Shinshu M ed J, 62⑶ :155〜165, 2014

Long‑term Trial of Corticosteroid Therapy for the Recurrence of Cerebral Amyloid
Angiopathy‑related Hemorrhages:A Case Study Using［11C］BF‑227 Amyloid‑PET
Takuji YASUDE, Kazuko MACHIDA and Shu‑ichi IKEDA
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine

Aim :To clarify a long‑term preventive eﬀect of corticosteroid therapyfor the recurrence of cerebral amyloid
angiopathy (CAA)‑related hemorrhages.
Subjects and methods:Cases consisted of one male and two females, being consistent with the diagnosis of
G3 to G4 in Boston validation criteria of CAA. To detect cerebral Aβamyloidosis, they underwent positronemission tomography combined with a novel amyloid speciﬁc tracer, BF‑227, all showing positive brain
shadow.A 66‑year‑old man (case 1)with a diagnosis of G3 was given an initial dose of prednisolone at 50 mg/
day.The dose was gradually reduced and was tapered oﬀ6 months later,but after the next 6 months cerebral
hemorrhage recurred.He again received similar corticosteroid therapy.A 69 ‑year‑old woman (case 2)with adiagnosis of G3 was given dexamethasone 16 mg/day after suﬀering recurrent cerebral hemorrhages.A week
later dexamethasone was switched to prednisolone 30 mg/dayand the dose of this corticosteroid was gradually
reduced,until being kept at 8 mg/day.Another 75‑year‑old woman (case 3)with a diagnosis of G4 was given
an initial dose of prednisolone at 30 mg/day and the dose of this corticosteroid was gradually reduced and has
been kept at 8 mg/day.
During the observation periods they were evaluated by clinical manifestations and T2 MR images:thetotal area of microbleeds was assessed by computer‑assisted morphometry. After treatment two cases
received a second PET scan and the regional standard uptake value ratio (SUVR)of BF‑227 at the occipital
lobe was compared with the previous one.
Results: Case 1 suﬀered a small hemorrhage in the left frontal lobe at 20 months after receiving thecorticosteroid therapy and steroid pulse therapy was added.During the remaining 33 months he has been freeof cerebral hemorrhages. SUVR in his PET scan showed 2.0 to 2.2 in a 14‑ month follow‑up period and thetotal area of microbleeds extended from 410.2 to 445.5 mm during the 48‑month observation period. Case 2
showed two simultaneous small hemorrhages at 29 months after starting the corticosteroid therapy and her
dose of prednisolone was temporally increased. During the remaining 17 months she has not had any strokes
and SUVR in her PET showed 1.5 to 1.4 in an 18‑month follow‑up period. The total area of microbleeds
extended from 512.5 to 560.8 mm during the 27‑month observation period. Case 3 has been free of cerebral
hemorrhages for 22 months after this corticosteroid therapyand the total area of microbleeds ranged from 152.
5 to 154.1 mm during the 13‑month observation period.
Conclusions:Corticosteroid therapy seems to be clinically eﬀective for the long‑term prevention of recurrences of CAA‑related hemorrhages but current brain image data are inadequate to lead to this conclusion.
This is the ﬁrst report showing that domestically developed BF227 PET scan is useful in visualizing CAA
lesions. Shinshu Med J 62 : 155 ―165, 2014
(Received for publication February 3, 2014;accepted in revised form February 18, 2014)
Key words:cerebral amyloid angiopathy, cerebral hemorrhage, Aβamyloid, corticosteroid,amyloid‑imaging, positron emission tomography

Corresponding author:Shu‑ichi Ikeda
Department of Medicine (Neurology and Rheumatology),

Introduction

Shinshu University School of M edicine, 3‑1‑1 Asahi,
M atsumoto, Nagano 390‑8621, JapanE‑mail:ikedasi＠shinshu‑u.ac.jp

No. 3, 2014

Cerebral amyloid angiopathy (CAA)is caused by
the accumulation of Aβ amyloid ﬁbrils on cere155

Yasude.Machida.Ikeda

brovascular walls and is well known to be a cause ofpatients non‑invasively.

cerebral hemorrhages in the elderly .This disease

Subjects and Methods

manifests as recurrent or multiple simultaneous
subcortical hematomas, occasionally leading to

The subjects were the following three cases who

fatal lobar hemorrhages :in a cohort study of 71

were diagnosed as having probable (G3)or possible

consecutive survivors with CAA‑related hemor-(G4) CAA on the basis of validation of the Boston

rhages,the two‑year cumulative recurrence rate ofcriteria .

this hemorrhage was reported to be 21 percent,indicating a very high risk of recurrence .Addition-

Case Reports

ally, it is noteworthy that CAA‑related hemor-

Case 1 was a 66‑year‑old male when he ﬁrst

rhages can develop in individuals aged around 50

visited us.During the previous 2 years he had gradu-

years .For the prevention oftherecurrenceofCAA‑

allysuﬀered from cognitive decline including speech

related hemorrhages, the usefulness of corticoster-

disturbance and memory loss. He underwent mag-oid was described in a number of reported cases .

netic resonance imaging (MRI)at another hospital,

However,this therapy has not been widelyacceptedwhich showed bilateral white matter degeneration

since there is limited evidence supporting this strat-

with multiple microbleeds, and he was hospitalizedegy.

in March 2008. Cerebral angiography was normal

A recent in vitro studyhas demonstrated that Aβ‑

and revised Hasegawa dementia scale(HDS‑R)was

induced cerebrovascular smooth muscle cell death17 out of 30. He was discharged with oral adminis-

is signiﬁcantly suppressed by dexamethasone . We

tration of cilostazole 200 mg/day but three months

also have reported the postmortem ﬁndings of alater he developed intractable headache and CT

CAA patient treated by corticosteroid in whichshowed two small hematomas in the left parietal

diminishing of the cerebrovascular amyloid deposits

and occipital lobes (Fig. 1A). He was suspected to

was noted in comparison with the previous biopsy

be suﬀering from CAA‑related hemorrhages.Thus,. To address the long‑term preventive

cilostazole was stopped and he was given an initialeﬀect of corticosteroid therapy for CAA‑related

dose of prednisolone at 50 mg/day in August 2008.

hemorrhages we studied three cases with this dis-

The dose of prednisolone was gradually reducedorder by quantitative analyses of brain images in-

and was tapered oﬀ six months later. Six months

cluding positron emission tomography (PET)com-

after from cessation of corticosteroid therapy he［2‑bined with a novel tracer, (11)C‑labeled‑(2‑suﬀered hemorrhages in the left fronto‑parietal［ﬂuoro］
dimethylaminothiazol‑5‑yl］
ethenyl)‑6‑(2‑lobe (Fig. 1B). Prednisolone 40 mg/day was, there-

ethoxy) benzoxazole ［( (11)C］
BF‑227).［(11)C］
BF‑

fore,started again in August 2009 and he was refer-

227 is a tracer having speciﬁc binding to amyloid

red to us:he was 162.3 cm tall and weighted 56.5 kg.

ﬁbrils including Aβamyloid ﬁbrils ,and the useful-His pulse rate was 63 per minute and was regular,

ness of this［(11)C］
BF‑227 amyloid‑PET was previ-

and blood pressure was 135/76 mmHg. His generalously reported for the evaluation of cerebral

condition was good and showed no neurologicalamyloid deposits in patients with Alzheimerʼs dis-

disability.Routine laboratory data were all normal.

and transthyretin‑derived amyloid deposi-

PET with BF227 showed positive shadow mainly intion on myocardium . The present case study

the bilateral occipital lobes (Fig. 2A). Prednisolone

aimed to obtain evidence that corticosteroid ther-was gradually reduced, until being kept at 10 mg/

apy is eﬀective for the prevention of recurrence ofday.In April 2011 he developed slight paresis in the

CAA‑related hemorrhages,paying special attention

right leg and a small hematoma in the left frontal

to the usefulness of［(11)C］
BF‑227 amyloid‑PET inlobe was seen on CT (Fig. 1C). He received anevaluating cerebrovasuclar amyloid deposits inadditional steroid pulse therapy (methylpred-ﬁndingsease

156

Shinshu M ed J Vol. 62

Corticosteroid therapy for CAA‑related hemorrhages

Fig. 1 CT ﬁndings and clinical course of case 1.
A :CT ﬁnding of initial cerebral hemorrhages, B :recurrent cerebral hemorrhage after cessation of prednisolone, C : recurrent cerebral hemorrhage even when taking a small dose of prednisolone. All arrows
indicate hematomas on CT images. Abbreviations:PSL :prednisolone, ICH :intracranial hemorrhage.

Fig. 2 BF227 PET ﬁndings in case 1.
A :before corticosteroid treatment, B :after that. In panel A patchy distribution of increased uptake of a
tracer is seen mainly in frontal and occipital lobes, while in panel B this ﬁnding is less impressive.

No. 3, 2014157

Yasude.Machida.Ikeda

Fig. 3 M RI and CT ﬁndings, and clinical course of case 2.
A :MRI ﬂair image of a subcortical hematoma, B :CT ﬁnding of recurrent cerebral hemorrhage, C :CTﬁndings of two recurrent simultaneous small hemorrhages.All arrows indicate hematomas on MRI and CT
images. Abbreviations:PSL :prednisolone, ICH :intracranial hemorrhage.

nisolone 1 g/day for three days) and his leg weak-

In March she complained of headache and diﬃcultyness improved.Since that event he has been free ofin writing and CT disclosed a small hematoma in

cerebral hemorrhage for 33 months (Fig. 1).

the left frontal lobe (Fig. 3B). In April 2010 she

Case 2 was a 69 ‑year‑old female who had astarted to be treated with dexamethasone 16 mg/

history of cerebral hemorrhages:in M ay 2008 sheday,which was then switched to prednisolone 30

suddenly developed disorientation of time and day,mg/day. The dose of this drug was graduallyand confused communication.M RI at another hospi-

reduced, andhas since been kept at 8 mg/day. She

tal revealed a subcortical hematoma in the rightshowed two simultaneous small hemorrhages at 29

frontal lobe (Fig. 3A). Her symptoms graduallymonths after starting the corticosteroid therapy,

recovered but M RI showed multiple microbleeds inand her dose of prednisolone was temporally in-

the bilateral temporal‑occipital lobes. She wascreased to 30 mg/day (Fig. 3C)and then decreased

referred to us in February 2010.On examination she

to 8 mg/day. During the remaining 17 months she

was 141.0 cm tall and weighted 42.2 kg. Her pulse

has not suﬀered any cerebral hemorrhages.

rate was 67 per minute and was regular, and blood

Case 3 was a 75‑year‑old woman who developed

pressure was 126/80 mmHg. Since she had beencognitive decline two years ago.One year before her

suﬀering from severe osteoarthropathy of the thor-

visit to us she experienced right hemiparesis andacolumbar spine she used a stick when walking.

aphasia. She was transferred to another hospital

Mini‑mental state examination (MMSE)was 18 out

where she was found to have a cerebral hemorrhageof 30 and PET with BF227 showed positive shadow

in her left frontal lobe (Fig. 5A). Although her

in the bilateral temporal‑occipital lobes (Fig. 4A).

motor disability gradually recovered, her cognitive

158

Shinshu M ed J Vol. 62

Corticosteroid therapy for CAA‑related hemorrhages

Fig. 4 BF227 PET ﬁndings in case 2.
A : before corticosteroid treatment, B : after that. Although both panels show patchy distribution of increased uptake of a tracer mainly in frontal and occipital lobes,panel B seems to be more highly visualized.

Fig. 5 BF227 PET and CT ﬁndings, and clinical course in case 3.
A :CT ﬁnding of a left frontal lobe hematoma, B :PET scan showing positive shadow mainly in bilateral
occipital lobes.

No. 3, 2014159

Yasude.Machida.Ikeda

Serial changes of MRI T2 ‑weighted images and calculated values indicating
microbleed area in case 1.
Comparing between panels A and E microbleed‑related lesions have apparently expanded in the latter.
Fig. 6state did not improve. She was, therefore, referred

Quantitative Analysis of Brain Images

to our hospital in November 2011. At examination
she was 148.7 cm and weighted 50.3 kg. Her pulse

A MRI analysis

rate was 72 per minute and was regular, blood

To detect cerebral microhemorrhages or microb-pressure being 128/76 mmHg.Her general condition

leeds T2 ‑weighted M R

was good and she looked apathetic, but lacked any

ployedspeciﬁc neurological deﬁcits. M MSE was 17 out offrom 3 cases. For the three serial photographs in-

30 and M RI showed an abnormal lesion in the leftcluding a large area of the fronto‑tempro‑occipital

frontal lobe, indicating an old hematoma, whilelobes the total area of microbleeds was calculated

microbleeds were barely visible in the temporalby computer‑assisted morphometry with the use oflobes.A regimen of 8 mg of galantamine twice daily

Image J software (NIH, USA) and, the numbers

improved her cognitive function,raising her M MSE

obtained were serially compared before and afterscore to 25 out of 30.Then she underwent PET withcorticosteroid therapy.

BF227, showing marked uptake mainly in parietal

B

and occipital cortical regions (Fig. 6B). She was［(11)C］BF‑227 amyloid‑PET scan was performed

diagnosed as having possible CAA (G4) and wasat the Department of Radiology, Minami‑Tohoku

given an initial dose of prednisolone at 30 mg/dayin

General Hospital, Kouriyama, Fukushima. The

February 2012.The dose of prednisolone was gradu-［(11)C］
BF‑227 PET study was carried out using aally reduced, until being kept at 8 mg/day (Fig. 5).

PET SET‑2400 W scanner (Shimadzu Inc., Tokyo,

She has been free of cerebral hemorrhage for 22

Japan). After intravenous injection of 211‑366 mBqmonths.

of［(11)C］
BF‑227,dynamic serial PET images wereimagery was em-: this imagery was repeatedly obtained(11)C BF‑227 amyloid‑PET analysis

obtained from 20 to 60 minutes with each subjectʼs160

Shinshu M ed J Vol. 62

Corticosteroid therapy for CAA‑related hemorrhages

Fig. 7

Serial changes of MRI T2 ‑weighted images and calculated values indicating

microbleed area in case 2.
The distribution of microbleeds seen on panels A and D is typical for CAA and the number of these lesions
increased at an advanced stage.

eyes closed.The regional standardized uptake value

microhemorrhages ranged from 152.5 to 154.1 mm

ratio (SUVR), which reﬂected the ratio of regional

during the 13‑month observation period (Fig. 8A,

cerebral SUV to cerebellar, was calculated as an

8B). SUVR of amyloid plaque deposition onindex of BF‑277 binding.Actually in Cases 1 and 2,

BF227PET before therapy was 1.44 (Fig. 5B), but

SUVR for amyloid plaque deposition on the tempo-

the next PET scan using this machine could not be

ral‑occipital area was evaluated before treatment

performed because of the Great East Japan Earth-and about a year after that.The study protocol was

quake.

approved by the local ethics committee.
Results
In case 1 the total area of microhemorrhages on

Discussion
CAA usually involves small and medium‑sized
vessels of the cerebral cortex, subcortex, and le-T2 ‑weighted M R images extended from 410.2 toptomeninges

445.5 mm during the 48‑month observation period

only by histopathological examination of brain tis-

(Fig. 6A, 6E)and SUVR in his PET scan showed 2.

sues , but recent advances in brain imaging can

0 to 2.2 in a 14‑month follow‑up period (Fig. 2A,

provide very reliable information on cerebrovas-

2B). In case 2 the total area of microhemorrhages

cular amyloid deposits in living individuals:a CT

extended from 512.5 to 560.8 mm during the 27‑

ﬁnding of intracerebral hemorrhage with a distinc-month observation period (Fig. 7A, 7D)and SUVR

tive cortical‑subcortical distribution is the ﬁrst cluein her PET revealed 1.5 to 1.4 in a 17‑month follow‑

for the possibility of CAA

up period (Fig. 4A, 4B). In case 3 the total area of

becomes more conﬁdent if the patients are aged andNo. 3, 2014

. This ﬁnding can be conﬁrmed

and this suspicion

161

Yasude.Machida.Ikeda

Two panels of MRI T2 ‑weighted images and calculated values indicating
microbleed area in case 3.
There is no signiﬁcant change in microbleed‑related areas between panels A and B.
Fig. 8have no history of hypertension. Next the patients

Among the present three cases 1 and 2 possessedshould undergo M R imaging including a T2 ‑weigh-manymicrobleeds on T2 ‑weighted MR images,theted gradient‑echo sequence. This MR imaging candistribution of which was typical for CAA. Addi-

sensitively disclose deposits of hemosiderin ascrib-

tionally,in these three cases,Aβamyloid deposition

able to previous minor hemorrhages or microb-

on an extensive area of cerebral cortex was in-

leeds.Although microbleeds are associated withdirectly shown by a positive BF‑227 PET scan.The

some neurological conditions such as Binswangerʼsexperience of the use of a PiB PET scan,of course,

disease, traumatic brain injury, or primary angiitis

has revealed that cortical PiB retention is a featureof the central nervous system, they are most fre-

not onlyof Alzheimerʼs disease,but also of function-quently observed in patients with a long history ofally normal aged brain with Aβamyloid deposition,

hypertension or those with CAA . It has been

mild cognitive impairment,CAA and dementia withshown that cortico‑subcortical distribution of mi-

Lewy bodies associated with Alzheimerʼs pathol-crobleeds is diﬀerent between hypertension andogy

CAA, the latter being located mostly in the poste-

these ﬁve brain conditions the clinical histories ofrior half of the brain, with a predilection for the

non‑hypertensive subcortical hemorrhages in ourparietal lobes.Recently,the direct in vivo dem-

three cases strongly suggested that amyloid deposit-

onstration of cerebral Aβ amyloid deposits has

ed as CAA was the dominant source of this BF‑227

become possible using a PET combined with novel

PET signal,ensuring the clinical diagnosis of CAA.

amyloid‑speciﬁc tracers:a Pittsburgh Compound‑

The usefulness of corticosteroid therapy is well

B (PiB)tracer has been used worldwide,while. In considering the diﬀerential diagnosis of

known for CAA‑related inﬂammation: thisour BF‑227 tracer is domestic and has been applied

pathology coexists with CAA and isolated cerebral

for patients with mild cognitive impairment orangiitis

Alzheimerʼs disease , producing very sensitive

angiitis and cerebral amyloid inﬂammatory vas-

detection of Aβ‑derived senile plaque amyloid depo-

culopathy , causing diﬀuse deep white mattersition.

degeneration. However, this therapeutic strategy

162

and is alternatively called Aβ‑related

Shinshu M ed J Vol. 62

Corticosteroid therapy for CAA‑related hemorrhages

was applied to a limited number of cases with CAA‑

disease immunization therapy can signiﬁcantly

derived hemorrhages . In this study we evaluatedreduce the Aβ amyloid plaque burden in thethe long‑term preventive eﬀect of corticosteroid

brain

therapy for CAA‑related hemorrhages in 3 cases.In

regression of cerebrovascular Aβamyloid deposits

case 1 symptomatic hemorrhage occurred 6 months

occurred in a case after corticosteroid treatment

after the cessation of corticosteroid therapy, uponin which proteomic analysis of the crude amyloid

which corticosteroid therapy was restarted and has

fractions isolated from the leptomeningeal vessels

been maintained with a low dose of prednisolone,

in CAA cases disclosed that the quantity and molec-

resulting in an absence of symptomatic cerebral

ular pattern of Aβand its derivatives were clearly

hemorrhages for 33 months.Similarlyin cases 2 anddiﬀerent between the CAA case with and the one

3,freedom from symptomatic cerebral hemorrhages

without corticosteroid treatment . The latterhas been 17 to 22 months respectively with low doseﬁnding suggests that corticosteroid inﬂuences thecorticosteroid therapy. After treatment, SUVR ofturn‑over of constituent amyloid ﬁbril protein

amyloid plaque deposition showed slight changes:it

cerebrovascular walls with Aβ amyloid deposits.

was increased in case 1, but decreased in case 2,

Other actions of corticosteroid are surmised toboth being insigniﬁcant for estimating any altera-

reduce brain edema around hemorrhages,secondar-tion in cerebrovascular amyloid deposits.We quan-

ily decreasing mechanical stress for CAA aﬀectedtitatively examined another CAA‑related brain

vessels with vascular fragility or to suppress CAA‑

lesion, that is, the area of microbleeds on T2 ‑related perivascular inﬂammation

weighted MR imagery. Since visualization of thiscular rupture. However, the detailed molecularlesion is known to be changeable either in diﬀerent

basis for the beneﬁcial eﬀects of corticosteroid on

machines or diﬀerent imaging conditions,we did notthis cerebrovascular amyloid lesion remains un-

use the same machine under similar conditions inclear. To demonstrate the eﬀectiveness of corticos

the series in this study. Even when considering thisteroid therapyfor the prevention of recurrent CAA‑

methodological bias,the lesions involved bymicrob-

related hemorrhages more precisely,further studies

leeds apparently extended in cases 1 and 2,indicat-

including a double‑blind clinical trial on a large

ing that CAA‑related subclinical hemorrhages wor-

scale are required.

sened irrespective of the use of corticosteroid ther-, and we have recently reported thatonleading to vas-

Acknowledgment

apy. In fact cases 1 and 2 experienced one symptomatic attack with small cerebral hemorrhages in

The authors thank Dr. Toshiyuki Saginoya,spite of taking a low dose of prednisolone. On the

Department of Radiology,Minami‑Tohoku Generalbasis of all these ﬁndings it is likelythat corticoster-

Hospital, Kouriyama, Fukushima, for useful com-

oid therapy is clinically eﬀective for the long‑termments on BF227 PET scan.This work was support-

prevention of recurrence of CAA‑related hemor-

ed by a grant from the Intractable Disease Division,

rhages,while the M RI ﬁndings are not supportive of

the Ministry of Health and Welfare, Amyloidosis

our tentative conclusion.

Research Committee, Japan.

It has been shown that in patients with Alzheimerʼ
s
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