. She suffered sei¬
zures postoperatively and was treated with
phenytoin and acetazolamide sodium. Six
months postoperatively, she had continuing
complaints of slurred speech and left-sided
numbness and weakness.
CASE 4.—A 69-year-old white male smok¬
er (two packs per day of unknown duration)
with a history of controlled hypertension and
carotid and peripheral artery disease was
admitted for mental status changes and diffi¬
culties with activities of daily living in 1989.
Four days before admission, headaches de¬
veloped. On the day before admission, he
drove into a parked car. No clear history of
head trauma was obtained. Subsequently,
slight confusion and difficulty with ambulation and dressing developed. On examina¬
tion, he had a left-sided homonymous hemianopsia, a left-sided hemiplegia, and
ataxia.
A right frontal lobe biopsy specimen was
believed initially to be consistent with a ster¬
ile abscess or cerebritis. Subsequent Congo
red staining demonstrated CAA. Postopera¬
tively, he experienced fluctuating mental
status changes with periods of confusion and
disorientation and periodic episodes of left
upper extremity weakness and numbness.
Three months postoperatively, he suffered a
severe episode of acute confusion. He was
given colchicine (0.5 to 1 mg/d), which ap¬
peared helpful in reducing his neurological
deficits for several months. By 1 year postop¬
eratively, he had increasing memory loss and
irritability marked by rage attacks.
CASE 5.—An 82-year-old white woman
was admitted for severe headache, slurred
speech, and right-sided hemiparesis. Her
medical history included intraductal carcino¬
ma in 1987, a history of myocardial infarc¬
tion, and congestive heart failure. Her family
reported that she had had frequent head¬
aches for several years. She did not smoke
and was not hypertensive. She was living
independently at home, where she cared for
her husband. Three months before admis¬
sion, she fell at home and reported minor
aches and pains, which resolved. In Decem¬
ber 1990, she suffered a severe headache,
slurred speech, and a right-sided hemipare¬
sis. A head CT scan demonstrated a large
left-sided occipital subdural and intraparenchymal hematoma with a 1.0-cm shift of midline structures to the right. A subdural and
intraparenchymal hematoma measuring
6.0x4.0x2.0 cm was evacuated, and CAA
was demonstrated in the biopsy material.
Postoperatively, neurological status im¬
proved only minimally. A repeated head CT
scan demonstrated some increased cerebral
edema and continued right shift. Recovery of
neurological function seemed a remote possi¬
bility at the time of manuscript preparation
of this article.
CASE 6.—In January 1991, an 86-year-old
Japanese man with a vague history of cardiac
disease had an episode of malaise, nausea,
and vomiting. He became ataxic and con¬
fused. On examination, he had left-sided he¬
miparesis and was obtunded. A CT scan
without contrast revealed a hemorrhage in
the right parietal and temporal lobes with
extension into the ventricles and a 1-cm midline shift to the left. He underwent a right-

Fig 3. —Patient 3. Computed tomographic scan
without contrast of a superficial frontal lobe
hemorrhage. There is acute hemorrhage with
surrounding edema (low density) and midline
shift.

Fig 4. —Patient 3. Cerebral biopsy specimen
shows abundant acute hemorrhage and thick¬
ened ectatic amyloid-laden microvessels (ar¬
rows) (hematoxylin-eosin,

sided parieto-occipital craniectomy, and the
hematoma was evacuated. Microscopic ex¬
amination showed CAA. Postoperatively, he
was alert and oriented but had a left-sided
homonymous hemianopsia and left-sided he¬
miparesis. A CT scan revealed a largely
evacuated hematoma and decreased midline
shift. On postoperative day 5, pneumonia de¬
veloped. Treatment with antibiotics was fol¬
lowed by return to a fully oriented state after
1 day. He was subsequently transferred to a
rehabilitation facility.
RESULTS

Summary of Biopsy Findings
Brain tissue from all patients demon¬
strated the characteristic light micro¬
scopic features2,6 of CAA, with thick¬

ened, hyaline, eosinophilic vessel walls
(Fig 4). Congo red staining confirmed
the finding in all cases (Table 2). Bielschowsky's (silver) staining in selected
cases

showed a relative lack of senile

(neuritic) plaques compared with large

numbers of amyloidotic microvessels.
Quantisation of this finding was difficult
in view of the relatively small size of
some of the biopsy specimens.
All specimens revealed spongiosis
and inflammatory cells. A frontal lobe
biopsy specimen of patient 3 was re¬
markable for markedly ectatic amyloi¬
dotic vessels (Fig 4). A right frontal lobe
biopsy specimen from patient 4 re¬
vealed focally prominent histiocytes
and clusters of mononuclear cells, pri¬
marily in a perivascular location. Mito¬
ses
seen

(including granular forms) were
among the reactive cells. Some

larger arteries demonstrated fibrous in¬
timai hyperplasia and others showed or-

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200).

ganizing thrombi. Excessive numbers
of thick-walled blood vessels initially
suggested the presence of a vascular

malformation.
Both anti-A4 and anti--y-trace consis¬
tently labeled leptomeningeal and cere¬
bral microvessels in all patients (Fig 5).
The anti-A4 labeled the few plaques ob¬
served, while - -trace did not. The antiA4 and anti-7-trace inconsistently la¬
beled reactive astrocytes (Table 2). In
patient 2, gliosis was prominent, and
strong immunoreactivity for both peptides was observed in numerous astro¬
cytes. In patient 4, reactive astrocytes
were only lightly stained by anti-A4,
while anti-7-trace labeling showed

strong immunoreactivity. Conversely,

in patient 1, anti-7-trace revealed mini¬
mal staining of astrocytes, but anti-A4
reacted strongly. The astrocytes from
patient 6 showed only light staining by
anti-A4.
Rarely, strongly immunostained ves¬
sels (whether reactive for anti-A4 or
-trace) were surrounded by acute hem¬
orrhage (Fig 6, left). Less commonly,
sites of apparent extravasation of blood
from immunoreactive vessels were en¬
countered (Fig 6, right). Large meningeal arteries, when present within the
biopsy material, sometimes showed im¬
munoreactive material largely confined
to their adventitial component (Fig 7).
COMMENT
Clinical Features

The age of the patients with CAAassociated hemorrhage is comparable

Fig 5. —Patient 1. Left, A section of brain biopsy specimen immunostained for Alzheimer A4 peptide demonstrates prominent
staining of media and adventitia (arrow) of a small artery. Note the virtual absence of parenchymal (senile plaque)
immunoreactivity. Center, Another section Immunostained for -y-trace peptide shows intense labeling of the vessel wall. Note
rare astrocytes in the surrounding neuropil that show light cytoplasmic immunostaining (arrow). Right, Leptomeningeal vessels,
immunostained for -y-trace. Note the patchy nature of peptide deposition within the vessel wall. The smaller of the two labeled
vessels shows segments of its wall that do not demonstrate ¡mmunolabeling (arrow) ( 550).

with that of previous reports of CAA, all
indicating that the incidence of this
CAA-related complication increases in
those over 50 years of age.2,3'28,24 Four of
the patients in this study are near or
below the mean ages (male, 71 years;
female, 73 years) of those with CAAassociated hemorrhages.3 No sex pre¬
dominance has been consistently docu¬
mented,3 and there was none in this
small sample. The presentation of CAA
may include nonspecific symptoms such
as headache, nausea, and vomiting in
addition to focal neurological deficits.25
Recurrent hemorrhages often occur.3
One report describes a 58-year-old
woman who suffered a total of eight
strokes.26 In our study, patient 1 ap¬
pears by imaging studies to have had
seven hemorrhagic or ischemie events,
though not all presented clinically as
strokes. Of particular interest is patient
3, who experienced three TIAs refer¬
able to the left cerebral hemisphere
over the course of 7 years and subse¬
quently had a TIA referable to the right
hemisphere. Ultimately, she experi¬
enced hemorrhage in the hemisphere
most recently affected by TIAs. It is
unclear why the hemisphere that first
produced symptoms was not the one in
which clinically significant bleeding
first occurred. Possibilities include two
distinct types of CAA lesion (one more
likely to hemorrhage than the other), or
different rates of evolution in CAA-re-

Fig 6. —Left, Anti-Alzheimer A4 peptide-immunostained section from patient 6 shows labeled
parenchymal and meningeal vessels but virtually no senile plaques. An occasional parenchymal
vessel (arrow) is surrounded by acute hemorrhage (x95). Right, A mlcrovessel from patient 5
shows -y-trace immunoreactivity (arrow) along one portion of its wall, while there is acute
extravasation of blood at its opposite end. Rare labeled astrocytes (arrowhead) are present (AntiA4 and anti-gamma trace immunostaining performed as described in Vinters et al,17 625).
lated lesions. Transient ischemie at¬
tacks referable to CAA have previously
been described,27 and this patient's his¬
tory reinforces this rare origin of TIAs,

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though the mechanism of such TIAs is
not apparent. Microinfarcts or microhe-

morrhages have been suggested as the
cause.8

Radiological Features

Fig 7. —Patient 5. A large meningeal artery (anti--y-trace stain) shows prominent adventitial peptide
(arrows, left) that is not visible in a parallel section (right) stained with adsorbed antibody (see
"Subjects and Methods" section) (left, 625; right, 245).

While Torack2* has reported cerebral
bleeding after and others29 have noted
frequent hemorrhage during neurosurgical procedures, interventions ranging
from biopsy to hematoma evacuation
did not exacerbate intraoperative or
postoperative hemorrhage in our pa¬
tients. A study of 11 patients with CAA
also suggested that neurosurgery may
be safely performed.30 Hypertension is
not believed to be a major risk factor for
CAA-associated hemorrhages, and only
one of the six patients in this study (pa¬
tient 4) had a clear hypertensive histo¬
ry. Four of our patients were normotensive, with diastolic systemic blood
pressures consistently not exceeding
90 mm Hg. There is no statistically sig¬

nificant difference in the incidence of
infarcts or hemorrhages in hyperten¬
sive and nonhypertensive patients who
have CAA associated with AD/SDAT,31
nor is there a correlation between ele¬
vated blood pressure and the presence
of CAA.32
A history of heavy smoking, was pre¬
sent in at least four of six patients. Giv¬
en the advanced age of patients 5 and 6
and their fulminant presentation, an ab¬
sence of smoking history may not reflect
their life experience. In patient 6, smok¬
ing history was not documented at all.
Since smoke toxins are known to dam¬
age blood vessels,3334 it is interesting to
speculate on a possible association be¬
tween smoking and symptomatic forms
of this vasculopathy. In a study of pa¬
tients with "probable AD" by National
Institutes of Health criteria, 37% of fe-

males and 98% of males had used tobac¬
co, but only 10% of those females and
14% of those males were still smoking at
the time of AD onset.35 The mean inter¬
val between smoking cessation and dis¬
ease onset was 18.3 years for women
and 16.6 years for men. Average daily
consumption before cessation of smok¬
ing was 18.2 and 18.8 cigarettes per day,
respectively, and mean use was 32 years
for females and 44 years for males. Since
almost 100% of patients with AD have
CAA, smoking may play a role in this
vasculopathy. Unlike the majority of
those clinically diagnosed with AD, four
of our patients had not stopped smok¬
ing. Caution must be taken in drawing
parallels between the AD smoking
study and our patients, since none of the
patients in our study was given the diag¬
nosis of AD by clinical criteria, and no
independent assessment of CAA was
made in the AD smoking study. A more
extensive and rigorous study on a larger
sample will be necessary to demon¬
strate conclusively an association be¬
tween smoking and CAA.
Patient 2 demonstrated a long history
of depression that appeared to be exac¬
erbated in the period preceding her
CAA-associated hemorrhage, though
whether this represents a truly organic
effect is unclear. It is extremely unlike¬
ly, however, that her initial depression
was due to CAA, since it began at the
age of 20 years, when nonfamilial CAA
is not known to occur.3 Of note is the
information that her daughter also suf¬
fers from depression.

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The radiological features of CAA may
mimic other forms of brain abnormality
that enter into the clinical differential
diagnosis. While it has been suggested
that CAA should be considered in the
differential diagnosis when multiple
subcortical lobar lesions appear in the
normotensive elderly person, in prac¬
tice it may be difficult to distinguish
from other lesions without a biopsy.36
When examined by CT scan without
contrast, CAA hemorrhages tend to be
superficial, lobar, dense when acute and
hypodense when subacute or chronic,
and somewhat irregular, and at times to
show "fingers" or extensions, even into
the subarachnoid space.36"3' Hemor¬
rhages may be multiple, bilateral, and
recurrent. Resolution can result in leu¬
komalacia and localized ventricular dila¬
tation.39 Extension from the cortical and
subcortical areas into the subarachnoid
space appears common, though it does
not usually delineate the gyri, as seen in
Fig 1, bottom. However, pure subar¬
achnoid hemorrhage secondary to CAA
is rare.37,4" Hemorrhage favors the frontoparietal cortex and white matter,
though CAA may predominate in the
parieto-occipital regions.24" While most
CT scan studies of CAA-related hemor¬
rhages have been done without con¬
trast, the few done with contrast indi¬
cate that ring enhancement may
occur.36,38 Filloux and Townsend38 noted
that ring enhancement persisted up to 2
weeks after the first CT scan. Thus,
waiting for a hemorrhagic CAA lesion to
resolve as a means of distinguishing it
from tumor may not be optimal. In par¬

ticular, multiple, peripherally placed
ring-enhancing lesions that would be

consistent with metastatic tumor in an
elderly patient may require biopsy to
rule out the latter possibility. Magnetic
resonance imaging may also be superior
to CT scan in the detection of subacute
or remote

hemorrhage.

Patient 1 demonstrated multiple periventricular
white-matter
lesions
(PWMLs) by MRI that were at first

thought to represent demyelination sec¬
ondary to multiple sclerosis. However,

autopsy revealed old infarcts and hem¬

orrhage related to CAA. Similar MRI
findings of leukoencephalopathy in the
periventricular regions have been noted

in spontaneous and Dutch variants of
CAA.41,42 However, patchy white mat¬
ter lesions may be detected by MRI in
20% to 30% of asymptomatic subjects
and are associated with increased age
and vascular risk factors such as hyper¬
tension, diabetes mellitus, coronary ar¬
tery disease, and TIAs.434·5 While
PWMLs appear to be common in heredi¬
tary cerebral hemorrhage with amyloi-

dosis-Dutch type (HCHWA-D),46 they

appear less commonly in spontaneous
CAA.14* The occurrence of PWMLs has
been attributed to hypoperfusion of the
deep white matter due to stenosis of

long perforating arterioles.14 Periven-

tricular white-matter lesions in
HCHWA-D were not related to demen¬
tia according to Haan et al,46 since de¬
mentia was approximately equally
prevalent in patients with and without
PWML.

Microscopic and Immunocytochemical
Features in Relation to Pathogenesis of CAA
Senile plaque cores in AD and SDAT,
and amyloid in CAA, are composed of a
4200-d molecular weight protein that is
only minimally different.47 This 4200-d
Alzheimer A4 or ß-peptide is cleaved
from a 695-amino acid precursor en¬
coded by a gene on chromosome 21.48~50
In our study, the immunohistochemical
methods used involve polyclonal anti¬
bodies against the C-terminal end of the
Alzheimer A4 precursor molecule. The
site of origin of the A4 precursor mole¬
cule is controversial.6 Some patients
demonstrate exclusive anti-A4 staining
of cortical arteriolar or capillary walls,
and others have strong perivascular
and/or parenchymal immunolabeling. 17,2°
In this study, arterioles, capillaries,
and reactive astrocytes were labeled by
both anti-A4 and anti-7-trace. Colocalization of both types of antibodies has
also been observed in microvessels of
patients with AD.01 The finding of prom¬
inent colocalization within vessel walls
of A4 and 7-trace peptides in this group
of six patients with cerebral hemor¬
rhage supports the view that 7-trace
peptide may be a significant cofactor in
the pathogenesis of bleeding in
CAA.1718"51 Our patients were also of in¬
terest insofar as they usually showed
predominantly or exclusively microvascular deposition of brain amyloid, in this
regard resembling patients with
HCHWA-D, though examination of
more extensive brain tissue may show
that significant amounts of plaque amy¬
loid were also present.
The role of astrocytes in cerebral
amyloidogenesis is unclear. The reac¬
tivity of astroglial cells with anti-A4 and
anti-7-trace antibodies raises the possi¬
bility that these cells are phagocytosing
peptides from the parenchyma, mi¬
crovessels, or perivascular regions. Ini¬
tial production of A4 or cystatin C may
be by other cells. Anti-cystatin C serum
has labeled neurons in neocortical biop¬
sy specimens of patients with cerebral
tumors52 and in postmortem hypothalami.'3 In vitro, human astrocytes have
demonstrated phagocytic potential.54
However, in animal models, adult astro-

cytes do not appear to phagocytose col¬
loidal carbon, though there appears to
be evidence that neonatal astrocytes

have that capability.55"56 Alternatively,
the astroglial cells themselves may be
producing the amyloid peptides. Microglial and astroglial cells are capable
of constitutive secretion of lysozyme
and cystatin C in vitro.57 Interleukin 1
produced by microglial cells stimulates
astrogliosis.58,59 Possibly, the stimulus
for astrocytes to produce glial fibers
may also trigger the increased produc¬
tion of both A4 precursor protein and
cystatin C. Since not all astrocytes were
immunolabeled, there may be either lo¬
cal differences in the quantities of amy¬
loid protein available for phagocytosis
or varying levels of stimulus for the pro¬
duction of amyloid.
In nonhereditary CAA, chronic in¬
flammation may be one starting point
for amyloid formation. The late age at
onset of CAA is consistent with a pro¬

longed exposure to some inflammatory

agent. Since abnormalities of cerebral

microvessels as seen in AVMs or angiitis11'1215·16 are associated with CAA, an
inflammatory agent, in a similar man¬

ner, may change the properties of the
microvessel walls over time to permit qi
amyloidosis. Smoke may be such an
agent, since it is known to cause damage

to-fetal and adult vessels in animal mod¬
els and to adult vessels in humans.83,34,60'61
The blood-borne toxin may stimulate
ameboid microglial cells (which are be¬
lieved to be the primary source of inter¬
leukin 1 in the brain62), macrophages,
and possibly other cells to secrete that
factor. Interleukin 1 produced by mac¬
rophages in the brain or in extracranial
sites may in turn stimulate production
of A4 precursor protein in their respec¬
tive locations. As suggested above, as¬
trocytes may be one source of the pep¬
tides. Under the influence of interleukin
1 or perhaps additional factors, periph¬
eral mononuclear or localized cell wall
proteases may cleave A4 precursor pro¬
tein to form A4. Localized proteolytic
enzymes have been suggested to ex¬
plain the selective distribution of CAA
lesions.68 By postulating a factor similar

to amyloid enhancing factor, a glyco-

peptide that accelerates amyloid depo¬
sition in animal models of systemic amy¬
loidosis,64 and differing local levels of it,
one could explain varying evolutional
rates of CAA and related lesions.
Finally, this study reemphasizes the
importance of carefully examining evac¬
uated nontraumatic cerebral hemato¬
mas, especially from elderly patients, in
an attempt to establish a causative
mechanism for the bleeding.6'' Such ex¬
amination is enhanced by the use of immunohistochemical techniques (such as

Downloaded From: http://archneur.jamanetwork.com/ by a University of Iowa User on 06/21/2015

we have

described) in tissue from appro¬

priately selected patients.

This research was supported in part by US Pub¬
lic Health Service grant R29 NS26312 and P30
AG10123 (Dr Vinters).
A portion of this work was submitted in fulfill¬
ment of senior thesis requirements of the UCLA
School of Medicine (Dr Yong).
Illustrations were prepared by Carol Appleton
and Stephen Kaufman, MS.

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