Impact of point spread function modeling and time-of-flight on myocardial blood flow and myocardial flow reserve measurements for rubidium-82 cardiac PET

ORIGINAL ARTICLE

Impact of point spread function modeling andtime-of-flight on myocardial blood flow andmyocardial flow reserve measurements forrubidium-82 cardiac PET

Ian S. Armstrong, MSc,a Christine M. Tonge, MSc,a and Parthiban Arumugam,

MDa

a Nuclear Medicine, Central Manchester University Hospitals, Manchester, UK

Received Jun 28, 2013; accepted Jan 8, 2014

doi:10.1007/s12350-014-9858-8

Background. Myocardial flow reserve (MFR) obtained from dynamic cardiac positronemission tomography (PET) with rubidium-82 (Rb-82) has been shown to be a useful mea-surement in assessing coronary artery disease. Advanced PET reconstructions with pointspread function modeling and time-of-flight have been shown to improve image quality but alsohave an impact on kinetic analysis of dynamic data. This study aims to determine the impact ofthese algorithms on MFR data.

Methods. Dynamic Rb-82 cardiac PET images from 37 patients were reconstructed withstandard and advanced reconstructions. Area under curve (AUC) of the blood input function(BIF), myocardial blood flow (MBF) and MFR were compared with each reconstruction.

Results. No significant differences were seen in MFR for the two reconstructions. Arelatively small mean difference in MBF data of 111.9% was observed with advanced recon-struction compared with the standard reconstruction but there was considerable variability inthe degree of change (95% confidence intervals of 216.2% to 140.0%). Small systematicrelative differences were seen for AUC BIF (mean difference of 26.3%; 95% CI 217.5% to15.4%).

Conclusion: . MFR results from Rb-82 dynamic PET appear to be robust when generatedby standard or advanced PET reconstructions. Considerable increases in MBF values mayoccur with advanced reconstructions, and further work is required to fully understand this. (JNucl Cardiol 2014)

Key Words: PET/CT imaging Æ coronary blood flow Æ image reconstruction Æ basic science

INTRODUCTION

The benefits of myocardial perfusion imaging with

rubidium-82 (Rb-82) and positron emission tomography

(PET) compared with single photon emission tomogra-

phy (SPECT) have been widely reported.1,2 A key

advantage of Rb-82 cardiac PET is the ability to

measure myocardial blood flow (MBF) at rest and stress

and, consequently, calculate myocardial flow reserve

(MFR)3 with high repeatability and reproducibility

across operators and multi-vendor software.4-6 MFR

has particular value in the detection of multi-vessel or

balanced three-vessel coronary artery disease (CAD)7

and in predicting outcome in patients assessed for

ischaemia.8 However, like attenuation-corrected SPECT

cardiac imaging, Rb-82 cardiac PET is prone to artifacts

due to mis-registration,9 which have been shown to

produce errors in MFR measurements.10 Time-of-flight

(TOF) PET has been shown to potentially offer

increased resilience to mis-registration artifacts.11,12

Furthermore, advanced PET reconstructions with point

spread function (PSF) modeling and TOF have been

Reprint requests: Ian S. Armstrong, MSc, Nuclear Medicine, Central

Manchester University Hospitals, Oxford Road, Manchester, UK;

[email protected]

1071-3581/$34.00

Copyright � 2014 American Society of Nuclear Cardiology.

shown, in many studies, to offer considerable benefits in

FDG oncology studies.13-15 By contrast, the number of

studies that have investigated the impact of these

reconstructions on Rb-82 cardiac PET is far smaller.16-18

These studies do show some benefits but the complete

impact on all aspects, including kinetic analysis, of Rb-

82 cardiac PET has yet to be determined. This is

relevant because it has been shown, in dynamic brain

imaging, that reconstructions with PSF modeling have a

significant impact on the image-derived blood input

function (BIF).19 The BIF is a key factor in the

determination of MBF and changes influence the mea-

surement20 and hence the calculation of MFR. With the

assumption that PSF modeling and TOF reconstructions

should offer advantages in Rb-82 cardiac PET, in terms

of image quality, the rationale of this study was to

determine the impact of these algorithms on MBF and

MFR measurements in Rb-82 cardiac PET.

MATERIALS AND METHODS

Patient study group

Forty consecutive patients referred for assessment of

CAD with Rb-82 cardiac PET were retrospectively selected for

inclusion in this study. All data were fully anonymised before

analysis. After inspection of dynamic data, three patients were

excluded: one for poor myocardial segmentation in the MBF

processing software and two for excessive movement during

the stress acquisition. The remaining 37 patients consisted of

26 males (mean [range] age: 63.1 year [35–90]; mean [range]

weight: 83.4 kg [62–110]); mean [range] body mass index

(BMI): 27.9 [17.5–37.6] kg/m2 and 11 females (mean [range]

age: 61.6 year [50–82]; mean [range] weight: 93.0 kg [74–

116]); mean [range] BMI: 36.5 kg/m2 [27.9–44.4]. There were

8 male and 8 female patients with obese BMI ([30 kg/m2). In

the male patients, 13 were referred with known CAD or

previous myocardial infarction (MI), and 13 with suspicion of

CAD. One female patient was referred with previous MI with

the remaining patients referred with suspicion of CAD. After

seeking advice from the institutional research department,

ethical approval was not deemed necessary for reprocessing of

anonymised retrospective data.

Rb-82 cardiac PET imaging

All patients were asked to abstain from caffeine for

12 hours before imaging. For both rest and stress imaging, all

patients were administered with 1110 MBq (30 mCi) of Rb-82

from a Cardiogen� Sr-82 generator (Bracco Diagnostics). The

rest scan was performed first in all patients. Other studies have

used weight-based protocols for determining the level of

administered activity5,6 but, due to the requirement of the

Cardiogen� generator to perform a calibration for every

change made to the level of administered activity, this was not

logistically feasible. Previous work from our institute showed

that with a fixed 30-mCi dose, minor detector saturation occurs

in less than 1% of all patients.21 Patients underwent pharma-

cological stress with adenosine using 140 lg/kg/min. The total

adenosine infusion lasted 4.5 minutes. For stress imaging, the

Rb-82 infusion began 2.5 minutes after the start of the

adenosine infusion. All images were acquired on a Siemens

Biograph mCT (Siemens Healthcare, Knoxville, US) with

extended 21.6-cm axial FOV and 64 slice CT. The scanner

uses lutetium oxyorthosilicate (LSO) scintillation crystals and

acquires in 3D mode only. For all patients in this study, a

single low-dose CT (0.4 mSv) was acquired prior to the rest

Rb-82 scan and used for attenuation correction of rest and

stress images. A seven minute list mode PET acquisition was

started at the same time as the Rb-82 infusion. All scans were

checked for mis-registration between PET and CT, using a non

attenuation-corrected summed static PET image. If any mis-

registration was evident, a translational adjustment was applied

prior to attenuation-corrected reconstruction. For the dynamic

reconstructions, data were reframed as 1 9 10 second,

8 9 5 second, 3 9 10 second, 2 9 20 second, and 4 9 60

second frames. Any adjustments to PET and CT registration

were applied to all dynamic frames. Dynamic frames were

reconstructed with the department’s standard reconstruction:

3D Ordered Subset Expectation Maximization (OSEM) using

3 iterations, 8 subsets and a 6.5-mm full-width half maximum

(FWHM) Gaussian post-filter, which was specified in the

manufacturer’s recommendations. Data were also recon-

structed with advanced PSF modeling and TOF (PSF?TOF)

reconstruction using 2 iterations, 21 subsets and a 6.5-mm

FWHM Gaussian post-filter. Given the lack of published data

on the use of PSF?TOF reconstruction with Rb-82, the

number of iterations and subsets were chosen based upon

typical parameters that have been used in recent FDG

oncology studies.13 It is noted that the products of iterations

and subsets for the two reconstruction algorithms are different

but this will illustrate the effect of using the two algorithms

with these parameters.

Blood flow analysis

Measurements of MBF and MFR were performed using

syngoMBF (Siemens Healthcare, Oxford, UK). This software

uses a single tissue compartment model for Rb-82 kinetics22

such that tracer concentration in the myocardium over time,

Cm(t), is given as

CmðtÞ ¼ K1e�k2t;

where K1 and k2 are rate constants for myocardial extraction

and clearance, respectively.23 Corrections for myocardial

spillover and partial volume effects (PVE) were applied in the

software. The BIF was measured using a cylindrical volume of

interest, 2-cm diameter and 1.5-cm long, placed in the left

ventricular cavity. To measure activity concentration in the

myocardium, the myocardium was segmented into 15 rings

from apex to base with 36 angular segments in each ring using

the automatic edge detection on the software. Activity con-

centration in each segment was measured using the mean of

pixel values within a region of interest of 1-cm radial thickness

I. S. Armstrong et al. Journal of Nuclear Cardiology�Impact of PSF modeling and TOF on MFR

centered on the middle of the myocardial surface. For each

reconstruction, the area under curve (AUC) of the BIF was

calculated along with measurements of MBF at rest and stress

and MFR (MFR = stress MBF/rest MBF). The ratio of the

blood pool activity concentration measurements for the two

reconstructions were calculated at each time point in the time-

activity curve (TAC) in order to deduce if any differences

occurred at a particular phase of the acquisition. For the BIF

AUC, MBF, and MFR data, ratios were obtained between the

two reconstructions and compared in males and females and

also for patients above and below the mean weight of the study

population (85 kg). The decision to use patient weight instead

of BMI was a result of previous work that showed the impact

of PSF?TOF reconstruction correlated most strongly with

patient weight.18

Statistical testing

Absolute differences in continuous data did not satisfy

Shapiro-Wilk tests for normality (P \ 0.05) and, as such, a

non-parametric Wilcoxon’s signed rank test for paired sam-

ples was performed to determine differences in BIF AUC,

MBF, and MFR. No evidence of non-normality was seen for

the relative percentage differences of BIF AUC, MBF, and

MFR and, as such, Bland-Altman analysis24 was performed

on the relative differences with mean and 95% confidence

intervals (95% CI) being calculated. To determine differences

between the ratios in patient gender and the two weight

groups, a Mann-Whitney U test for unpaired samples was

used. Statistical analysis was performed using StatsDirect

v2.7.8 (StatsDirect Statistical Software, Altrincham, UK). In

all cases, statistical significance was considered for P values

less than 0.05.

RESULTS

BIF area under curve

Figure 1(A) shows the BIF TAC for a single patient

at rest and stress. It can be seen from the plot that the

structure of the TACs are very similar for rest and stress.

Performing the Mann-Whitney test on the BIF AUC for

rest against stress data in either reconstruction showed

no significant difference between the two data sets. As

such, BIF AUC data were analyzed as a single group

irrespective of whether they were from the rest or stress

acquisitions. The plot of the average ratio of individual

TAC points in Fig. 1(B) shows that there is a marked

reduction in the BIF activity concentration in the first

two frames and then a gradual, but increasing, reduction

at the end of the acquisition. Figure 2 shows an example

image of the myocardium at stress and rest obtained

from the two reconstruction algorithms, demonstrating

the location and size of the bloodpool VOI.

The BIF AUC was significantly lower (P \ 0.001)

with PSF?TOF reconstruction compared with OSEM,

with a mean percentage difference of -6.3% (95% CI

-17.5% to ?5.4%), with the Bland-Altman plot shown

in Fig. 3. When analyzing the data according to patient

gender, significant differences were only seen in the

male patients. When comparing the magnitude of

reduction of BIF AUC with PSF?TOF in the male

patients, BIF AUC was 8% lower in the lower weight

group compared with 6% in the upper weight group

(P = 0.037). Table 1 shows the BIF AUC obtained from

the two reconstruction algorithms. Figure 4 shows the

ratios of the BIF AUC obtained from the two recon-

structions for the gender and weight groups.

Myocardial blood flow and flow reserve

Significant increases (P \ 0.001) were seen in both

stress and rest MBF values with PSF?TOF reconstruc-

tion compared with OSEM reconstruction. When

analyzing the data in the gender and weight categories,

all data except for the male patients in the upper weight

group showed statistically significant differences, how-

ever, even for these obese males, the differences were

close to significant (P = 0.074 for stress MBF and

P = 0.055 for rest MBF). Table 2 shows the MBF for

stress and rest obtained from the two reconstruction

algorithms.

The mean percentage difference in stress MBF

with PSF?TOF was ?10.0% (95% CI -16.5% to

?36.6%) and for the rest MBF, the mean percentage

difference was ?13.8% (95% CI -15.8% to ?43.3%).

There was no significant difference between the rela-

tive percentage differences of MBF ratios at stress and

rest indicating a systematic relative increase for

PSF?TOF reconstruction and the mean percentage

difference for combined stress and rest data was

?11.9% (95% CI -16.2% to ?40.0%). The Bland-

Altman plots are shown in Fig. 5 for MBF and MFR

relative differences. As both stress and rest MBF are

increased by approximately the same relative amount,

no significant difference was seen in MFR between the

two reconstructions. It can be seen in Fig. 5(A) and

5(B) that PSF?TOF reconstruction produced increases

of up to 52% for rest MBF and up to 40% for stress

MBF. Details from three example patients with high

relative increases in MBF are given in Table 3. In

order to determine the possible source of the differ-

ence, a polar plot was produced to show the ratio of

the MBF for the two reconstructions, which is shown

in Fig. 6(A). Resting perfusion images from patient

#12 are shown in Fig. 6(B). This patient had a small

heart with evidence of considerable spill-over of the

myocardium into the bloodpool VOI with OSEM

reconstruction, which was reduced with PSF?TOF,

resulting in a 16% lower BIF AUC with the latter

Journal of Nuclear Cardiology� I. S. Armstrong et al.

Impact of PSF modeling and TOF on MFR

reconstruction. The second factor evident in the figure

is the apparent reduction of septal wall activity in the

OSEM images compared with PSF?TOF images. In

this region, an increase of MBF by approximately 60–

70% was observed with PSF?TOF as can be seen in

Fig. 6(A). The increase in global resting MBF for this

patient with PSF?TOF reconstruction was 35%.

In all cases, no significant differences in the relative

percentage differences were seen for the weight and

gender groups.

DISCUSSION

We believe that this is only the second study to

investigate the use of advanced PET reconstructions

with PSF modeling and TOF in Rb-82 cardiac PET

and the first to evaluate their impact on MBF and

MFR for dynamic data. The work has shown that

MFR measurements appear to be robust for the two

reconstruction algorithms. However, we noted a con-

siderable variability in the relative changes seen for

MBF between the two reconstructions (Fig. 5(A) and

Figure 1. (A) Example time-activity curve for blood input function at stress (red line) and rest(yellow line). (B) Average ratios (PSF?TOF/OSEM) of the activity concentration measurements ateach time point for the two reconstructions. Each data point is obtained by averaging the ratios at aparticular time point over all acquisitions.

Figure 2. Screen capture of the myocardial uptake at stressand rest in the last frame of the dynamic reconstruction takenfrom Syngo MBF analysis for both reconstruction algorithms.The green rectangle represents the blood pool volume ofinterest.

Figure 3. Bland-Altman plots of the relative percentagedifferences for BIF AUC data for the two reconstructions. Thesolid line shows the mean percentage difference betweenreconstructions while the dashed lines show 95% confidenceintervals.


5(B)). In addition, substantial increases in MBF, of up

to 52%, were seen in some patients. This is most

likely to be a consequence of increased cavity contrast,

which has been reported with PSF reconstruction.15

This reduces the amount of spillover of myocardial

activity into the bloodpool VOI, particularly in the

later frames, as shown in Figs. 1(B) and 2, resulting in

an apparent reduction in the BIF and hence greater

MBF. This appeared to be most prominent in small

hearts where the bloodpool VOI occupied the majority

of the ventricular cavity. In addition, a reduction of

the BIF was also seen in the first and second frames

(Fig. 1(B)) with PSF?TOF. This appeared to be due

to a reduction of spillover from activity in the right

ventricle with PSF?TOF compared with OSEM

because of the increased convergence of PSF?TOF

as a consequence of the greater product of iterations

and subsets.

In some patients, a regional increase in perfusion

was seen with PSF?TOF resulting in a greater

regional MBF that lead to an increased global MBF

with PSF?TOF. This may be due to a reduction in

PVE when using PSF?TOF reconstruction in a myo-

cardium that is particularly thin. Unfortunately, the

lack of contrast enhancement in the CT data in this

study meant that it was not possible to visualize the

myocardial wall from the cavity in order to estimate

the thickness of the myocardium. One may consider

that a reduction in PVE would produce more accurate

MBF and this provides scope for follow-up work to

include anatomical measurements of myocardial thick-

ness. However, partial volume corrections and the non-

linear extract correction of rubidium3 that are incor-

porated into dynamic processing software are likely to

require modification to account for differences in PVE

from the advanced reconstructions to maintain consis-

tent flow results. The changes seen in this study to

MBF results may be clinically significant and caution

should be applied if processing software is not adapted

for data using advanced reconstructions. However, the

MFR values, which are considered the prime prog-

nostic indicator, both in predicting three-vessel

disease7 and patient outcome,8 do not appear to be

affected by the advanced reconstruction. The magni-

tude of the relative increase for the MBF data was not

found to be dependent on gender or weight. Con-

versely, the relative differences for BIF AUC obtained

from PSF?TOF and OSEM did appear to be depen-

dent on weight in the male patients. It is not clear why

these differences only occur in the male patients. A

possible explanation for why the relative increases of

Table 1. Data for area under curve (AUC) of the blood input function (BIF) obtained from the tworeconstructions

Median for BIF AUC (Bq/mL 3 seconds)

No. images OSEM (3106) PSF 1 TOF (3106) P

All patients 74 20.5 19.3 \0.001

\85 kg 40 22.9 21.2 \0.001

[85 kg 34 18.5 18.1 \0.001

Male 52 22.0 20.4 \0.001

\85 kg 34 23.2 21.4 \0.001

[85 kg 18 19.3 18.2 \0.001

Female 22 17.5 17.9 0.330

\85 kg 6 18.7 18.9 0.438

[85 kg 16 17.2 17.3 0.720

Figure 4. Box-whisker plots of the ratios between the tworeconstructions (PSF?TOF/OSEM) for the area under curve(AUC) of the blood input function (BIF) in the male (M) andfemale (F) upper and lower weight groups. Statistical testingwas performed using the Mann–Whitney test.



MBF do not appear to be dependent on gender or

weight is that any effects of the PSF?TOF recon-

struction that are related to patient gender or weight

are likely to be similar for the measurements of the

BIF and also the Rb-82 activity in the myocardium

and hence cancel out during the MBF calculation.

On our scanner, the use of PSF modeling and TOF

reconstruction results in approximately 50% longer

Table 2. Myocardial blood flow values for the two reconstructions at stress and rest

Median stressMBF (mL/g/min)

Median restMBF (mL/g/min)

n OSEM PSF 1 TOF P OSEM PSF 1 TOF P

All 37 2.61 2.80 \0.001 1.21 1.27 \0.001

\85 kg 20 2.89 2.99 0.019 1.30 1.46 0.006

[85 kg 34 2.49 2.63 0.005 1.11 1.10 0.002

Male 26 2.55 2.66 0.008 1.23 1.28 0.002

\85 kg 17 3.08 3.06 0.045 1.34 1.47 0.020

[85 kg 9 2.10 2.45 0.074 0.83 1.08 0.055

Female 11 2.65 2.89 0.014 1.15 1.23 0.005

\85 kg 3 2.24 2.57 – 1.06 1.14 –

[85 kg 8 2.74 2.94 0.039 1.18 1.32 0.020

Statistically testing was performed using the Wilcoxon signed rank test. A P value could not be deduced for female patients in theupper weight category due to the sample size

Figure 5. Bland-Altman plots of the relative percentage differences for rest MBF (A), stress MBF(B), and MFR (C) for the two reconstructions. The solid line shows the mean percentage differencebetween reconstructions while the dashed lines show the 95% confidence limits.

Table 3. Three example patients that were considered to have a large percentage increase in MBFwith PSF ? TOF reconstruction compared with OSEM

PatientStress MBF (mL/g/min) Rest MBF (mL/g/min) MFR

OSEM PSF 1 TOF OSEM PSF 1 TOF OSEM PSF 1 TOF

#12 (M, 63 kg) 3.22 4.10 (?27%) 1.48 1.99 (?35%) 2.20 2.10 (-4.5%)

#24 (M, 103 kg) 2.58 3.60 (?40%) 0.84 1.28 (?52%) 3.12 2.92 (-5.3%)

#27 (F, 94 kg) 3.16 4.02 (?27%) 1.21 1.65 (?36%) 2.62 2.48 (-6.4%)


reconstruction times, which may impact on logistics

during a busy PET service. However, TOF may offer

potential advantages in reducing attenuation artifacts

from mis-registration in cardiac studies,11 which have

been shown to impact detrimentally on MBF and MFR.9

From our experience, excellent motion-free

dynamic images can be obtained in almost all resting

studies through effective communication and patient

preparation. Despite the best efforts, motion can occur

during the stress acquisition due to patient discomfort

from the effects of the adenosine infusion. While

registration is checked, and adjusted if necessary using

the summed static stress perfusion images, there is

currently no way of correcting for motion-related mis-

registration on a frame-by-frame basis on the dynamic

images. Motion may cause mis-registration in some of

the dynamic frames between the stress PET and the CT

for attenuation correction and hence errors in MBF and

MFR results. As such, the use of a reconstruction

algorithm that reduces the impact of errors from mis-

registration would be of benefit. The findings from this

study and other work would encourage the use of TOF

reconstruction, which may reduce such errors without

impacting on the results obtained for MFR. It is our

intention to evaluate this hypothesis in future work.

Study limitations

This study has limitations. Statistically significant

differences were seen for BIF AUC and MBF for the

two reconstructions in this study. However, without a

gold standard measurement, it is impossible to deduce

with certainty which reconstruction resulted in the more

accurate measurements. While we note that considerable

differences in MBF can occur in small hearts due to

reductions in spillover when using PSF?TOF recon-

struction, we are unable to draw solid conclusions from

apparent changes in myocardial uptake that may be due

to PVE. The lack of information on the myocardial wall

visualization in this study does not allow for estimates of

myocardial thickness to be estimated, which would

provide evidence to support the PVE hypothesis. There

is a variety of possible explanations for the differences

seen with patient gender and weight in MBF that could

include: differences in reconstruction convergence at

different patient weights and differences in size of the

myocardium, which would impact on myocardial spill-

over. Due to relatively small sample size in this study,

the exact reasoning cannot be deduced confidently.

CONCLUSION

This preliminary study has indicated that myocar-

dial flow reserve measurements from dynamic rubidium-

82 dynamic PET appear to be robust when generated by

standard or advanced PET reconstruction algorithms

with PSF modeling and TOF. Differences in MBF

values were seen, possibly due to reductions in partial

volume effects, which warrant further investigation,

supported by additional anatomical imaging such as

contrast-enhanced CT or cardiac MR. Potential

improvements in the robustness of the technique when

using PSF modeling and TOF reconstruction, such as

reduced sensitivity to mis-registration, encourage the

adoption of these advanced algorithms into routine use

for rubidium-82 cardiac PET.

Figure 6. (A) Ratio of resting MBF (PSF?TOF/OSEM) for patient #12, which had a globalincrease of 35% for their MBF with PSF?TOF compared with OSEM reconstruction. The twoperfusion images in (B) show a reduction in perfusion in the septal wall with OSEM compared withPSF?TOF that correlated with the area of increased MBF. The window levels are set equal in thetwo uptake images. The flow data for the patient are given in Table 3.



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Documents

Impact of point spread function modeling and time-of-flight on myocardial blood flow and myocardial flow reserve measurements for rubidium-82 cardiac PET