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Cerebral -amyloid detected by Pittsburgh compound B positron emission topography predisposes to recombinant tissue plasminogen activator-related hemorrhage.

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Ly et al: CAA Predisposes to rt-PA Related Hhemorrhage
Cerebral b-Amyloid Detected
by Pittsburgh Compound B
Positron Emission Topography
Predisposes to Recombinant
Tissue Plasminogen
Activator-Related
Hemorrhage
John V. Ly,1 Christopher C. Rowe,2
Victor L. Villemagne,2 Jorge A. Zavala,1
Henry Ma,1 Graeme O’Keefe,2 Sylvia J. Gong,2
Rico Gunawan,1 Leonid Churilov,1 Tim Saunder,2
Uwe Ackerman,2 Henri Tochon-Danguy,2 and
Geoffrey A. Donnan1,3
Cerebral amyloid angiopathy (CAA) may be an
important predisposing factor for the hemorrhagic
complications of recombinant tissue-type plasminogen
activator (rt-PA) therapy. We studied patients treated
within 3 hours of onset of ischemic stroke with rt-PA
using positron emission tomography to compare
Pittsburgh compound B (PiB) (a cerebral b-amyloid
ligand) retention in those with and without parenchymal
hemorrhage (PH) and normal controls. Neocortical PiB
retention was higher among patients with PH compared
with patients without PH and normal controls,
suggesting underlying CAA as a predisposing factor for
rt-PA–related hemorrhage. This finding may provide an
impetus for the development of a more practical rapid
pretreatment screening technique.
ANN NEUROL 2010;68:959–962
T
he most serious complication of intravenous thrombolysis (recombinant tissue-type plasminogen activator [rt-PA]) in the treatment of acute stroke is intracranial hemorrhage. The pathophysiology of rt-PA–related
hemorrhage is poorly understood. There is increasing circumstantial evidence that cerebral amyloid angiopathy
(CAA) may be a contributing factor.1
N-methyl-[11C]2-(40 -methylaminophenyl)-6-hydroxybenzothiazole positron emission tomography (11C-PiB
PET), has been successfully used to detect b-amyloid deposition in the living human brain with CAA.2,3 Therefore,
we tested in a prospective group of patients who received
rt-PA within 3 hours of stroke onset and age-matched
healthy controls the hypothesis that PiB uptake in rt-PA–
treated ischemic stroke patients with parenchymal hemorrhage (PH) would be increased compared to those without hemorrhage and controls.
December, 2010
Subjects and Methods
Subjects
Patients with ischemic stroke treated with rt-PA within 3 hours
of onset were recruited subject to 11C-PiB PET availability
from the Austin Hospital from February 2005 to October
2007. Selection was controlled to ensure that approximately
50% of the subjects had PH and patients completing imaging
studies were included consecutively. Patients with a history of
previous intracerebral hemorrhage, cerebral infection, severe
head trauma, tumor, brain surgery, or neurodegenerative conditions, including dementia, were excluded.
Age-matched healthy normal controls were randomly
selected from a cohort of subjects participating in the longitudinal Healthy Aging Study at the Mental Health Research Institute of Victoria. The study was approved by the Human
Research Ethics Committee of the Austin Hospital, and all participants gave written consent to participate.
Imaging
All subjects underwent a brain 11C-PiB PET scan and T1-magnetic resonance imaging (MRI) scan for anatomical coregistration only. Stroke patients also had admission and 24-hour posttreatment brain computed tomography (CT) scans.
IMAGING ACQUISITION. PET data were acquired using a
Philips Allegro PET camera with resolution of approximately
4.4mm (full width half maximal). A thermoplastic facemask
was used for head fixation. All subjects underwent a short transmission scan to ensure correct head position and attenuation
correction, followed by injection of 370MBq 11C-PiB and a
dynamic 0–70/90-minute scan.
rt-PA–related hemorrhages were defined according to the
European Cooperative Acute Stroke Study (ECASS) II classification. Here, PH with blood clot in 30% of the infarcted
area with some space-occupying effect and >30% of the
infarcted area with substantial space-occupying effect are
defined as PH1 and PH2, respectively. Hemorrhagic infarct
(HI) is defined as small petechiae with no space-occupying
effect.4,5 Symptomatic intracerebral hemorrhage is defined as
PH associated with an increase of 4 points on the National
Institutes of Health Stroke Score (NIHSS). Ischemic stroke
patients were stratified into those with and without PH (PH1
or PH2) on the post-treatment CT.
From the 1National Stroke Research Institute, Austin Health, University of
Melbourne, Heidelberg Heights, Australia; 2 Department of Nuclear
Medicine, Centre for PET, Heidelberg, Australia; and 3Florey Neuroscience
Institutes, University of Melbourne, Carlton South, Australia.
Address correspondence to Dr Donnan, Director, Florey Neuroscience
Institutes, Level 2, Alan Gilbert Building, University of Melbourne, 161
Barry Street, Carlton South, Victoria 3053, Australia. E-mail: gdonnan@
unimelb.edu.au
Received Jan 13, 2010, and in revised form Apr 19, 2010. Accepted for
publication Apr 30, 2010.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.
22072
959
ANNALS
of Neurology
TABLE: Demographics
Characteristic
Controls, n 5 15
PH, n 5 7
No PH, n 5 8
p
Age, yr
74 (71–76)
77 (71–79)
77 (70–79)
NIHSS
N/A
13 (11–17)
10.5 (8–14)
0.35b
Stroke onset to PET scan, days
N/A
10 (7–14)
11 (9–21)
0.45b
0.63a
Age, National Health Stroke Scale (NIHSS), and days from onset to positron emission tomography (PET) scan of patients with
parenchymal hemorrhage (PH), no PH, and controls, shown as median (interquartile range).
a
Kuskal-Wallis statistic.
b
Mann-Whitney statistic.
N/A ¼ not applicable.
IMAGE ANALYSIS. Distribution volume ratio (DVR) maps
were generated by applying Logan analysis to the dynamic PET
data using the cerebellar cortex as a reference.6,7 MRI and PET
images were coregistered using the automated method from
SPM5 (Statistical Parametric Mapping) software. Regions of interest (ROIs) were defined on individual coregistered MRI
images and included neocortical frontal, parietal, lateral temporal, and occipital regions. The area weighted mean of these
cortical regions was used to define the neocortical PiB DVR.
Areas of infarct were excluded from the analysis. The ROIs
were used to sample the DVR PET images for comparative
analysis between the normal control subjects, and the patients
with and without PH. Lobar to global PiB ratio was also compared between groups. All PiB PET and CT images were analyzed independently and blinded to each other. Similarly, imaging data were analyzed blinded to the clinical details of the
patients and controls.
Statistics
Kuskal-Wallis test was used to determine overall differences
among groups, followed by the Mann-Whitney tests for differences between individual groups (unadjusted) and median
regression (adjusted). To determine the likelihood of a particular individual treated with rt-PA having PH based on neocortical PiB retention, a receiver operator curve (ROC) analysis was
used. The area under the ROC curve ranges from 0.5 to 1.0,
where 0.5 signifies only a random association, whereas an area
of 1.0 suggests a perfect classification.
Results
Fifteen ischemic stroke patients who were eligible for the
study and consecutively studied, together with 15 control
subjects, were recruited. The relatively low number was
mainly due to limited availability of PET scanning time.
None of the ischemic stroke patients had evidence of
hemorrhage on the admission CT scans. Seven had PH
on the post-treatment follow-up scan. Of these, 3 had
PH1 and 4 had PH2. None had a 4-point decline on
the NIHSS and were, therefore, asymptomatic. Of the 8
patients without PH, 2 had HI, and 6 had no hemor960
rhage. The PH patients compared to non-PH patients
were of comparable age and stroke severity (Table 1).
Similarly, there was no significant difference in cardiovascular risk factors between the PH and non-PH patients.
None had hemorrhage outside the ischemic region.
There was a trend of higher neocortical PiB retention
in patients with hemorrhagic transformation overall (ie, PH
or HI) compared to those with no hemorrhage (p ¼ 0.08).
However, when the more stringent definition of PH was
applied, there was a difference in PiB retention between
those with PH (median neocortical DVR, 1.47; interquartile
range [IQR], 1.66–1.44), those without PH (median DVR,
1.33; IQR, 1.38–1.29; p ¼ 0.005), and age-matched controls (median DVR, 1.31; IQR, 1.39–1.20; p ¼ 0.008)
(Figs 1 and 2). Among the non-PH patients, there was no
difference in PiB retention between the 2 patients with HI
and those without HI, nor was there a difference between
non-PH patients and normal controls (see Fig 2). These
findings did not alter significantly when adjusted for age.
The occipital to global ratio of PiB retention did not differ
significantly between PH (0.93; IQR, 0.90–1.04) and nonPH subjects (1.02; IQR, 1.00–1.06; p ¼ 0.20)
ROC curve analysis showed the area under the
curve to be 0.93 (95% confidence interval, 0.78-1.0; p ¼
0.005). A neocortical PiB DVR of 1.43 was the optimal
threshold value for predicting PH on follow-up 24-hour
CT in this group of rt-PA–treated patients, with a sensitivity of 0.86 and a specificity of 0.87.
Discussion
Parenchymal hemorrhage occurs after rt-PA treatment for
ischemic stroke in about 12% of patients.5 In our small
sample, the rate was 46%, reflecting the emphasis in our
subject selection toward patients with PH to explore the
relationship between PiB PET and PH status. The mechanism of rt-PA–related hemorrhage remains poorly
understood. Reperfusion injury may play a major role.8
Although not seen in our subjects, about 20% of rt-PA–
Volume 68, No. 6
Ly et al: CAA Predisposes to rt-PA Related Hhemorrhage
FIGURE 1: A representative Pittsburgh compound B (PiB)
positron emission tomography (PET) image and a corresponding 24-hour follow-up computed tomography (CT)
scan of 2 thrombolysis (tissue-type plasminogen activator)treated right hemisphere ischemic stroke patients with (top)
and without (bottom) parenchymal hemorrhage (PH) are
shown.
related hemorrhages occur outside the area of infarction,9
and may also occur in patients with acute myocardial infarction or pulmonary embolism without cerebral infarction who have received rt-PA,10,11 suggesting that other
underlying intrinsic factors may be responsible.
The major risk factors associated with symptomatic
hemorrhage include age, stroke severity including infarct
size, high serum glucose, diabetes mellitus, congestive heart
failure, lower platelet count, and the presence of leukoaraiosis on CT scan.12–16 Onset to treatment time after
stroke remains an uncertain factor, particularly because this
was not increased between 3 and 4.5 hours in the recent
ECASS III trial.17 However, when the broader definition
of hemorrhagic transformation (HT) is considered, there is
some evidence that after 3 to 6 hours, larger perfusionweighted imaging lesion volume and a higher NIHSS are
all independently associated with a higher HT risk.18 PH
specifically may relate to the biologic effects of tissue plasminogen activator itself and other pre-existing conditions
such as age and possibly CAA.4,5,18 Nevertheless, there is
still no reliable way to select patients according to their
risk profile of hemorrhage.
This is the first study to assess the relationship between
cerebral amyloid burden and post–rt-PA hemorrhage in
patients with ischemic stroke using PiB PET. The advantage
of this approach is the direct in vivo visualization and quantification of cerebral amyloid burden. Although infarct size
December, 2010
was not directly assessed in our patients, and may contribute
to the relationship of neocortical PiB retention and PH, the
stroke severity as measured by NIHSS was similar between
PH and non-PH patients. Importantly, none of our ischemic
stroke patients had a history of dementia, given that this was
an exclusion criterion for study recruitment, and both rtPA–related PH and non-PH groups had similar vascular risk
factors. None of the PH patients had neocortical PiB retention in the range of previous b-amyloid burden for Alzheimer disease (AD) patients.19 Hence, the relative PiB increase
likely reflects either very early AD-related intracerebral accumulation of b-amyloid or underlying asymptomatic CAA in
patients with PH.
Our findings further strengthen existing circumstantial evidence that CAA increases the risk of rt-PA–
related hemorrhage. How CAA predisposes to the risk of
rt-PA–related hemorrhage is uncertain. Matrix metallopeptidase-9 (MMP-9), a protein involved in the breakdown of extracellular matrix, may be a key player in this
complex interaction. In an APP23 CAA transgenic
mouse model, there was a lower hemorrhagic threshold
compared to wild-type mice after thrombolytic therapy.20
This may relate to increased expression of MMP-9 in the
b-amyloid–laden blood vessels, particularly those with
microvascular hemorrhages. Interestingly, MMP-9 has
been associated with both hemorrhagic transformation
and rt-PA–related hemorrhage,21,22 and is upregulated by
rt-PA in stroke patients.21 Both rt-PA– and CAA-related
hemorrhage share similar clinical profiles, including a
predisposition to lobar or superficial regions of the brain,
FIGURE 2: Box plot shows increased neocortical Pittsburgh
compound B distribution volume ratio (DVR) in ischemic
thrombolysis (tissue-type plasminogen activator [tPA])treated patients with parenchymal hemorrhage (PH) compared to non-PH ischemic tPA patients and normal controls.
*Significantly different from non-PH (Mann-Whitney test),
p 5 0.005. †Significantly different from normal controls
(Mann-Whitney test), p 5 0.008.
961
ANNALS
of Neurology
multiple hemorrhages, increasing frequency with age, and
an association with dementia.4,23,24 Postmortem data
documenting the presence of CAA in cases of rt-PA–
related hemorrhage are limited, but in anecdotal rt-PA–
related hemorrhage cases with pathologically proven
CAA, the CAA prevalence is higher than in an agematched unselected population.1
PiB PET may be a reasonable prognostic marker
for PH in rt-PA–treated patients. Although the numbers
were small, the ROC analysis showed sensitivity and
specificity when using the Neocortical DVR cut off of
1.43 for the relationship between PiB retention and
PH. Interestingly, this value closely matches the upper
limit of mean neocortical DVR value of 1.2 6 0.2
(standard deviation) seen in normal healthy controls of a
similar age in a previously published PiB PET imaging
study.19 Although significant, these preliminary data
require confirmation in larger data sets and studies from
other centers. 11C-PiB PET has restricted availability, and
this resulted in relatively low recruitment for this study.
Should our results be substantiated, a more rapid and
practical measure of amyloid burden will be needed for
screening for CAA prior to rt-PA therapy.
Potential Conflicts of Interest
7.
Lopresti BJ, Klunk WE, Mathis CA, et al. Simplified quantification
of Pittsburgh compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med 2005;46:1959–1972.
8.
Jean WC, Spellman SR, Nussbaum ES, Low WC. Reperfusion
injury after focal cerebral ischemia: the role of inflammation and
the therapeutic horizon. Neurosurgery 1998;43:1382–1396; discussion 1396-1397.
9.
Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke 1997;28:
2109–2118.
10.
Gore JM, Sloan M, Price TR, et al. Intracerebral hemorrhage,
cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in
Myocardial Infarction Study. Thrombolysis in Myocardial Infarction, Phase II, pilot and clinical trial. Circulation 1991;83:
448–459.
11.
Kase CS, O’Neal AM, Fisher M, et al. Intracranial hemorrhage after use of tissue plasminogen activator for coronary thrombolysis.
Ann Intern Med 1990;112:17–21.
12.
Saver JL. Hemorrhage after thrombolytic therapy for stroke: the clinically relevant number needed to harm. Stroke 2007;38:2279–2283.
13.
Demchuk AM, Morgenstern LB, Krieger DW, et al. Serum glucose
level and diabetes predict tissue plasminogen activator-related intracerebral hemorrhage in acute ischemic stroke. Stroke 1999;30:34–39.
14.
Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhagic
transformation in patients receiving intra-arterial thrombolysis.
Stroke 2002;33:717–724.
15.
Tanne D, Kasner SE, Demchuk AM, et al. Markers of increased
risk of intracerebral hemorrhage after intravenous recombinant tissue plasminogen activator therapy for acute ischemic stroke in
clinical practice: the Multicenter rt-PA Stroke Survey. Circulation
2002;105:1679–1685.
16.
Palumbo V, Boulanger JM, Hill MD, et al. Leukoaraiosis and intracerebral hemorrhage after thrombolysis in acute stroke. Neurology 2007;68:1020–1024.
17.
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3
to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:
1317–1329.
18.
Thomalla G, Sobesky J, Kohrmann M, et al. Two tales: hemorrhagic transformation but not parenchymal hemorrhage after
thrombolysis is related to severity and duration of ischemia: MRI
study of acute stroke patients treated with intravenous tissue plasminogen activator within 6 hours. Stroke 2007;38:313–318.
19.
Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718–1725.
Nothing to report.
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