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Quantification and data optimisation of heart and brain studies in conventional nuclearmedicineDobbeleir, André Alfons

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RIJKSUNIVERSITEIT GRONINGEN

Quantification and data optimisation of heart and brain studies in

conventional nuclear medicine

Proefschrift

ter verkrijging van het doctoraat in de

Medische Wetenschappen

aan de Rijksuniversiteit Groningen

op gezag van de

Rector Magnificus, dr. F. Zwarts,

in het openbaar te verdedigen op

woensdag 25 januari 2006

om 14.45 uur

door

André Alfons Dobbeleir

geboren op 14 september 1949

te Kruibeke, België

2

PROMOTORES :

Prof. dr. R.A.J.O. Dierckx

Prof. dr. H.R. Ham

Prof. dr. A.M.J. Paans

Prof. dr. A-S. E. Hambÿe

BEOORDELINGSCOMMISSIE :

Prof. dr. W. Vaalburg

Prof. dr. J.H.A. De Keyser

Prof. dr. Ph. Franken

ISBN-10 : 9090198687

ISBN-13 : 9789090198682

3

Paranimfen : Ann Vervaet

Gerda Dobbeleir

The publication of this thesis was supported by a grant from Amersham-Health (part of GE

Healthcare) Belgium.

4

Stellingen

Behorende bij het proefschrift :

Quantification and data optimisation of heart and brain studies in conventional nuclear medicine.

1. De analyse van gated SPECT vervolg studies bij een individuele patient dienen gedaan te

worden met dezelfde kwantitatieve gated SPECT software.

2. Snelle, herhaalde en reproduceerbare hoge telsnelheid linker ventriculaire functie studies

kunnen verkregen worden met het kortlevende radionuclide 191m

Ir.

3. Zonder scatter correctie wordt myocardiale mismatching tussen BMIPP en MIBI gedeeltelijk

verborgen.

4. De SPECT kwantitatieve bevindingen met HMPAO wijzen erop dat in DAT patienten de

perfusie van het cerebellum onaangetast is waardoor deze regio kan gebruikt worden als

referentie.

5. Indien berekend met een resolutie onafhankelijke methode kunnen dopamine transporters

resultaten met 123

I-FP-CIT afkomstig van verschillende centra en systemen met elkaar

vergeleken worden.

6. Zelfs na geschikte scatter en attenuatiecorrectie, blijven de problemen verbonden aan de

beperkte resolutie van het SPECT systeem onopgelost voor accurate kwantificatie. P. Jarritt

and K. Kouris. New trends in nuclear neurology and psychiatry 1993: p57.

7. Wij zijn allen voor vereenvoudiging en standaardisering maar de geschiedenis van nucleaire

geneeskunde leert ons dat dit zelden leidt naar absolute kwantificatie. A. Gottschalk.

Yearbook of Nuclear Medicine 1995: p275.

8. Statistiek is als een lantaarnpaal voor een dronken man, meer ter ondersteuning dan ter

verlichting.

9. Zoals dit proefschrift is creativiteit een langzaam proces.

10. 2005 is het jaar van de natuurkunde; daarom is Fietsica dit jaar uitgeroepen tot een belangrijke

activiteit in Groningen.

11. Alleen wie tegen de stroom inzwemt komt aan de bron. (Volgens A. Vervaet en G. Dobbeleir

ook van toepassing op A. Dobbeleir)

5

Contents

1. Introduction and outline of the thesis

2. Determination of left ventricular ejection fraction by first pass and gated SPECT

studies.

2.1 Performance of a single crystal digital gamma camera for first pass cardiac studies.

2.2 Variability of left ventricular ejection fraction and volumes by quantitative gated

SPET : influence of algorithm, pixel size and reconstruction parameters in normal

and small-sized hearts.

2.3 Clinical applications of first pass studies (abstracts of articles)

-Clinical usefulness of ultrashort-lived Iridium-191m from a carbon-based

generator system for the evaluation of the left ventricular function.

-Comparison between exercise myocardial perfusion and wall motion using 201

Tl

and 191m

Ir simultaneously.

3. Myocardial perfusion and viability.

3.1 SPET generated colour-coded polar maps to quantify the uptake of 99mTc-

sestaMIBI and 123I-BMIPP in chronically dysfunctional myocardium: comparison

with coronary anatomy and wall motion.

3.2 Influence of high-energy photons on the spectrum of iodine-123 with low-and

medium-energy collimators: consequences for imaging with 123I- labelled

compounds in clinical practice.

3.3 Influence of methodology on the presence and extent of mismatching between

99mTc-MIBI and 123I-BMIPP in myocardial viability studies.

3.4 Clinical applications ( abstracts of articles)

-BMIPP imaging to improve the value of sestamibi scintigraphy for predicting

functional outcome in severe chronic ischemic left ventricular dysfunction.

-Quantification of 99mTc-sestaMIBI and 123I-BMIPP uptake for predicting

functional outcome in chronically ischaemic dysfunctional myocardium

-Prediction of functional outcome by quantification of sestamibi and BMIPP after

acute myocardial infarction.

4. Perfusion of the brain.

4.1 Quantification in SPECT using non-invasive methods.

4.2 Quantification of technetium-99m hexamethylpropylene amine oxime brain uptake

in routine clinical practice using calibrated point sources as an external standard:

phantom and human studies.

4.3 Clinical applications ( abstracts of articles)

6

-Parameters influencing SPET regional brain uptake of technetium-99m

hexamethylpropylene amine oxime measured by calibrated point sources as an

external standard.

-Validation of the cerebellum as a reference region for SPECT quantification in

patients suffering from dementia of the Alzheimer type.

5. Dopamine transporter imaging in the human brain.

Quantification of Iodine-123-FPCIT SPECT with a resolution independent technique.

6. Summary and future directions

Samenvatting en toekomstperspectieven

7. List of publications

8. Dankwoord

7

1. Introduction and outline of the thesis

Introduction

After the introduction of planar nuclear medicine images obtained with the Anger gamma camera

(1957) and connection to a computer system (early 1970s), attempts have been made to enhance the

quality of the scintigrams by filtering and noise subtraction(1,2). Using manual or automatic regions

of interest on static or dynamic images, quantitative analysis of the radiopharmaceutical distribution

let to the development of nuclear medicine procedures for many organs. Quantification reduces the

inter- and intra-observer variability and improves the sensitivity and specificity of the nuclear

medicine procedures (3). Using planar imaging, the superimposition of activity in front and behind

the organ results in decreased image contrast and prevents accurate quantitative measurements. At

the end of the 1970s three-dimensional information of the radionuclide distribution in humans was

obtained by means of single photon emission computed tomography (SPECT) (4-6).

The ultimate goal was to quantify the absolute distribution of radioactivity. To achieve this goal

many obstacles need to be overcome, some inherent to the gamma camera and planar acquisition,

others to the tomographic reconstruction (7-11). In SPECT, photon absorption and scatter,

particularly in the chest, produce regional inhomogeneities. Poor attenuation maps and

misalignment between transmission and emission data also influence quantitative measurements

(12). Step by step, solutions appear in literature and the new generation gamma cameras permit

correction for photon absorption and scatter (13). In spite of all that, some physical properties

hamper accurate quantification.

In the next paragraph physical parameters of the gamma camera are summarised. Then their impact

on different quantification methods is highlighted. Finally in the aim and outline of the thesis, the

application of correction methods or alternative approaches necessary for quantification of heart and

brain studies is mentioned.

Physical properties

Calibration

The first requirement of an imaging system is that the image of an object is independent of its

position in the field of view. Originally this is not the case due to impurities in the crystal and

variations in the response of the photomultipliers, affecting both the energy estimate and event

localisation. Variations of energy, non-linearity and uniformity can be corrected by calibration

measurements. Tomographic reconstruction needs additional calibration for the centre of rotation of

the detectors (14-16).

Scatter

Due to a limited energy resolution, usually a 20% energy resolution is used. Therefore, scattered

events can amount to 20% in a typical brain study and even to 40 % of the total counts in a cardiac

study. The nature of scatter is thus study dependant in a complex manner both on the composition

of the patient, the distribution of the tracer and the collimator and detector characteristics. Scatter is

nonstationary. In SPECT, these scattered events must be removed before attenuation correction or

in some cases a reduced linear attenuation coefficient can be used (17-19).

Dead-time

The sensitivity of an imaging system is defined by the number of counts per unit time detected by

the device for a unit activity in the source. Only a fraction of the photons passes through the

collimator and is absorbed by the crystal. Some of these events are rejected depending of the setting

8

of the photopeak window. Some of the events are lost because the system is still busy processing a

previous event. The probability of this situation increases with higher activities. As a result of the

dead time of the system, the detected counts do not rise linearly with the activity. With further

increase of activity, a saturated stage and even drop in the detected count rate may be observed

(20,21).

Partial volume effect

Planar and SPECT images have a characteristic resolution. Images of objects larger than 2x the full

width at half maximum of the point spread function will reflect both the size and radioactive

concentration of the object. However for smaller objects, the signal is blurred; so that the total

counts is preserved although the activity per pixel is decreased. This effect, known as partial

volume effect, is particularly severe for SPECT images of the brain. Textures are below the

resolving power of the methodology and accurate determination of radioactive concentrations is

impossible (22-24).

Acquisition Parameters

The acquisition matrix must be chosen in function of the detector size, and the obtained pixel size

defines the spatial sampling. Optimally, the pixel size should be less than the FWHM / 3 e.g. about

3-4 mm for a SPECT system characterized by a 10-12 mm FWHM resolution. The angular sample

is defined by the number of projections in 360°. In order to ensure similar spatial and angular

sampling for the reconstruction region, the angular interval should be such that the arch length is

equal to the spatial sampling interval. For the circumference of the brain, optimal angular sampling

interval should be about 3°. In cardiac studies, due to larger detector distance the FWHM is higher

and the heart is more in the centre of the reconstructed volume, so angular sampling between 4° and

6° is used (25-27).

Reconstruction parameters

Reconstructing the angular images by filtered backprojection needs filtering by a Ramp filter to

correct for image blurring. This enhances however the high spatial frequency noise in the

reconstructed image. To suppress this noise, filters with specific parameters defining the degree of

smoothing of the image are used. This reduces the information in the reconstructed image (27-29).

Quantification

Quantification of radioactive tracer concentrations depends and is limited by previous mentioned

factors. Quantification analysis can be subdivided in three subclasses: the measurement of size and

volume of features within the image, the relative activity concentrations within regions and the

absolute tracer concentration in units of MBq/ml.

Size and volume

Size measurements always require some kind of contour definitions. Accurate size measurements

are limited by the finite resolution of the system and the statistical errors in the reconstruction. The

accuracy of the edge detection algorithms depends on the signal-to-noise ratio and the contrast

range within the image. The partial volume effect defined by the finite resolution of the imaging

process requires a different threshold for different sized structures. System and user defined

parameters influence size measurements. The user can effect the final resolution of the image by the

choice of the collimator, the acquisition pixel size and the reconstruction filter.

9

Relative concentration

Quantification comparing total activity or concentrations within several regions is the most

common method in nuclear medicine procedures. The amount of activity can also be expressed

relative to the maximum activity or mean activity in the image or the study. Reference anatomic

regions or control subjects are used. The choice of region of interest size and placement, the

adequate definition of anatomical regions and the identification of the reference site are critical.

Taking care, data obtained within one centre or between centres with identical equipment for

acquisition and processing might be compared. For centres using different detector systems with

different resolutions, different acquisitions protocols and reconstruction methods, results will

almost certainly be different.

Comparing different activities supposes a uniform sensitivity of the imaging system. This is

achieved by calibration. At high count rate activity linearity during dynamic acquisitions is no

longer present and dead time corrections are obliged.

In myocardial perfusion studies profiles normalised to the maximum activity or the most normal

region can be compared with those of normal subjects. The localisation, extent and severity of a

defect can be calculated and compared between rest and stress studies.

In myocardial viability studies, the profile of perfusion with Tc99m-sestaMIBI can compared to the

profile obtained with I123-BMIPP. Even acquired separately a supplementary problem rises. In the

photo-peak Iodine-123 considerably higher scatter is measured from high-energy photons.

Moreover, the distribution of the tracers are different. The nature of scatter depends in a complex

manner both on the distribution of the tracer and the collimator and detector characteristics. Scatter

is non-stationary and adds background activity in the myocardial profile. Scatter correction must be

applied for quantitative comparison of these different isotopes. Absolute quantification

The elusive but ultimate goal of quantification in nuclear medicine is the measurement of absolute

tracer concentration in units of MBq/ml or in % of the injected dose. This would take in account all

centre specific problems and data become non-centre specific. Absolute quantification performed in

a specific centre can also be used to prove that an anatomic region remains stable within different

patients, groups or treatment and thus can be used further on as reference region in relative

quantitative measurements.

Although not totally accurate, absolute quantification might also be a supplementary tool for studies

where small organs are involved and relative quantification is hampered by a huge partial volume

effect.

Aim of the thesis

The aim of this work was to obtain accurate quantitative measurements useful in clinical practice in

some heart and brain nuclear medicine procedures, applied in our department.

In the development of each method several of the following steps have to be covered:

- investigate the appropriate physical characteristics

- optimise and / or correct for physical characteristics

- figure out a practical method useful for clinical practice

- determine the accuracy of the method

- apply the method in patient studies

10

Outline of the thesis.

Chapter 2. Determination of left ventricular ejection fraction by first pass and gated SPECT

studies.

2.1 At high count rate activity linearity during dynamic acquisitions is no longer present and

dead time corrections are required. The performance of a single crystal digital gamma camera was

studied for the evaluation of the left ventricular function.

Ultrashort-lived Iridium-191m permitted rapid, repeat first pass studies.

2.2 System and user defined parameters influence size measurements. The variability of left

ventricular ejection fraction and volumes calculated by quantitative gated SPECT modifying the

acquisition pixel size and the reconstruction filter was measured. The impact on normal and small-

sized hearts calculated by different algorithms on several processing stations was studied.

2.3 First pass studies were applied in patients at increasing levels of exercise. Exercise

myocardial perfusion and wall motion using 201

Tl and 191m

Ir simultaneously was studied.

Chapter 3. Myocardial perfusion and viability of the heart

3.1.1 In myocardial studies profiles are normalised to the maximum activity or the most normal.

We generated colour-coded polar maps to quantify the uptake of 99mTc-sestaMIBI and 123I-

BMIPP in chronically dysfunctional myocardium. The difference in extent and severity of a defect

was compared with coronary anatomy and wall motion.

3.2.1 In the photo-peak of Iodine-123 a considerably higher scatter portion is measured than with

Tc99m-sestaMIBI. The influence of high-energy photons on the spectrum of iodine-123 with low-

and medium-energy collimators is studied and the consequences for imaging with 123I-labelled

compounds in clinical practice discussed.

3.2.2 The influence of methodology on the presence and extent of mismatching between perfusion

using 99mTc-MIBI and metabolism using 123I-BMIPP in myocardial viability studies was

investigated.

3.3 Several clinical applications were published taking into account the previous mentioned

spectral analysis. Comparative quantification of 99mTc-MIBI and 123I-BMIPP tomography

predicted functional outcome in chronically ischaemic dysfunctional myocardium and after acute

myocardial infarction. BMIPP imaging improved the value of sestamibi scintigraphy for predicting

functional outcome in severe chronic ischaemic left ventricular dysfunction.

Chapter 4. Perfusion of the brain

4.1 A review of quantification of brain perfusion and cerebral blood flow was published in a

textbook presenting an up-to-date and systematic approach of SPECT in the major neurological and

psychiatric disorders.

4.2 We calculated the absolute technetium-99m hexamethylpropylene amine oxime (HMPAO)

brain uptake and proved that the cerebellum remains stable within different patients, groups or

treatment and can be used as reference region in relative quantitative measurements.

11

4.3 Parameters influencing the SPECT regional brain uptake of technetium-99m HMPAO were

studied in volunteers and patients. The cerebellum was validated as a reference region for SPECT

quantification in patients suffering from dementia of the Alzheimer type.

Chapter 5. Dopamine transporter imaging in the human brain

In a small organ like the striatum relative quantification is hampered by a huge partial volume

effect. We developed a region of interest independent method. Using gamma camera calibration

factors for the radio-ligand Iodine-123-FPCIT we transformed the striatal uptake in absolute

quantification. Although not totally accurate, absolute quantification might also be a supplementary

tool for inter-centre comparison.

References:

1. Goris ML. Nontarget activities: can we correct for them ? J Nucl Med 1979; 20: 1294,1300.

2. King MA, Schwinger RB, Doherty PW, Penney BC. Two-dimensional filtering of SPECT

images using the Metz and Wiener filters. J Nucl Med 1984; 25: 1234-1240.

3. Berger BC, Watson DD, Taylor GJ et al. Quantitative thallium-201 exercise scintigraphy for

the detection of coronary artery disease. J Nucl Med 1981; 22: 585-593.

4. Jaszczak RJ, Murphy PH, Huard D, Burdine J. Radionuclide emmision computed

tomography of the head with 99m-Tc and a scintillation camera. J Nucl Med 1977; 18: 373-

380.

5. Keyes JW, Orlandea N, Heetderks WJ et al. The Humongotron – a scintillation camera

transaxial tomograph. J Nucl Med 1977; 18: 381-387.

6. Larsson SA. Gamma camera emmision tomography. Acta Radiol 1980; 363: 5-75.

7. Goulding P, Burjan A, Smith R et al. Semi-automatic quantification of regional cerebral

perfusion in primary degenerative dementia using technetium-99m hexamethylpropylene

amine oxime and single photon emmision computer tomography. Eur J Nucl Med 1990; 17:

77-82.

8. Hooper HR, McEwan AJ, Lentle BC et al. Interactive three-dimensional region of intrest

analysis of HMPAO SPECT studies. J Nucl Med 1990; 31: 2046-2051.

9. Eisner RL, Tamas MJ, Cloninger K et al. Norma SPECT thallium-201 bull’s-eye display:

gender differences. J Nucl Med 1988; 29: 1901-1909.

10. Nuyts J, Mortelmans L, Suetens P et al. Model-based quantification of myocardial perfusion

images from SPECT. J Nucl Med 1989; 30: 1992-2001.

11. Garcia EV, Van Train K, Maddahi J et al. Quantification of rotational thallium-201

myocardial tomography. J Nucl Med 1985; 26: 17-26.

12. Ficaro E, Wackers F. Should SPET attenuation correction be

more widely employed in routine clinical practice? Eur J Nucl Med 2002;29: 409-415.

13. Fricke H, Fricke E, Weise R et al. A method to remove artifacts in attenuation-corrected

myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-

derived attenuation maps. J Nucl Med. 2004;45:1619-25.

14. Fahey FH, Harkness BA, Keyes JW et al. Sensitivity, resolution and image quality with a

multi-head SPECT camera. J Nucl Med 1992; 33: 1859-1863.

15. Lim CB, Walker R, Pinkstaff C et al. Triangular SPECT system for 3-D organ volume

imaging: performance results and dynamic imaging capability. IEEE Trans Nucl Sci 1986;

33: 501-504.

16. Cyrill Burger and Gustav K. von Schultness. (1998) Gamma rays: nuclear medicine. In:

Gustav K. von Schultness and Jurgen Hennig (eds) Functional Imaging. Lippincott-Raven

Publishers. (157-216)

12

17. Ljundberg M, Strand SE. Scatter and attenuation correction in SPECT using density maps

and Monte Carlo simulated scatter functions. J Nucl Med 1990; 31: 1560-1567.

18. Ogawa K, Harata Y, Ichihara T et al. A new method for scatter correction in SPECT. Med

Phys 1990; 17: 518.

19. Jaszczak RJ, Floyd CE, Coleman RE. Scatter compensation techniques for SPECT. IEEE

Trans Nucl Sci 1985; 32: 786-793.

20. Ullman V, Husak V, Dubroka L. Deadtime correction in dynamic radionuclides studies by

computer. Eur J Nucl Med 1978; 3: 197-202.

21. Johnston AS, Arnold JE, Pinsky SM. Anger camera deadtime: marker source correction and

two parameter model. J Nucl Med 1975; 16: 539.

22. King MA, Long DT, Brill BA. SPECT volume quantification: influence of spatial

resolution, source size and shape, and voxel size. Med Phys 1991; 18: 1016-1024.

23. Kim HJ, Zeeberg BR, Fahey FB et al. Three-dimensional SPECT simulations of a complex

three-dimensional mathematical brain model and measurements of the three-dimensional

brain phantom. J Nucl Med 1991; 32: 1923-30.

24. Kim HJ, Zeeberg BR, Reba RC. Compensation for three-dimensional detector response,

attenuation and scatter in gray matter imaging using an iterative reconstruction algorithm

which incorporates a high resolution anatomical image. J Nucl Med 1992; 33: 1225-1234.

25. Muehllehner G. Effect of resolution improvement on required count density in ECT

imaging: a computer simulation. Phys Med Biol 1985; 30: 163-173.

26. Mueller SP, Pollak JF, Kijewski MF, Holman BL. Collimator selection for SPECT brain

imaging: the advantage of high resolution. J Nucl Med 1986; 27: 1729-1738.

27. Jarritt P.H. and Kouris K. (1993) Instrumentation for brain SPET: guidelines and

quantification. In: D.C. Costa, G.F. Morgan, N.A. Lassen (eds) New trends in neurology and

psychiatry. John Libbey & Company. (39-62)

28. Lee KH, Liu H, Chen D et al. Volume calculation by means of SPECT: analysis of imaging

acquisition and processing factors. Radiology 1988; 167: 259-262.

29. Blokland K, Reiber H and Pauwels E. Quantitative analysis in single photon emission

tomography (SPET). Eur J Nucl Med 1992;19:47-61.

13

2. Determination of left ventricular ejection fraction by first pass

and gated SPECT studies.

2.1.Performance of a single crystal digital gamma camera for first pass cardiac

studies.

A. Dobbeleir

1, P.R. Franken

1, H.R. Ham

2, C. Brihaye

3, M. Guillaume

3, F.F. Knapp

4 and

J. Vandevivere1

1Division of Nuclear Medicine, Middelheim General Hospital Antwerpen, 2020 Belgium,

2Division

of Nuclear Medicine, St Peter’s Hospital, 1000 Bruxelles, Belgium, 3Cyclotron Research Center,

University of Liège, Belgium, 4Nuclear Medicine Group, Health and Safety Research Division, Oak

Ridge National Laboratory (ORNL), Oak Ridge, TN 37831-0622, USA

Nuclear Medicine Communications 1991; 12: 27-34.

Summary

First pass radionuclide angiocardiography (FPRNA) has gained increasing interest because of the

development of new 99Tc

m-labelled perfusion agents and of new

191Os/

191Irm generator systems. The

aim of the study was to evaluate the performance capacities of a small field of view crystal digital

gamma camera for 99Tc

m and

191Irm at high count rates. The camera dead time for

99Tc

m (window

30%) was well corrected up to 300 kcps in fast acquisition mode using the relative decrease of a

small shielded reference source. Using the decaying activity method for 191

Irm the non-linearity

response of the gamma camera was corrected by an 191

Os reference source up to 210 kcps at 70

keV, 75 kcps at 129 keV and 320 kcps including both peaks. Saturation count rates were

respectively 270 kcps, 150 kcps and 420 kcps and high count rate resolution (FWHM) 9.0, 7.3 and

10.3 mm. Since the accuracy of the first pass measurements is more sensitive to count rate than to

spatial resolution the 50-150 keV window was chosen for clinical studies. In data obtained from 32

ECG gated FPRNA patient studies, the whole field of view count rate during the left ventricular

phase ranged from 100 to 250 kcps with 80 to 120 mCi (2960-4400 MBq) of 191

Irm and 100 to 180

kcps with 20 to 25 mCi (750-925 MBq) of 99Tc

m red blood cells permitting for both tracers accurate

non-linearity correction.

Introduction

First pass radionuclide angiocardiography (FPRNA) has recently gained increasing interest for

measuring left ventricular function. Firstly, because of the availability of new 99Tc

m-labelled

myocardial perfusion agents allowing simultaneous assessment of myocardial perfusion and

function [1, 2]. Secondly, because of the development of new high performance 191

Os/191

Irm

generator systems [3-5] offering the opportunity to conduct rapid, repeat, multiple first pass studies

of the cardiovascular system with the ultrashort half-lived 191

Irm [6-8]. The aim of this study was to

evaluate the performance capacities and the limitations of a single crystal digital gamma camera

(SCDGC) with respect to the high count rates needed for accurate measurements of ventricular

function with the FPRNA method.

14

Materials and methods

191

Irm

191Irm is the daughter of

191Os (

191Os:β-

emission ; T1/2 = 15,4 days) and decays with a half-life of

4,96 s to stable iridium emitting a gamma-ray at 129 keV and three X-rays at 63 keV, 16%; 65 keV,

28%; and 74 keV, 12%. The X-rays cannot be resolved with the Na crystal and appear thus as one

single peak at about 69 keV (Fig 1.). In this study, 191

Irm was produced by elution of a carbon-based

191Os/

191Irm generator system with pH 2, 0,9% NaCl solution containing potassium iodide and

subsequently neutralized with a TRIS buffer. Details concerning the preparation and use of this

generator system have been published elsewhere [3, 8, 9].

Data acquisition

Data were acquired in the ‘normal’ acquisition mode or in the ‘fast’ acquisition mode with a small

field of view (20 cm) SCDGC (APEX 215M, Elscint) equipped with a very high sensitivity, low-

energy, parallel hole collimator. In the ‘fast’ mode, a higher number of counts can be acquired using

a different electronic circuit integrating only the first 400 ns of the scintilation.

Fig. 1. Spectrum of

191Ir

m measured with a gamma camera.

Camera resolution

The resolution of the camera for different energies was tested with 99Tc

m, 201

Tl and 191Os point

sources in the ‘normal’ and in the ‘fast’ acquisition modes [10]. 191

Os decays to 191

Irm by β-

emission without emitting photons. The FWHM, FW20M and FW10M were calculated in a 30%

window centered over the 140 keV 99Tc

m photopeak, in a 40% window centered over the 70 keV

201Tl photopeak and in the 50-100, 100-150 and 50-150 keV windows of the

191Irm spectrum.

Count-rate linearity

The linearity of the gamma camera for 99Tc

m was measured by placing an increasing number of

small vials (1 cm diameter) on the collimator. The activities were measured using a dose calibrator

15

and no scattering material was used. Data were acquired in the ‘fast’ mode with the energy of the

pulse height analyser set at 140 keV with a 30% window. Increasing 99Tc

m activities were measured

together with a 10 kcps activity shielded reference source of 99Tc

m placed in the field of view of the

camera. The measured activity was corrected for the dead time of the camera by a software

correction program based on the detected counts before the pulse height analyser (provided by the

manufacturer) and by the relative decrease of activity of a reference source [11, 12]. The linearity of

the gamma camera for 191

Irm was tested using the decaying source method. For that purpose a bolus

of 100 mCi (3700 MBq) of 191

Irm was extracted from the generator system using 15 ml of normal

saline solution, collected in an extension tube and directly divided through a three-way stopcock

into two 100 ml beakers placed on the collimator. The beakers contained a small quantity of water

in order to obtain a distributed source. A 10 kcps activity shielded 191

Os source was placed on the

camera as reference. Data were acquired in dynamic mode (25 frames per second) for 30 s. This

procedure was repeated three times in the 50-100, 100-150 and 50-150 keV windows. Time-activity

curves were then generated from regions of interest (ROI) drawn over the reference source, over the

two beakers and over a region between the two beakers ROIs, the latter being used to estimate the

relative amount of misplaced pile-up events [13, 14]. The activity curves of the two beakers were

added together and corrected for camera dead time by the relative decrease of the reference source

activity. The linearity response of the gamma camera was then established by comparing the dead

time corrected activity curve to the theoretical decaying curve of 191

Irm. For this purpose, a linear fit

with a slope = -0.140 corresponding to the decay constant of 191

Irm was applied on the low values of

the corrected activity curve expressed in the natural log (Fig. 2). Accepting a 1% deviation as

criteria, the limits of the linearity response of the system was determined for the above-mentioned

windows of the 191

Irm spectrum.

Fig. 2. Linear fit with a slope of –0.140 is applied to the dead time corrected decay curve of

191Ir

m in order to

determine the limits of linearity response of the system.

Patient studies

First pass radionuclide angiocardiographic studies were obtained at rest in 32 patients with 80-120

mCi (2960-4400 MBq) of 191

Irm and a few minutes later with 20-25 mCi (750-925 MBq) of

99Tc

m

red blood cells. Pulse height analyser windows were set over the 50-150 keV windows for 191

Irm

16

studies and over the 119-161 keV windows for the 99Tc

m studies. Data were collected in the ‘fast’

mode in a 32 x 32 x 8 matrix (25 frames per second) for 30 s.

Results

Camera resolution

The FWHM, FW20M and FW10M with 99Tc

m, 201Tl and

191Os point sources are given in table 1.

Table 1. Spatial resolution on point sources of

99Tc

m, 201Tl and

191Ir

m (50-100, 100-150 and 50-150 keV

windows) in the ‘normal’ (N) and ‘fast’ (F) acquisition modes.

191Ir

m

99

Tcm

201Tl 50-100 keV 100-150 keV 50-150 keV

N F N F N F N F N F

FWHM 6.0 7.3 6.5 8.6 6.9 9.0 6.4 7.3 7.7 10.3

FW20M 9.8 11.2 10.3 12.9 10.3 14.2 9.9 12.0 11.2 15.0

FW10M 12.4 14.2 13.3 16.3 12.5 16.3 12.0 14.2 13.3 18.1

As expected, the spatial resolution of the system was better for 99Tc

m than for

201Tl in the ‘normal’

as well as in the ‘fast’ acquisition modes. In the latter, a small but consistent degradation of the

resolution was observed with both isotopes. The resolution of the system for 191

Irm depends

obviously on the window selection. The resolution was similar to that of 201Tl for the 50-100 keV

window (FW20M 10.3 mm versus 10.3 mm) and similar to that of 99Tc

m for the 100-150 keV

window (FW20M 9.9 mm versus 9.8 mm) while the largest window (50-150 keV) gave the largest

FW20M (11.2 mm). Again the ‘fast’ acquisition mode induced a degradation of the spatial

resolution for all energy windows. This influence of window selection on the spatial resolution of

the gamma camera was further observed in clinical studies comparing 191

Irm FPRNA to

99Tc

m. The

left ventricular ROI area averaged 164 ± 29 pixels in 99Tcm studies and 192 ± 28 pixels in the 191Irm studies (P<0.0001).

Camera linearity

Using the relative decrease of the shielded point source activity as a reference, the camera dead time

for 99Tc

m (with a 30% window) was corrected up to 80 kcps in the ‘normal’ acquisition mode and

up to 300 kcps in the ‘fast’ acquisition mode, corresponding to true count rates of about 160 and

650 kcps, respectively. The software correction resulted in systematic undercorrection of the

linearity response of the camera. The saturation count rate for 191

Irm was 270 kcps in the 50-100

keV window, 150 kcps in the 100-150 keV window and 420 kcps in the 50-150 keV window. Using

the decaying source method, the camera dead time was corrected with an error of less than 1% up to

210 kcps in the 50-100 keV window, 320 kcps in the 50-150 keV window, but only up to 75 kcps in

the 100-150 keV window. The number of pile-up events was estimated from the ROI drawn

between the two beakers. At bolus arrival up to 9% of the total measured activity in the camera field

of view was related to misplaced events in the 100-150 keV window compared to 2.5% in the 50-

100 keV window and 5.5% in the 50-150 keV window (Fig. 3). A 1% or less misplaced events were

observed in the 50-100 keV window at the maximal count rate capacity of the camera (270 kcps), in

the 50-150 keV window at 70% (300 kcps) of the maximal capacity, but in the 100-150 keV at only

40% (60 kcps) of the maximal capacity of the camera system.

Patient studies

The highest count rates in the WFOV and in the right and left ventricular ROIs during the first

transit of 191

Irm (50-150 keV window) observed in 3 of the 32 patients are given in table 2. In

Patient 1, although left ventricular count rate was rather low the WFOV count rate during the right

17

phase of the transit was just below the maximal limit of accurate dead time correction of the system.

In Patient 2, and certainly in Patient 3, the count rates during the right transit phase were out of the

limits of dead time correction: the maximum WFOV count rate was reached at 0.3 and 2.6 s,

respectively, after the passage of the bolus in the right ventricle, indicating saturation of the gamma

camera and precluding simultaneous assessment of right and left ventricular function studies during

a single injection of 191

Irm.

Table 2. Maximal count rates during

191Ir

m (50-150 keV window) FPRNA studies in three patients.

FPRNA RV phase LV phase

WFOV RV WFOV LV WFOV

Patient (kcps) (kcps) (kcps) (kcps) (kcps)

Delay

max FPRNA-

max RV phase ( s)

1 306 201 306 51 132 0.0

2 400 278 398 99 212 0.3

3 441 187 380 195 331 2.6

The maximal count rate in the 20 cm field of view of the camera observed in most patients during

the left ventricular transit of the 191

Irm bolus ranged between 100 and 250 kcps. The maximal count

rate observed in those patients during the left ventricular transit of the 99Tc

m bolus ranged between

100 and 180 kcps. Left ventricular counts in the 40 ms end-diastolic image of the ECG-gated left

ventricular representative cycle averaged 14.8 kcounts (range 5.3-30.3) with 191

Irm and 10.2 kcounts

(range 3.6-22.1) with 99Tc

m.

Discussion

The count rates observed during left ventricular FPRNA studies using 99Tc

m and

191Irm were within

the limits of accurate dead time correction for this gamma camera system. Left ventricular counts

were sufficiently high to measure left ventricular function accurately [15].

Window selection on the 191

Irm spectrum with the pulse height analyser is of major importance for

both camera resolution and linearity when performing studies with this tracer. Although the 100-

150 keV window is associated with the best camera resolution, this selection is the worst with

respect to count rate capacities and dead time correction because the relative low contribution of

those photons to the total number of photons reaching the crystal and because of the pile-up events.

Accurate dead time corrections with the reference activity source were obtained, in the 50-100 keV

as well as in the 50-150 keV window, for count rates higher than those observed in patients during

left ventricular first pass studies. Although the spatial resolution of the 50-100 keV was somewhat

better than the 50-150 keV window, this latter was chosen for clinical studies because the accuracy

of first pass measurements is known to be more sensitive to count rate than to spatial reslution [15].

Using this window, the number of counts in the left ventricular cavity with 191

Irm were at least equal

to those obtained with 99Tc

m in all patients.

During the right ventricular transit phase of the bolus, the total count rate was obviously over the

count rate capacities of the camera in most patients precluding simultaneous studies of the right en

left ventricles during a single injection of 191

Irm.

In our patient population, the mean total activity in the 20 cm field of view of the camera was about

1.15 times higher during diastole than during systole, introducing a relative dead time correction of

1.03 to 1.04. On the other hand, for 191

Irm, the relative decay correction between diastolic and

systolic frames ranged between 1.04 and 1.06. As the linearity correction factor and the decay

correction factor work in the opposite direction, an error of maximum 3% would be made on the

ejection fraction not applying any correction. For large field of view gamma cameras one can

expect a smaller relative dead time correction between diastolic and systolic frames due to a less

varying total activity in the large field of view.

18

Fig. 3. Time-activity curves of a decaying

191Ir

m source (initial activity 100 mCi) in the 50-100, 100-150 and

50-150 keV windows, respectively. For display purposes, the activity of the 191Os reference source and of the

misplaced events recorded simultaneously, were multiplied by a factor of 5.

References

1. Sporn V, Perez Balino N, Holman BL et al. Simultaneous measurement of ventricular

function and myocardial perfusion using the technetium-99m isonitriles. Clin Nucl Med

1988; 13: 77-81.

2. Baillet GY, Mena IG, Kuperus JH et al. Simultaneous technetium-99m MIBI angiography

and myocardial perfusion imaging. J Nucl Med 1989;30: 38-44.

3. Brihaye C, Butler TA, Knapp FF Jr et al. A new osmium-191/iridium-191m radionuclide

generator system using activated carbon. J Nucl Med 1986; 27: 380-7.

19

4. Packard AB, Treves ST, O’Brien GM, Lim KS. An osmium-191/iridium-191m radionuclide

generator using an oxalato osmate parent complex. J Nucl Med 1987; 28: 1571-6.

5. Issachar D, Abrashkins S, Weinigerr J et al. Osmium-191/iridium-191m generator based on

silica gel imregnated with tridodecylmethylammonium chloride. J Nucl Med 1989; 30: 538-

41.

6. Heller GV, Treves ST, Parker JA et al. Comparison of ultrashort-lived iridium-191m with

technetium-99m for first pass radionuclide angiocardiographic evaluation of right and left

ventricular function in adults. J Am Coll Cardiol 1986; 7: 1295-302.

7. Hellman C, Zafrir N, Shimoni A et al. Evaluation of ventricular function with first pass

iridium-191m radionuclide angiography. J Nucl Med 1989; 30: 450-7.

8. Franken PR, Dobbeleir A, Ham HR et al. Clinical usefulness of ultrashort-lived iridium-

191m from carbon-based generator system for the evaluation of the left ventricular function.

J Nucl Med 1989; 30: 1025-31.

9. Brihaye C, Dewez S, Guillaume M et al. Reactor production and purification of osmium-

191 for use in a new OS-191/Ir-191m radionuclide generator system. Appl Radiat Isot 1989;

40: 183-9.

10. Performance standards of scintillation cameras, Standards Publication/No. NU 1-1986.

National Electrical Manufacturers Association.

11. Ullman V, Husak V, Dubroka L. Deadtime correction in dynamic radionuclides studies by

computer. Eur J Nucl Med 1978; 3: 197-202.

12. Johnston AS, Arnold JE, Pinsky SM. Anger camera deadtime: marker source correction and

two parameter model. J Nucl Med 1975; 16: 539.

13. Lange D, Hermann HJ, Wetzel E, Schenck P. Critical parameters to estimate the use of a

scintillation camera in high dose dynamic studies. Medical Radionuclide Imaging (Proc.

Symp. Los Angeles) 1. Vienna: IAEA 1977; 85-100.

14. Johnston AS, Gergans GA, Kim I et al. Deadtime of computers coupled with anger cameras:

counting losses and false counts. Single photon emission computed tomography and other

selected computer topics (Proc. Symp. Miami 1980). Sorenson, ed. New York: Society of

Nuclear Medicine.

15. Dymond DS, Elliot A, Stone D et al. Factors that affect the reproducibility of measurements

of left ventricular function from first pass radionculide ventriculograms. Circulation 1982;

65: 311-22.

20

2.2 Variability of left ventricular ejection fraction and volumes by quantitative gated

SPET : influence of algorithm, pixel size and reconstruction parameters in normal

and small-sized hearts.

Anne-Sophie Hambye1, Ann Vervaet

2, André Dobbeleir

2,3

1Nuclear Medicine, CHU-Tivoli, La Louvière, Belgium

2Nuclear Medicine, Middelheim Hospital, Antwerp, Belgium

3Nuclear Medicine, University Hospital Ghent, Ghent, Belgium

Eur J Nucl Med Mol Imaging 2004; 31: 1606-1613.

Abstract

Several software are commercially available for quantification of left ventricle ejection fraction and

volumes from myocardial gated SPET, all with a high reproducibility. However, their accuracy has

been questioned in patients with a small-sized heart. This study aimed at evaluating the

performances of different software and the influence of modifications in acquisition or

reconstruction parameters on ejection fraction and volumes measurements, depending on the heart

size. Methods: Sixty-four2 and 1282 matrix size acquisitions were consecutively obtained in 31

patients referred for gated SPET. After reconstruction by filtered backprojection (Butterworth, 0.4,

0.5 or 0.6 cyc/cm cutoff, order 6), LVEF and volumes were computed with different software (3

versions of Quantitative Gated SPECT (QGS), Emory Cardiac Toolbox (ECT) and the Stanford

University (SU) Medical School algorithm), and processing workstations. Depending upon their

end-systolic volume (ESV), patients were classified into 2 groups: Group I (ESV>30ml, n=14) and

Group II (ESV <30ml, n=17). Agreement between the different software, and the influence of

matrix size and sharpness of the filter on LVEF and volumes were evaluated in both groups.

Results: In Group I, the correlation coefficients between the different methods ranged from 0.82 to

0.94 except for SU (r=0.77), and were slightly lower for volumes than ejection fraction. Mean

differences between the methods were not significant, except for ECT which LVEF values were

systematically higher by more than 10%. Changes in matrix size had no significant influence on

LVEF or volumes. On the other hand, a sharper filter was associated with significantly larger

volume values though this did usually not result in significant LVEF changes. In Group II, many

patients had a LVEF at the higher range. The correlations coefficients between the different

methods ranged between 0.80 and 0.96 except for SU (r=0.49), and were slightly worse for volumes

than LVEF values. Contrary to Group I, a majority of mean differences between LVEF

measurements was significant. LVEF was systematically the highest by ECT and the lowest by SU.

With QGS, changes in matrix size from 642 to 1282 were associated with significantly larger

volumes as well as lower LVEF values. Increasing the filter cutoff frequency had the same effect.

With SU-Segami, a larger matrix was associated with larger end-diastolic and smaller end-systolic

volumes, resulting in a highly significant increase in LVEF. Increasing the filter sharpness on the

other hand had no influence on LVEF though the measured volumes were significantly larger.

Conclusion: In patients with a normal-sized heart, LVEF and volume estimates computed from

different commercially available software for quantitative gated SPET are well correlated. LVEF

and volumes are little sensitive to changes in matrix size. Smoothing on the other hand was

associated with significant changes in volumes but usually not in LVEF values. However, owing to

21

the specific characteristics of each algorithm, software should not be interchanged for follow-up in

an individual patient.

In small-sized hearts on the other hand, both the used software and the matrix size or smoothing

significantly influence the results of quantitative gated SPET. LVEF at the higher range are

frequently observed with all the studied software except for SU-Segami. A larger matrix or a

sharper filter could be suggested to enhance the accuracy of most commercial software, more

particularly in patients with a small heart.

Keywords: quantitative gated SPET – LVEF – small heart – inter-software comparison

Introduction

Gated myocardial SPET has become the state-of-the-art for myocardial perfusion imaging, offering

the simultaneous evaluation of left ventricular perfusion and function with a single test. Different

methods to quantify left ventricular ejection fraction (LVEF) and volumes have been described [1-

6], all with a high reproducibility and a good agreement with various non nuclear or nuclear

techniques [6-10].

However, owing to the specific characteristics of each algorithm, software interchangeability for

repeated examinations in an individual patient should not be recommended [9,11] despite the good

correlations reported between different software computing the same gated SPET data [8,9,11].

Moreover, experimental data have revealed the sensitivity of gated SPET measured LVEF to

particular acquisition conditions such as time of imaging, background activity or injected dose [12],

filtering and zooming [13-15], and larger discrepancies between the methods have been described

for LV volumes [8], particularly at both ends of the scope of volume values.

Another problem in using quantitative gated SPET for LVEF calculation is encountered in patients

with a small heart such as children or some small women. Indeed, due to the limited spatial

resolution of the gamma cameras, the opposite endocardial edges of the left ventricle overlap, so

that the ventricular cavity may become almost virtual especially at end-systole. This results in an

underestimation of volumes, hence overestimation of LVEF [13-17], particularly using algorithms

based upon edge detection.

The purpose of our study was to compare LVEF and volumes computed from the same gated SPET

data by different versions of the QGS-package [1], the Emory Cardiac Toolbox [4,5] and the

Standford-University algorithm [6], and to evaluate the influence of filter and matrix size on the

measurements.

Material and methods

Patients and acquisition

During a 3-month period, QGS-analysis [1] was systematically performed in all patients undergoing

a stress test as a part of a two-day stress-rest gated myocardial SPET. Depending upon their end-

systolic volume (ESV) calculated on a GE-Elscint Expert system, the patients were classified into a

group with a normal or large-sized heart (ESV >30 ml, Group I) and a group with a small-sized

heart (ESV <30 ml, Group II). This value of 30ml-ESV was chosen based upon data from Ford et

al, reporting that the difference between measured and true LVEF in a cardiac phantom becomes

pronounced when the end-diastolic volume is <70 ml and the true LVEF is >40% [14]. Clinical

characteristics of the both patients groups are reported in Table 1.

Among those who required a comparative rest test, 31 underwent two consecutive gated SPET at

rest: 14 of Group I and 17 of Group II. Decision to perform this double rest study was based solely

upon the availability of free time-slots on the gamma-camera. The first acquisition in matrix 642,

zoom 1.28 (6.9 mm-pixel size) started about 1 hour after injection of 740-1000 MBq 99mTc-

sestamibi and was immediately followed by a second acquisition in a 1282 matrix, zoom 1.28 (3.45

mm-pixel size). Both SPET acquisitions lasted 25-30 minutes and were performed with a GE-

22

Elscint VariCam dual-head gamma camera equipped with VPC-35 collimators (system resolution of

9.0 mm FWHM at 10 cm distance; 290 cpm/µCi), using an eight-bin gated protocol (90 projections

(45/head) of 35 second/each; 360°-rotation; automatic body-contouring).

Gated SPET Analysis

Acquisition data sets were transferred from the GE-Elscint Expert system to a Sun Ultra10 Link

Medical system (Link Medical, Hamshire, UK), a PC-Windows NT GE system (GE Medical

Systems, Milwaukee, USA) and a PC-Windows NT Segami system (Segami, Columbia, USA)

using DicomP10, and to a Nuclear Diagnostic Hermes system (Nuclear Diagnostic, Stockholm,

Sweden) using modified interfile. The rough 642 and 1282 matrix gated SPET acquisitions were

reconstructed with Butterworth filters of 0.4, 0.5 or 0.6 cyc/cm cutoff (order 6) on different

workstations. LVEF and volumes were automatically quantified from the gated coronal slices using

commercially available software routinely used by the nuclear medicine community (three versions

of Quantitative Gated SPECT (QGS), Cedars-Sinai Medical Center, Los Angeles, CA; Emory

Cardiac Toolbox (ECT), Emory University, Atlanta, GA; Stanford University (SU) Medical School

algorithm). These six different processings will be further referred to as QGS-Link, QGS-GE, QGS-

Hermes, QGS-eNTEGRA, ECT-eNTEGRA and SU-Segami respectively. All have been described

in detail elsewehere [1,3-5] and widely validated.

Table 1. Clinical characteristics of the patient population (p=NS if >0.05).

Group I: ESV > 30ml; Group II: ESV <30 ml; CRF: cardiovascular risk factors; MI: myocardial infarction;

bicycle: upright bicycle stress test, 25W increment/2 min up to maximum heart rate; adenosine:

140µg/kg.min during 6 minutes; dobutamine: 10 to 40µg/kg.min with 3-min increments, + atropine if

required.

Group I (n=14) Group II (n=17) P value

Age (years); mean±SD 55.3±14.6 65.1±12.1 0.048

Gender (M/F) 7 / 7 2 / 15 0.044

CRF 7 10 NS

Prior MI 5 1 NS

Prior revascularization 5 4 NS

Referral reason

Chest pain

Abnormal stress EKG

Other

9

2

3

16

1

0

NS

NS

NS

Kind of stress test

(bicycle/adenosine/dobutamine)

9 / 4 / 1

8 / 9 / 0

NS

Evidence of stress ischemia on SPECT 5 6 NS

23

Statistical analysis

Results are expressed in absolute EF units for LVEF and in ml for the volumes.

All statistical analyses were performed using the SPSS statistical program package (SPSS Inc,

Chicago, USA). Inter-method variability was expressed as mean difference +/- SD. The significance

of the difference between two groups of data was assessed by the paired or unpaired Student’s t-test

and chi squared test or Fisher’s exact test, when appropriate. Paired data among three or more

groups were compared using repeated measurements ANOVA. A p value of 0.05 or less was

considered significant.

To identify the differences for multiple testing, a Bonferroni correction was applied for comparing

each pair of methods. With this correction, a p value of less than 0.0033 was considered significant.

Pearson correlation coefficients were calculated, and Bland-Altman plots [18] were generated to

search for trends by plotting the differences versus averages of paired values. For this part of the

analysis, QGS-Link was arbitrarily chosen as a reference against which the other methods were

plotted, as it constituted the last version of the most widely spread quantification method.

Fig 1. Bland-Altman plots showing the agreement for ejection fraction between the reference method (QGS-

Link) and the other packages. (ESV>30ml in open circles; ESV<30ml in solid circles).

LVEF: left ventricular ejection fraction; ESV: end-systolic volume.

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

0,0 20,0 40,0 60,0 80,0 100,0

mean

QGS GE - QGS Link

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

0,0 20,0 40,0 60,0 80,0 100,0

mean

QGS Hermes-QGS Link

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

0,0 20,0 40,0 60,0 80,0 100,0

mean

QGS eNTEGRA-QGS Link

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

0,0 20,0 40,0 60,0 80,0 100,0

mean

SU Segami-QGS Link

-25

-20

-15

-10

-5

0

5

10

15

20

25

30

35

0,0 20,0 40,0 60,0 80,0 100,0

mean

ECT eNTEGRA-QGS Link

24

Results

Using repeated measures analysis of variance between the six processings and the two groups of

patients, a highly significant interaction was found, indicating that the impact of the software

differed for the two patients groups. In addition, a significant overall difference was found between

the six methods and also between the two patients groups (both p<0.001).

Influence of the processing algorithm on ejection fraction and volume values.

Group I (ESV> 30 ml).

The different methods were fairly correlated with QGS-Link, with r values ranging between 0.82

and 0.94, except for SU-Segami (r=0.77).

Mean LVEF and volume values were quite similar for the different methods, except for ECT-

eNTEGRA which resulted in higher LVEF (Table 2). By Bland-Altman analysis, no significant

trend toward higher or lower LVEF was found across the whole range of values for any method but

ECT-eNTEGRA compared to QGS-Link (Figure 1, open circles). By paired Student’s t-test, highly

significant differences (0.0001<p<0.0033) were noted between ECT-eNTEGRA and the other

methods for LVEF and end-systolic but not for end-diastolic volume values (Table 3). Significant

differences were also found for volume values between the QGS versions.

Group II (ESV<30 ml)

In keeping with Group I, all methods except SU-Segami correlated well with QGS-Link (r values

between 0.80 and 0.96; r=0.49 for SU-Segami).

Mean LVEF values were above 70% for all programs except for SU-Segami (mean LVEF: 60.4%,

Table 2), and was highest by ECT-eNTEGRA. Opposite to Group I however, inter-method

variability was quite large and most mean LVEF differences were significant (Table 3). Significant

disparities in volume estimates were more frequent for end-systolic than end-diastolic volumes, and

were particularly large for SU-Segami (between 10ml and 20ml, all p values <0.0001, Table 3).

Compared to QGS-Link, LVEF was systematically higher by ECT-eNTEGRA (8.1±5.46%) and

lower by SU-Segami (-13.7±8.01%) as shown on the Bland-Altman plots (Figure 1, solid circles).

More surprisingly, a small but systematic difference in LVEF was also found by Bland-Altman

analysis between the three versions of the QGS software, reaching the level of statistical

significance for QGS-Hermes (Table 3).

Table 2. Mean±SD ejection fraction and volumes for the different software

(Group I: ESV > 30ml; Group II: ESV <30 ml; LVEF: left ventricular ejection fraction;

EDV: end-diastolic volume; ESV: end-systolic volume).

QGS Link QGS GE QGS Hermes QGS

eNTEGRA

ECT

eNTEGRA

SU Segami

LVEF (%) 45.1±12.98 47.4±12.43 49.4±12.48 47.5±13.53 62.0±14.13 50.1±12.67

EDV (ml) 119.5±66.24 122.4±63.85 112.6±63.85 119.3±65.76 108.2±51.22 119.3±49.19

Group I

ESV (ml) 72.3±59.96 69.9±58.32 62.7±52.47 69.9±57.89 46.1±41.14 64.3±45.45

LVEF (%) 74.5±9.06 70.1±7.35 78.1±8.49 73.1±7.80 82.4±8.24 60.4±5.43

EDV (ml) 53.6±17.23 57.8±15.68 51.6±18.21 55.6±17.31 54.9±17.25 70.9±15.25

Group

II

ESV (ml) 14.8±9.02 17.1±6.86 12.8±8.38 15.9±8.41 10.1±5.76 28.5±7.65

25

Influence of filtering on left ventricular ejection fraction and volume values.

For this part of the study, 642 matrix size images were used. Due to technical limitations of some

programs at our disposal at the time of the study, only QGS-GE, QGS-Hermes and SU-Segami

were compared.

Group I (ESV> 30 ml).

Increasing the cutoff frequency of the Butterworth filter from 0.4 to 0.6 cyc/cm (order 6) resulted in

significantly larger volumes for both QGS versions, and smaller volumes

for SU-Segami. However, the subsequent changes in LVEF were significant only by QGS-GE

(Table 4). The effect of filtering was more striking for the end-systolic volumes in relative values,

although the absolute changes were usually higher for the end-diastolic (Table 4).

Group II (ESV<30 ml)

Sharper filtering resulted in significantly larger volumes for QGS, and particularly the end-diastolic,

and in smaller volumes for SU-Segami. The ensuing LVEF change was however significant only

for the QGS-versions, the SU-Segami LVEF remaining remarkably stable (Table 4).

Table 3. Mean±SD difference in ejection fraction and volumes value according to the processing method

used.

(Group I: ESV > 30ml; Group II: ESV <30 ml; LVEF: left ventricular ejection fraction (%); EDV: end-

diastolic volume (ml); ESV: end-systolic volume (ml)).

P values are calculated using the Student’s paired t-test after Bonferroni correction. *: 0.0001<p<0.0033; **:

p<0.0001. All p values >0.0033 are considered as not significant.

Group I Group II

LVEF EDV ESV LVEF EDV ESV

QGS Link-QGS GE -2.2+/-7.61 -2.9+/-12.26 2.4+/-11.52 3.3+/-4.39 -3.8+/-6.81 -1.6+/-3.07

QGS Link-QGS Hermes -4.3+/-4.60 6.9+/-9.33 9.6+/-8.36 * -2.9+/-2.50 * 2.2+/-8.27 1.7+/-2.95

QGS Link-QGS eNTEG -2.3+/-7.57 1.8+/-14.59 3.8+/-13.58 1.1+/-2.47 -0.9+/-2.76 -0.7+/-1.88

QGS Link-ECT eNTEG -16.9+/-8.16 ** 11.3+/-21.95 26.1+/-22.52 * -8.1+/-5.46 ** 0.6+/-8.79 5.1+/-4.50 *

QGS Link-SU Segami -4.9+/-8.69 0.2+/-23.9 8.0+/-19.48 13.7+/-8.01 ** -17.5+/-6.09 ** -13.5+/-4.29 **

QGS GE-QGS Hermes -2.1+/-5.94 9.8+/-8.46 * 7.1+/-10.60 -6.2+/-3.42 ** 5.6+/-11.9 3.1+/-3.29

QGS GE-QGS eNTEG -1.0+/-3.74 5.4+/-10.53 2.5+/-8.56 -2.4+/-3.05 2.8+/-6.88 1.1+/-2.82

QGS GE-ECT eNTEG -14.6+/-4.8 ** 14.2+/-17.68 23.7+/-18.94 * -11.8+/-6.35 ** 3.5+/-11.91 6.9+/-2.53 **

QGS GE-SU Segami -2.7+/-4.91 3.1+/-18.03 5.6+/-15.16 9.7+/-7.28 ** -13.2+/-7.61 ** -11.4+/-4.65 **

QGS eNT-QGS Herm -2.0+/-5.87 5.0+/-12.35 5.9+/-11.71 -4.1+/-2.25 ** 2.9+/-7.65 2.4+/-1.91 *

QGS eNT-ECT eNTEG -14.4+/-4.87 ** 10.9+/-16.8 23.0+/-16.84 * -9.4+/-5.32 ** 0.7+/-8.20 5.8+/-3.87 **

QGS eNTEG-SU Seg -2.2+/-7.06 -0.7+/-18.5 4.5+/-15.42 12.3+/-7.45 ** -16.4+/-4.92 ** -12.8+/-3.69 **

QGS Herm-ECT eNT -12.6+/-7.25 ** 4.4+/-15.69 16.6+/-15.66 * -5.2+/-5.54 -1.4+/-8.01 3.5+/-4.16

QGS Herm-SU Segami -0.6+/-6.77 -6.6+/-16.29 -1.6+/-11.98 17.1+/-8.43 ** -19.1+/-6.76 ** -15.1+/-3.92 **

SU Sega-ECT eNTEG -11.9+/-6.63 ** 11.1+/-12.45 18.1+/-9.4 ** -21.7+/-9.02 ** 17.1+/-8.27 ** 18.6+/-4.27 **

26

Table 4: Influence of the filter cutoff frequency (order 6) on mean values for ejection fraction, end-diastolic

and end-systolic volumes. The p values are calculated by overall repeated measurements ANOVA (p=NS if

>0.05)

(Group I: ESV > 30ml; Group II: ESV <30 ml; BW: Butterworth filter; LVEF: left ventricular ejection

fraction; EDV: end-diastolic volume; ESV: end-systolic volume).

Group I

Group II

BW 0.4 BW 0.5 BW 0.6 P value BW 0.4 BW 0.5 BW 0.6 P value

EF (%) 48.1 47.4 45.1 0.008 72.6 70.1 69.8 0.003

EDV (ml) 111.1 122.4 122.3 <0.001 50.7 57.8 57.5 <0.0001

QGS GE

ESV (ml) 62.0 69.9 72.7 <0.0001 13.7 17.1 17.1 <0.0001

EF (%) 49.6 49.5 48.7 NS 82.5 78.1 77.1 0.007

EDV (ml) 100.9 112.6 118.9 <0.0001 47.8 51.6 56.3 <0.0001

QGS

Hermes

ESV (ml) 55.7 62.7 67.7 0.002 10.0 12.8 13.9 0.004

EF (%) 49.5 50.1 49.0 NS 60.3 60.4 60.5 NS

EDV (ml) 128.6 119.3 112.9 <0.0001 74.3 70.9 67.9 0.002

SU

Segami

ESV (ml) 69.8 64.3 62.1 <0.001 29.8 28.5 26.9 0.003

Influence of matrix size on left ventricular ejection fraction and volume values.

For this part of the study, the 0.5 cyc/cm Butterworth filter images (order 6) were processed by

QGS-GE, QGS-Hermes and SU-Segami.

Group I (ESV> 30 ml).

In this group, modifying the matrix size did not significantly influence mean LVEF and volume

values except for the end-diastolic volumes by SU-Segami (Table 5). Mean± SD differences (matrix

642 – 128

2) for LVEF, EDV and ESV were respectively 0.7±5.88%, 3.6±13.3 ml and 1.9±12.05 ml

for QGS-GE, 0.6±6.15%, –1.7±8.97 ml and -1.3±8.96 ml for QGS-Hermes, and -3.9±7.18%, -

9.1±10.51 ml and -1.1±9.36 ml for SU-Segami.

Group II (ESV<30 ml)

Decreasing the pixel size from 6.9 to 3.45 mm significantly modified the LVEF and volume values

regardless of the used processing (Table 5).

Using QGS, a smaller pixel size was associated with lower LVEF and larger volumes. Mean± SD

differences (matrix 642 – 128

2) for LVEF, EDV and ESV were respectively 2.8±4.36% (p=0.021), -

6.8±8.28 ml (p=0.004) and -4.1±4.24 ml (p=0.001) for QGS-GE, and 5.1±4.66% (p=0.001), –

6.7±7.02 ml (p=0.003) and -3.8±3.07 ml (p<0.0001) for QGS-Hermes. The effect of a smaller pixel

size seemed particularly marked for end-diastolic volumes of 60ml and below.

Using SU-Segami, results were divergent for end-diastolic and end-systolic volumes, the former

increasing from a mean value of 70.9 ml to 76.1ml for the 1282 matrix (p=0.014), and the latter

decreasing from 28.5 ml to 20.5 ml (p<0.001). As a consequence, LVEF increased by 12.9±5.74%

on average (p<0.0001).

27

Table 5: Influence of the acquisition matrix (642 or 128

2) on mean values for ejection fraction, end-diastolic

and end-systolic volumes. The p values are calculated by paired Student’s t-test (p=NS if >0.05).

(Group I: ESV > 30ml; Group II: ESV <30 ml; LVEF: left ventricular ejection fraction; EDV: end-diastolic

volume; ESV: end-systolic volume).

Group I

Group II

Matrix size 642 128

2 P value 64

2 128

2 P value

LVEF (%) 47.4 46.6 NS 70.1 67.4 0.021

EDV (ml) 122.4 118.9 NS 57.8 64.6 0.004

QGS GE

ESV(ml) 69.9 68.0 NS 17.1 21.2 <0.001

LVEF (%) 49.4 48.9 NS 78.1 71.5 0.001

EDV (ml) 112.6 114.4 NS 51.6 58.5 0.003

QGS

Hermes

ESV(ml) 62.7 64.0 NS 12.8 17.4 <0.0001

LVEF (%) 50.1 53.9 NS 60.5 73.4 <0.0001

EDV(ml) 119.3 128.4 0.006 70.9 76.1 0.014

SU

Segami

ESV(ml) 64.3 65.4 NS 28.5 20.5 <0.0001

Discussion

Using gated myocardial SPET, several algorithms have been developed for the calculation of LVEF

and volumes, each owing its specific assumptions for left ventricle modeling. Among the various

commercial programs, Cedars-Sinai Quantitative Gated SPECT (QGS, 1) is currently the most

widely used in the clinical setting. Its reliability and reproducibility are excellent and have been

validated against a whole range of methods. Nevertheless, with increased routine use, some

limitations have appeared, such as a falsely elevated LVEF in patients with a small-sized heart like

children or some women [14,16].

In patients with a normal- or large-sized heart, our study confirms the good agreement for LVEF

between different processing methods [7-9] and the absence of significant bias through the whole

range of LVEF values. Indeed, except for ECT-eNTEGRA that systematically overestimated LVEF

by more than 10%, no significant method-related mean differences in LVEF were noted. This

overestimation of LVEF by ECT has also been reported by others, including the authors of the

program themselves [9,19], and might be due to specificities in time sampling or shape used for LV

modeling [19]. Despite this good agreement, interchanging algorithms, or even consecutive

versions of the same algorithm for follow-up studies in an individual patient should not be

recommended because of the rather large standard deviation of the differences between the

methods. For the volume values, and more particularly the end-systolic, we found a larger

variability than for LVEF, with significant differences not only between ECT-eNTEGRA and the

other programs, but also between the three versions of QGS, maybe due to (minor) modifications of

its algorithm. In this patient population, increasing the matrix size had no significant influence on

volume or LVEF values. Increasing the filter cutoff frequency on the other hand significantly

modified the volume measurements, though this resulted in significant changes in LVEF only with

QGS-GE.

In patients with a small-sized heart, most mean differences in LVEF were significant despite a good

agreement between the different methods except for SU-Segami. Moreover, a systematic bias was

noted not only for ECT-eNTEGRA but also for SU-Segami which volumes were systematically

28

markedly larger, probably due to differences in the location of the ventricular wall which

corresponds to the average position for the latter and to the endocardial surface for the former [7].

Also changes in matrix of filter cutoff significantly influenced volume and LVEF values in small

hearts. This influence of the pixel size has already been reported by Nakajima et al in a cardiac

phantom study [13]. They found a decrease from 49% to 3% in the overestimation of a 37-ml

chamber volume by increasing the zoom from none to 2x during the acquisition, and confirmed

their findings in a pediatric population, but only in children younger than 7 years [13]. However, the

1.28x-zooming applied in the present study is the maximum magnifying factor that can be used for

a 60cm-field of view gamma camera without mechanical device keeping the heart in the center of

rotation, so that we were compelled to increase the matrix from 642 to 128

2 to reduce the pixel size

from 6.9 to 3.45 mm and so improve the delineation of the left ventricle endocardial border. Using

QGS, this modification resulted in significantly larger volumes and lower LVEF, particularly for

end-diastolic volumes of 60ml and below. By SU-Segami on the other hand, the combination of

larger end-diastolic and smaller end-systolic volumes for a 1282 matrix resulted in a highly

significant increase in LVEF, probably because of an insufficient count density and thus enhanced

statistical fluctuations.

By increasing the cutoff frequency of the Butterworth filter from a smooth 0.4 to a sharper 0.6

cyc/cm, larger volumes and a significant decrease in LVEF was obtained by QGS. By SU-Segami

on the contrary, LVEF remained stable despite significantly smaller volumes with a sharper filter,

probably because of parallel changes in end-diastolic and end-systolic volumes. The influence of

smoothing on LVEF and volumes could be due to the fact that, because of the limited spatial

resolution of a gamma-camera, the proportion of LV volume contained in an individual pixel is

larger in small than in large-sized hearts. In this way, changes in count density of the (especially

endocardial) pixels related to the cardiac motion are probably more abrupt for higher cutoff

frequency filtering. With a smooth filter, the systolo-diastolic transition in count density might be

softer, hence volume estimates smaller and LVEF higher. The lesser filter-dependence observed

with SU-Segami could be explained by the fact that its algorithm relies on the average ventricular

wall position instead of the endocardial surface.

This study compared different processing methods for quantitative estimates of LVEF and volumes

using gated myocardial perfusion SPET. Despite good correlations with regard to the calculated

values, clear differences were found between the algorithms, and more particularly between SU-

Segami and the other methods, especially in patients with a small heart. No single external standard

was available in our patients to determine the “true” values, so that the most recent version of the

most widely used program was arbitrarily chosen as a reference. Therefore, the calculated results

might be only a rough estimation of the patients’ real LVEF and volumes. However, since we

aimed at correlating different processing methods computing the same gated SPET data, the use of

an external standard does not seem an absolute prerequisite to validate the results. Another

limitation consists in the use of low-energy general-purpose collimators (system resolution: 9.0 mm

FWHM at 10 cm distance) for the gated SPET acquisition. Indeed, a high-resolution collimator

should be preferred from a theoretical point of view since resolution recovery is expected to affect

small volumes more than large. With a high resolution collimator, a 1.5 mm gain in resolution could

be anticipated, but at the expense of a 40 %-count reduction which would require a smoother filter,

hence loss of resolution, for acceptable image quality. The choice of general-purpose collimators

constitutes thus a compromise between resolution and noise, especially using an automatic body-

contouring to reduce the patient-collimator distance. A last limitation concerns the small number of

patients included. Despite this small sampling, highly significant results could be found so that this

should not considered a major drawback, all the more as our purpose was to compare the different

software currently available and not to identify the best of them.

29

Conclusion

In patients with a normal-sized heart, quantitative estimates of left ventricular functional data

computed from gated myocardial perfusion SPET by different commercially available software

show excellent correlation. Inter-software, or even inter-version variability for an individual

software is however present, especially regarding the volume values. Technical parameters such as

matrix size or filter cutoff frequency have little influence on LVEF measurements but a sharper

filter significantly modify the calculated volumes. Consequently, definition of specific normal

limits should be advised for each algorithm, and software permutation should be avoided for

follow-up studies in an individual patient.

In small-sized hearts on the other hand, ejection fraction value in the (very) high range, most

probably overestimated, is observed in a significant number of cases, so that the accuracy of gated

SPET measured LVEF and volumes in these patients might be questioned. However, increasing the

matrix size or the filter cutoff frequency results in significantly lower, probably more realistic

LVEF with all the tested software except the SU-Segami. Although further confirmation of our

results and validation of the correctness of the measurements is required, a smaller pixel size and/or

a sharper filter might be suggested for quantitative gated SPET in patients with a small-sized heart.

Acknowledgments

The authors whish to thank H. Ham, MD, PhD, for his friendly comments and criticisms in the

review of this manuscript. None of the authors has a financial interest in any software package. This

study did not receive any vendor support.

References

1. Germano G, Kiat H, Kavanagh PB, Moriel M, Mazzanti M, Su H, et al. Automatic

quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 1995;

36:2138-47.

2. Germano G, Kavanagh PB, Kavanagh JT, Wishner SH, Berman DS, Kavanagh GJ.

Repeatability of automatic left ventricular cavity volume measurements from myocardial perfusion

SPECT. J Nucl Cardiol 1998; 5:477-483.

3. Goris ML,Thompson C, Malone L, PR Franken. Modeling the integration of myocardial

regional perfusion and function. Nucl Med Commun 1994; 15: 9-20.

4. Faber TL, Akers MS, Peshock RM, Corbett JR. Three dimensional motion and perfusion

quantification in gated single-photon emission computed tomograms. J. Nucl Med 1991; 32:2311-

2317.

5. Faber Tl, Cooke CD, Folks RD et al. Left ventricular function and perfusion from gated

perfusion images : an integrated method. J Nucl Med 1999; 40: 650-659.

6. Nichols K, DePuey RG, Rozanski A. Automation of gated tomography left ventricular

ejection fraction. J Nucl Cardiol 1996; 3: 475-482

7. Everaert H, Bossuyt A, Franken P. Left ventricular ejection fraction and volumes from gated

single photon emission tomographic myocardial perfusion images: Comparison between two

algorithms working in three-dimensional space. J Nuclear Cardiology 1997;4:472-476.

8. Nichols K, Lefkowitz D, Faber T, et al. Echocardiographic validation of gated SPECT

ventricular function measurements. J Nucl Med 2000;41:1308-14.

30

9. Nakajima J, Higuchi T, Taki J, Kawano M, Tonami N. Accuracy of ventricular volume and

ejection fraction measured by gated myocardial SPECT: Comparison of 4 software Programs. J

Nucl Med 2001; 42: 1571-78.

10. Vourvouri E, Poldermans D, Bax JJ, et al. Evaluation of left ventricular function and

volumes in patients with ischaemic cardiomyopathy : gated single-photon emission computed

tomography versus two-dimentional echocardiography. Eur J Nucl Med 2001;28:1610-15.

11. Lum DP, Coel MN. Comparison of automatic quantification software for the measurement

of ventricular volume and ejection fraction in gated myocardial perfusion SPECT. Nucl Med Comm

2003; 24: 259-266

12. Vallejo E, Dione DP, Bruni WL, et al. Reproducibility and accuracy of gated SPECT for

determination of left ventricular volume and ejection fraction: experimental validation using MRI. J

Nucl Med 2000; 41:874-882.

13. Nakajima K, Taki J, Higuchi T, Kawano M, Taniguchi M, Maruhashi K, Sakazume S,

Tonami N. Gated SPET quantification of small hearts: mathematical simulation and clinical

application. Eur J Nucl Med 2000;27:1372-79.

14. Ford P, Chatziioannou S, Moore H, Dhekne R. Overestimation of the LVEF by quantitative

gated SPECT in simulated left ventricles. J Nucl Med 2001;42:454-459.

15. Manrique A, Hitzel a, Gardin I, Dacher JN, Vera P. Influence of Wiener filter in

determining the left ventricle volume and ejection fraction using thallium-201 gated SPECT. Nucl

Med Comm 2003; 24: 907-914

16. De Bondt P, Van de Wiele C, De Sutter J, De Winter F, De Backer G, Dierckx RA. Age-

and gender-specific differences in left ventricular cardiac function and volumes determined by

gated SPET. Eur J Nucl Med 2001;28:620-24.

17. Achtert AD, King MA, Darlberg ST, et al. An investigation of the estimation of ejection

fractions and cardiac volumes by a quantitative gated SPECT software package in simulated gated

SPECT images. J Nucl Cardiol 1998;5:144-152.

18. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of

clinical measurements. Lancet 1986; 1: 307-310.

19. Nichols K, Santana CA, Folks R et al. Comparison between ECT and QGS for assessment

of left ventricular function from gated myocardial perfusion SPECT. J Nucl Cardiol 2002; 9:285-93

31

2.3 Clinical applications.

Clinical usefulness of ultrashort-lived Iridium-191m from a carbon-based generator system for the evaluation of the left ventricular function.

P.R. FRANKEN, A. DOBBELEIR, H.R. HAM, C. BRIHAYE, M. GUILLAUME, F.F. KNAPP and J. VANDEVIVERE. Nuclear Medicine, Middelheim Hospital, Antwerp and St-Peters Hospital , Brussels, Belgium. Cycloton Research Center, University of Liege, Belgium and Nuclear Medicine Group, Oak Ridge National Laboratory Tennessee, USA. Journal of Nuclear Medicine, 1989; 30: 1025-1031. Abstract

Ultrashort-lived

191mIr (4.96 sec; 63-74 and 129 keV photons) is potentially advantageous for first-pass radionuclide

angiocardiography, offering the opportunity to perform repeat studies with very low absorbed radiation dose to the

patient. Left ventricular (LV) first-pass studies were performed in 72 patients with 191m

Ir from a new bedside 1.3 Ci (48.1

GBq) 191Os/

191mIr generator system using an activated carbon support that offers high

191mIr yields (15-18%) and

consistent low 191Os breakthrough (2-4 x 10

-4 %/bolus). Using a single crystal digital gamma camera, uncorrected end-

diastolic counts in the left ventricular representative cycle ranged from 10 up to 30 k counts. The reproducibility of

repeated LV ejection fraction (LVEF) determination at 2-min intervals in 50 patients was r = 0.97, mean diff. = 2.08 ± 1.55

EF units. Comparison between 191m

Ir (80-120 mCi; 2960-4400 MBq) and 99mTc (20-25 mCi; 750-925 MBq) LV count rates

indicates a 3 wk useful shelf life of this new generator system for cardiac studies. Iridium-191m determined LVEF

correlated closely with 99mTc determined LVEF in 32 patients (r = 0.96, mean diff. = 1.87 ± 1.23 EF units). Parametric

images for LV wall motion analysis were comparable with both isotopes. We conclude that rapid, repeat, and

reproducible high count rate first-pass left ventricular studies can be obtained with 191m

Ir from this new 191Os/

191mIr

generator system using a single crystal gamma camera.

32

Comparison between exercise myocardial perfusion and wall motion

using 201Tl and 191mIr simultaneously.

P.R. FRANKEN, A. DOBBELEIR, H.R. HAM, R. RANQUIN, S. LIEBER, F. VAN DEN BRANDEN, P. VAN DEN HEUVEL, C. BRIHAYE, M. GUILLAUME, F.F. KNAPP and J. VANDEVIVERE. Nuclear Medicine and Cardiology, Middelheim Hospital, Antwerp, Belgium Nuclear Medicine St-Peters Hospital , Brussels, Belgium. Cycloton Research Center, University of Liege, Belgium and Nuclear Medicine Group, Oak Ridge National Laboratory Tennessee, USA.

Nuclear Medicine Communications, 1991; 12: 473-484. Summary

By exploiting the ultrashort halflive

191mIr as tracer for left ventricular first-pass angiocardiography and

201Tl as myocardial

perfusion agent, direct comparison between myocardial perfusion and regional wall motion was obtained during the

same exercise stress test in patients with non-significant coronary artery disease, in patients with recent myocardial

infarction, and in patients six weeks after successful percutaneous transluminal coronary angioplasty (PTCA). A good

agreement between regional myocardial perfusion and regional wall motion was observed in patients with non-significant

coronary artery disease and in most patients with recent myocardial infarction. In contrast, discrepancies occurred at

maximal exercise in patients studied six weeks after successful PTCA: only 38% of the patients with no evidence of

restenosis and with a completely normal myocardial perfusion scintigraphy had a normal regional wall motion at maximal

exercise stress. According to these results, a normal uptake of 201Tl six weeks after PTCA would mean that the

circulation has been successfully re-established but without predicting the functional capacities of the myocardial cells

which remain altered at least six weeks after the revascularization procedure in about two-thirds of the patients. We

conclude that 191m

Ir in combination with 201Tl offers the opportunity of performing myocardial perfusion and wall motion

studies simultaneously both at rest and during exercise.

201Tl myocardial perfusion score

2 1 0

Patients with <5% likelihood of CAD (group I)

2 28 2 0

1 0 0 0

191Irm left ventricular RNA

Wall motion

Score

0 0 0 0

Patients with recent

myocardial infarction (group II)

2 30 9 1

1 6 20 4

191Irm left ventricular RNA

Wall motion Score

0 1 5 14

Patients with successful PTCA (group III)

2 30 0 0

1 13 1 0

Comparison between regional myocardial perfusion score and regional wall motion

score at maximal exercise stress in the

anterior projection.

191Irm left ventricular RNA

Wall motion Score

0 1 0 0

Myocardial perfusion score: 2=normal, 1=moderate hypoperfusion,0=severe hypoperfusion. Regional wall motion score: 2=normal, 1=hypokinesis, 0=akinesis or dyskinesis.

33

3. Myocardial perfusion and viability.

3.1 SPET generated colour-coded polar maps to quantify the uptake of 99m

Tc-

sestaMIBI and 123I-BMIPP in chronically dysfunctional myocardium: comparison

with coronary anatomy and wall motion.

A.S. Hambÿe1, A. Dobbeleir

1, P.R. Franken

2.

1Middelheim General Hospital, Antwerp and

2University Hospital, Free University of Brussels,

Brussels, Belgium.

Nuclear Medicine Communications 1997;18: 1135-1147.

Abstract

The combined use of 123

I-BMIPP and 99m

Tc-sestaMIBI SPET imaging has been proposed as an

alternative to PET for the noninvasive detection of jeopardized myocardium after a myocardial

infarction, a mismatching quite accurately indicating jeopardized but still viable tissue. In this paper

a new quantitative approach is described, expressing the presence and degree of mismatching in %

of the left ventricular surface globally as well as for each major epicardial artery by means of

clearly identified colour-coded polar maps. With this method, the relative proportion of normal and

scar tissue, each characterized by a specific colour, is measured using thresholds of sestaMIBI

uptake of respectively 60% and 30% of the expected mean normal value, whereas the presence and

extent of mismatching between BMIPP and sestaMIBI are calculated only between these two

thresholds, typically corresponding to a flow decrease associated with a possible but uncertain post-

revascularization recovery. Applied to 15 patients with severely impaired left ventricular function

post myocardial infarction, small intra- and interobserver differences were noted in the assessment

of the relative % of normal, mismatched and scar tissue. More specifically analyzing the variability

in the calculated % mismatching, a good reproducibility was observed, with intra- and interobserver

correlation coefficients of 0.96 and 0.94 respectively, mean intraobserver difference of 0.25 % (SD:

2.0%) for the left ventricle globally, 1.65% (SD: 2.9 %) for the LAD, -1.56 % (SD: 3.6 %) for the

LCX and -1.24% (SD: 2.8%) for the RCA territories and mean interobserver variability of 0.91%

(SD: 2.4%) for the left ventricle globally, -1.51% (SD: 3.0%) for the LAD, -0.53% (SD: 2.9%) for

the LCX and -0.34% (SD: 3.9%) for the RCA territories. Using the second standard deviation of the

interobserver difference as criterion of significancy, significant mismatching between BMIPP and

sestaMIBI was noted in 13 arterial territories, corresponding to significant stenoses on coronary

angiogram and/or wall motion abnormalities in all cases. These results suggest that this new

quantitative method, showing a good reproducibility, may constitute a reliable and interesting tool

for the noninvasive evaluation of myocardial viability with SPET.

Key words: myocardial viability - single photon emission tomography - iodinated fatty acids

analogues - perfusion tracer - quantification.

34

Introduction

Despite its high cost and limited availability, positron emission tomography (PET) with 18F-

fluorodeoxyglucose (18F-FDG) remains the golden standard for the noninvasive assessment of

viability after a myocardial infarction (MI). However, attempts are made to replace it by less

expensive techniques, such as stress echocardiography with low-dose dobutamine[1], planar or

tomographic rest/redistribution imaging with 201

Tl [2], or quantification 99m Tc-sestaMIBI uptake at

rest[3]. Regarding this last method, disagreement exists concerning the value of sestaMIBI uptake

separating normal, jeopardized and scar myocardium. Usually, the lower limit of uptake

corresponding to viable tissue is set at 60 % of the maximum, and the upper limit of definitely

necrotic tissue at 30% to 40 %[3,4]. Myocardial regions with perfusion in between constitute a grey

zone, typically considered to contain an admixture of necrotic, viable and normal cells in various

amounts in which potential improvement post-revascularization is not clearly defined.

Recently, several studies have reported an improvement in the accuracy of sestaMIBI perfusion

imaging to assess viability by coupling it to the evaluation of cardiac metabolism using 123

I-labelled

modified fatty acids[5-8]. Indeed, due to an early metabolic switch from beta-oxydation to

glycolysis to preserve the ATP production in hypoxic myocardium, the uptake of fatty acids is

expected to be more reduced than flow in jeopardized but still viable myocardial segments.

Therefore, a mismatching between flow and metabolism, mirroring that obtained with 18F-FDG

PET, is supposed to represent a hallmark of myocardial viability [9]. We have developed a new method to quantify the degree and extent of mismatching between

metabolism (assessed by iodine 123-labeled beta-methyl iodophenyl pentadecanoic acid [123

I-

BMIPP]) and perfusion in terms of % of the left ventricle surface by means of colour-coded polar

maps for various values of 99m

Tc-sestaMIBI uptake.

The current paper describes this new quantitative analysis, and the preliminary results obtained in

15 patients with severe left ventricular dysfunction post myocardial infarction, regarding the intra-

and inter-observer reproducibility and the concordance with the coronary anatomy and the wall

motion assessed by contrast ventriculography.

Material and methods

Patient population

Fifteen patients (13 men; 2 women, mean age +/- SD: 66.1 +/-6.7 years, range: 57-78 years) were

included, all suffering from at least one myocardial infarction and presenting left ventricular

dysfunction (Table 1).The diagnosis of infarction was based upon documented CPK increase at the

time of the acute event, significant electrocardiographic (ECG) modifications and angiographically

proven wall motion abnormalities. Overall, on ECG there were 3 anterior, 7 anteroseptal, 5 inferior,

1 anterolateral and 2 lateral infarctions, with a mean age +/- SD (for the most recent) of 27.1 +/-

58.4 weeks (range: 2-230 weeks). Thrombolysis was the first-line treatment in 9 patients, balloon

angioplasty in 1 and intravenous heparin in 4, the last one having received other drugs.

In all patients, coronary angiogram and left ventricular ventriculogram, sestaMIBI and BMIPP

single photon emission tomography (SPET), and equilibrium radionuclide angiography were

performed within 10 days. Mean ejection fraction value at the time of the tests was 36.1% (SD:

9.6%, range: 19.9% to 51.6%°).

35

Table 1. Clinical characteristics of the patient population (MI: myocardial infarctio; Thr.: thrombolysis;

Hep.: heparin; PTCA: percutaneous transluminal coronary angioplasty; Misc.: other drugs; CABG: coronary

artery bypass grafting; LAD: left anterior descending artery; LCX: left circumflex artery; RCA: right

coronary artery; R. Interm: ramus intermedius; D1: first diagonal branch; L1: first lateral branch.)

Pat number Localization MI

(on ECG)

Age MI

(weeks)

Treated by Previous

revasculari-

zation

Coronary

anatomy (%

stenosis)

LVEF (%)

1 Anterolat. 4 Thr. No LAD:90

D1: 99

32.9

2 Anterosept. 10 Thr. No LAD: 75

LCX: 80

22.4

3 Lateral 3 Hep. No LAD: 70

LCX: 99

32.0

4 Anterosept. 4 Thr. No LAD: 100 41.9

5 Anterior 14 Thr. No LAD: 100

RCA: 50

38.8

6 Anterosept. 2 Thr. No LAD: 99

R. interm: 90

47.0

7 Anteroapic 40 Thr. PTCA LAD: 70

R. interm: 99

51.6

8 Anterosept. 22 Thr. No LAD: 100

LCX: 80

39.7

9 Inferior

Lateral

5

148

Thr. No LAD:70

D1: 99

LCX: 80

26.8

10 Anterosept.

Inferior

3

150

PTCA PTCA LAD: 100

LCX:70

RCA: 90

33.3

11 Anterosept. 3 Misc. No LAD: 99

RCA: 60

25.5

12 Inferior 230 Hep. No LAD: 70

LCX: 60

RCA: 100

19.9

13 Inferior 2 Hep. CABG LCX: 100

RCA: 100

47.6

14 Anterior

Inferior

6

350

Thr. CABG LAD: 100

D1: 70

LCX: 70

43.0

15 Anterosept. 58 Hep. CABG LAD: 100

LCX: 50

L1: 70

39.3

Coronary angiography and contrast ventriculography

Cardiac catheterization was performed using the Judkins technique and recorded on videotape. The

degree of stenosis was determined quantitatively on at least two orthogonal views using a

computer-assisted approach that compares the stenotic segment defined by the observer with a

"normal" segment in the same vessel and expresses the result as a percent narrowing. Significant

stenosis was defined as a reduction of at least 50% of the luminal diameter of one of the major

36

epicardial arteries and/or of their main side branches. Patients with significant narrowing in the

ramus intermedius were considered as suffering from a two-vessel disease (left anterior descending

[LAD] and left circumflex artery [LCX]). Using this criterion, there were no main left stenosis, 2

one-vessel disease, 11 two-vessel disease and 2 triple-vessel disease.

Regional left ventricular wall motion was visually assessed by well-trained invasive cardiologists

from the contrast left ventriculogram, using left and right anterior oblique projections. Seven

myocardial segments (anterobasal, anterolateral, septal, diaphragmatic, posterobasal, posterolateral

and apical) were defined and reported to the three main arterial territories (the first three segments

were assumed to represent the territory of the LAD, the posterobasal and diaphragmatic segments

the territory of the right coronary artery [RCA] and the posterolateral segment that of the LCX, the

attribution of the apical abnormalities if present depending on the location of coexistent

abnormalities in contiguous regions). Segmental contractility was described as normal, hypokinetic,

akinetic or dyskinetic.

Scintigraphic data

Radioiodination of BMIPP was realized at the Free University of Brussels using 123I (p, 5n) and

the Cu(I)-assisted isotopic exchange reaction developed by Mertens [10]. Rest sestaMIBI and BMIPP SPET images were acquired within three days, starting 90 min

postinjection of 925 MBq for 99m

Tc -sestaMIBI, and 30 min postinjection of 166.5 MBq for 123

I -

BMIPP. Both studies were performed after a fasting period of at least 6h and without

discontinuation of any of the patients’ medications. Potassium perchlorate was administered to the

patients 15 min before the injection of BMIPP to block thyroidal uptake of free iodine.

The tomographic images were acquired using a triple-head gamma camera (Triad 88, Trionix Lab.,

Twinsburg, Ohio, USA) equipped with low-energy all-purpose collimators, by using a 360° step-

and-shoot protocol in which each head rotates over 120° and acquires 30 frames of 40 sec for

sestaMIBI and of 60 sec for BMIPP.

Prior to reconstruction, the projection images were corrected for scatter, using a scatter image

acquired in a second window just under the photopeak. For this purpose, the photopeaks were set

respectively at 140 keV for 99m

Tc (window: 126-154 keV) and at 160 keV for 123

I (window: 143-

175 keV), the scatterpeaks being acquired between 100 and 124 keV for 99m

Tc and between 114

and 141 keV for 123

I.

During the processing, the images were compensated for scatter using a substraction method with k

values for the compensation of 0.7 for 99mTc and 1.0 for 123I. These values had been preliminary

established by measurements obtained in phantom studies in our laboratory[11]. Afterwards, reconstruction and reorientation were performed as usual using a Butterworth prefilter (cutoff

frequency 0.75 for sestaMIBI and 0.6 for BMIPP, and an order of 5) and a Ramp-backprojection

filter.

Image interpretation

SestaMIBI and BMIPP series were independently normalized to their own maximum,

corresponding to the region with the highest activity. The distribution of sestaMIBI and BMIPP

uptake was visually analyzed in the three standard orthogonal tomograms and on polar maps using a

10% colour-coded scale and a side-by-side display. The anterior, septal and apical walls were

assumed to represent the territory of the LAD, the lateral wall the territory of the LCX and the

inferior wall the territory of the RCA.

37

Fig. 1. Quantitative analysis of the perfusion and metabolism in a patient with a two-vessel disease, a 5-week

old inferior and 148-week old lateral infarction (patient nr 9).

SestaMIBI (D1) and BMIPP (D2) bull’s eyes are displayed in column D, next to the nine viability polar

maps obtained from the comparison between BMIPP and sestaMIBI uptake in between different thresholds

of perfusion corresponding to normal tissue on one hand (rows 1, 2, 3), and to scar on the other hand

(columns A, B, C). Row 1: normal perfusion if > 70% of the maximum, row 2: normal perfusion if > 60% of

the maximum, row 3: normal perfusion if > 50% of the maximum. Column A: scar if < 40% of the

maximum, column B: scar if < 30% of the maximum, column C: scar if < 20% of the maximum. Normal

tissue is represented by the red colour, scar by the blue colour, mismatching > 20% by the orange colour,

mismatching between 10% and 20% by the yellow colour and matching (equal activity) between BMIPP and

sestaMIBI by the green colour.

Quantitative analysis: the viability polar maps

Starting from the bull’ eyes generated from the short axis sestaMIBI and BMIPP data, nine polar

maps, called the viability polar maps and representing the accumulation of BMIPP for different

levels of sestaMIBI uptake, were generated as follows.

In a first step, since no attenuation correction was applied, the patient’s sestaMIBI and BMIPP polar

maps were divided by a polar map of normal subjects and multiplied by 100 in order to set the

perfusion in all normal myocardial bull’s eye pixels to the same maximum (100%), assuming that

both tracers have the same distribution in normals. The polar map of normal subjects had been

generated from data obtained from a previously described population of 20 healthy volunteers with

a low likelihood (<5%) for coronary artery disease [12].

38

Fig 2. Quantification of the amount of normal, jeopardized and scar myocardium for thresholds of sestaMIBI

uptake corresponding a to > 60% for normal tissue and < 30% for scar (viability polar map displayed on

upper left corner). The second upper polar map shows the surface correction applied to take into account the

relative contribution of each pixel and of each slice of the bull’s eye to the total myocardial surface. The 5

following bull’s eyes (upper row right and mid row left) depict graphically the proportion of the left

ventricular surface corresponding to each specific category (normal, mismatching >20%, mismatching 10%-

20%, equal activity (matching) and scar), proportions which are expressed in % of the left ventricular surface

globally and for the main coronary arteries in the lower row.

Second, since there is no clear consensus in the literature concerning both the lower limit of

sestaMIBI uptake corresponding to normal tissue and the higher value of perfusion definitely

considered as scar, nine different colour-coded bull’s eyes were created that represented the nine

possible combinations obtained by varying the lowest threshold of normal uptake between 50, 60

and 70 % of the expected mean normal value on one hand, and of highest uptake corresponding to

scar between 20, 30 and 40 % on the other hand. The lower limit of normal tissue, defined as a

minimal uptake of sestaMIBI of respectively 50, 60 or 70 %, was represented in red. Scar tissue,

defined as an uptake of sestaMIBI of less than respectively 20, 30 or 40 %, was represented in blue.

In between the defined lower “normal” and upper “scar” limits, the presence and degree of

mismatching between sestaMIBI and BMIPP (representing the amount of jeopardized myocardium)

was quantified and expressed by colour codes. Green was used for matched regions, where the

difference between the uptake of both tracers was less than 10 %. Yellow indicated regions with a

BMIPP uptake between 10 and 20 % lesser than that of sestaMIBI, and orange corresponded to

39

segments where the mismatching was beyond 20 % (Figure 1). Using the polar map display, the

amount of normal, jeopardized and scar tissue as well as the degree and extent of mismatching were

easily identified by means of the different colours.

Lastly, a quantitative analysis of the relative proportion of normal, jeopardized and scar tissue was

performed globally and for each arterial territory after surface correction (Figure 2) and expressed

in % of the left ventricular surface. This surface correction was made necessary to take into account

the surface deformation due to the bull’s eye display. For this purpose, a surface correction bull’s

eye was created. This bull’s eye, generated from data obtained in 14 normal subjects, represents the

relative contribution of each pixel of the bull’s eye to the total myocardial surface as well as of each

bull’s eye slice to the total myocardial surface.

Intra- and interobserver reproducibility

To evaluate the reproducibility of the quantification, intra- and interobserver variability were

assessed respectively by one observer processing the data twice with a 3-weeks interval without

knowledge of his first results, and by two observers unaware of each other reorientation or number

of slices used to create the bull’s eyes.

In both cases, BMIPP and sestaMIBI data were completely reprocessed in all patients starting from

the transaxial tomograms, using a standard software dual-tomo program to reorient the slices. In

this way, the same rotation was applied to all the transaxial images for each individual processing,

and the same number of short axis slices was used to create both sestaMIBI and BMIPP bull’s eyes.

However, the rotation angle as well as the number of slices could differ from one processing to the

other.

The variability of the obtained measurements was evaluated for three categories of tissue: normal,

jeopardized and scar. For the present study, normal tissue was defined as showing a sestaMIBI

uptake of >60% of the mean normal expected value (red colour on the polar map display),

jeopardized tissue as showing a significant mismatching and a sestaMIBI uptake between 30 and

60% (corresponding to the addition of the yellow (10-20% mismatching) and orange (>20%

mismatching) colours of the viability polar map), and scar as the sum of regions with an uptake of

sestaMIBI below 30% and those with matched sestaMIBI and BMIPP uptake (blue + green

colours), since it has been suggested that matching reflected nonviable tissue[5].

Statistics

Mean differences and their standard deviations (SD) were calculated to compare the measurements.

The mean difference constitutes an estimate of the average bias of one result relative to the other,

while the SD represents the likelihood of agreement between both values for an individual patient.

The 95% limits of agreement are given by the mean difference +/- 2 SD. Scatter diagrams of the

data were generated to compare the linear regression equation to the line of equality. The more

informative Bland-Altman analysis was used to evaluate the eventual systematic error in the

measurement of the left ventricular surface[13]. Briefly, this method plots the mean of the paired

observations on the abcissa against the difference between their value on the ordinate. In this way, it

depicts the degree of agreement between the two measurements and the degree of bias of one result

related to the other, and checks visually whether or not the differences are related to the size of the

sampling, using the average as the best estimate of the unknown value. Using this method, a r value

nearing 0, corresponding to an absence of bias between the two observations, must be achieved.

Wilcoxon signed rank test and linear regression analysis were used to evaluate the differences. A p

value of 0.05 or less was considered significant.

40

Fig 3. Scatter plot diagram of the correlation between the percentage jeopardized tissue measured by the two

observers for the global left ventricular surface, quantifying the degree and extent of mismatching for values

of sestaMIBI uptake between 30% and 60%, the values below 30% being considered as myocardial scar and

beyond 60% as normal tissue. The two estimates are highly correlated, with a r value of 0.94.

Results

Intra- and interobserver reproducibility

Using the 30-60% cutoff of sestaMIBI uptake, the amount of mismatching in the left ventricle

ranged between 0.3% and 24.6% of its total surface.

The mean intraobserver variability in assessment of the percentage mismatching in the 15 patients

was 0.25 % (SD: 2.0%) for the left ventricle globally (p=0.68), and 1.65% (SD: 2.9%, p=0.02), -

1.56 % (SD: 3.6 %, p=0.18) and -1.24% (SD: 2.8%, p=0.05) for the LAD, LCX and RCA territories

respectively.

For the assessment of the interobserver reproducibility, the average intraobserver measurement was

compared to the % mismatching obtained by the second observer, resulting in a mean difference of

0.91% (SD: 2.4%) for the total left ventricle surface (p=0.23), -1.51% (SD: 3.0%) for LAD

(p=0.15), -0.53% (SD: 2.9%) for LCX (p=0.68) and -0.34% (SD: 3.9%) for RCA territories

(p=0.91). The correlation coefficients for the left ventricle globally were 0.94 when the two

measurements were performed by two different observers, and 0.96 when the processing was

repeated by the same observer, with standard error of estimate of 2.55% and 2.08% respectively,

and a linear regression analysis showing a slope nearing the unit and a quite small intercept in both

cases as depicted in Figure 3 for the global interobserver variability. This good reproducibility was

confirmed by the Bland-Altman analysis showing small inter- and intraobserver variabilities for the

total left ventricle as well as for each arterial territory (with mean intra- and interobserver

differences +/- SD of 0.25 +/- 2.01% and -0.79 +/- 2.46% respectively), and very similar differences

regardless of the total amount of mismatching for both intra- and interobserver measurements

(interobserver variability: y = -0.04x - 0.51, r = 0.12, Figure 4).

Evaluating the intra- and interobserver reproducibility for the normal and scar tissue, the same

range of mean differences was found, without any statistically significant difference between the

measurements (Table 2).

41

Fig 4. Bland-Altman representation of the interobserver difference in assessment of the amount mismatching

for the left ventricular surface globally, showing a quite small mean +/- SD difference and almost no

relationship between the % mismatching and the total amount of jeopardized tissue (r=0.12).

Quantitative assessment of the presence and degree of mismatching

For the quantitative assessment of the mismatching, in keeping with the 2 standard deviation cutoff

criterion of positivity classically used to define the presence of ischemia when comparing stress and

rest imaging [14], it was decided that the percentage of jeopardized tissue should reach at least the value of the second standard deviation of the interobserver variability to be considered significant

(4.8 % of the left ventricular surface globally, 6.0% for the LAD, 5.8 % for the LCX and 7.8 % for

the RCA). Using these values, significant mismatching was noted in at least one arterial territory in

8 patients (LAD territory in 5 cases, LCX and RCA in 4 cases each). In all cases, the regions with

significant mismatching corresponded to significant stenosis and/or wall motion abnormalities on

coronary angiogram (Table 3). Notheworthy, the age of the myocardial infarction was not

necessarily related to the presence and extent of mismatching, since large amounts of jeopardized

tissue were observed in the LCX region (57.0%) and in the RCA territory (27.6%) in 2 patients

(patients 9 and 10) with 3-year old lateral and inferior MI respectively.

Correlation with the coronary anatomy

A good concordance was noted between the regions with decreased BMIPP and/or sestaMIBI

uptake (regardless of the presence of significant mismatching) on one hand, and the presence of

significant stenosis and/or wall motion abnormalities on coronary angiography on the other hand

even in the RCA territory (which could be expected to be less sensitive due to interference of liver

activity and its possible influence on the test accuracy).

42

Table 2. Intra- and interobserver variability for the assessment of normal, jeopardized or scar tissue, normal

tissue corresponding to a sestaMIBI uptake of more than 60% of the expected mean normal value,

jeopardized to a mismatching BMIPP-sestaMIBI of at least 10% in the sestaMIBI uptake range 30-60%, and

scar to a perfusion of less than 30% or a matching BMIPP-sestaMIBI. The results represent the mean

(standard deviation) surface (in %) corresponding to each category of tissue for the left ventricle globally as

well as for each major arterial territory. (LV: left ventricle; LAD: left anterior descending artery; LCX: left

circumflex artery; RCA: right coronary artery.)

Intraobserver variability (%) Interobserver variability (%)

Normal Mismatching Scar Normal Mismatching Scar

Total LV 0.39 (3.6) 0.25 (2.0) -0.63 (3.3) 0.71 (3.2) 0.91 (2.4) 0.21 (3.9)

LAD -0.33 (5.4) 1.65 (2.9) -0.69 (5.5) 2.03 (4.3) -1.51 (3.0) -0.72 (5.0)

LCX 0.53 (1.8) -1.56 (3.6) 1.08 (4.2) 0.04 (2.7) -0.53 (2.9) 0.49 (3.5)

RCA 0.89 (4.9) -1.24 (2.8) 0.33 (6.1) -2.01 (5.1) -0.34 (3.9) 2.4 (6.1)

Indeed, significant stenoses were present in the LAD territory in 14 patients, all showing wall

motion abnormalities (12 akinetic, 2 hypokinetic), in the LCX territory in 11 patients, only 4 of

them showing an impaired motion (hypokinesis in all cases), and in the RCA territory in 5 patients,

with only 3 showing motion disturbances (1 akinetic and 2 hypokinetic) while 2 other patients were

classified as having inferior akinesis despite the absence of significant stenosis after thrombolysis

(diffuse atheromatous vessel in both cases).

Using sestaMIBI, a decreased uptake (≤60% of the maximum after correction for the normal

distribution) was observed in the LAD territory in 12 of the 14 patients (all but one with akinesia)

and in the LCX territory in 4 of the 11 patients. In the RCA territory, a decreased sestaMIBI uptake

was noted in 4 of the 5 patients with significant stenosis and one of the two patients with akinesis

without significant narrowing.

Using BMIPP, a very high concordance was found with the sestaMIBI findings, although the

abnormalities observed with BMIPP were significantly more severe in 8 patients, suggesting the

presence of jeopardized but viable myocardium. A decreased uptake (≤60% of the maximum uptake

after correction for the normal distribution) was noted in all cases of impaired sestaMIBI uptake in

the LCX and RCA territories, while one more patient with LAD stenosis was correctly identified,

showing an impaired BMIPP distribution despite low normal sestaMIBI uptake. In this particular

patient (patient 12) with triple vessel disease (distal RCA 100%, proximal LAD 70% and distal

LCX 60%), severely impaired left ventricular function and a 4.5 years old inferior infarction,

besides a significant mismatching (16.4%) in the region of the infarction, a severe and extended

mismatching was found in the whole LAD territory (Figure 5) on visual analysis, corresponding to

an akinetic anteroseptal wall. This feature, which was almost not detected by the quantitative

because of a low normal sestaMIBI uptake (about 60% to 70% of the maximum), presumably

represented an area of stunned rather than hibernating myocardium as confirmed by the clinical

evolution of this patient who died immediately prior to the planned cardiac bypass operation from

an extended anterior infarction with sustained ventricular fibrillation.

43

Table 3. Concordance between coronary anatomy, wall motion abnormalities and sestaMIBI uptake in the

regions showing a significant mismatching on quantitative analysis. (LAD: left anterior descending artery;

LCX: left circumflex artery; RCA: right coronary artery.) Pat. number Localization

mismatching

% mismatching % uptake

sestaMIBI

% coronary

stenosis

Wall motion

2 LAD 16.7 40 75 Akinesis

3 LCX 9.8 40 99 Hypokinesis

6 LAD 25.4 50 99 Akinesis

9 LCX

RCA

57.0

32.3

30

50

80

Atheromatous

Hypokinesis

Akinesis

10 LAD

LCX

RCA

7.5

5.8

27.6

40

100

40

100

70

90

Akinesis

Normal

Normal

12 LAD

RCA

7.6

16.4

70

20

70

100

Akinesis

Hypokinesis

13 LCX

RCA

27.8

9.5

30

40

100

100

Hypokinesis

Hypokinesis

15 LAD 10.3 50 100 Akinesis

Discussion

Noninvasive assessment of residual viability in patients with poor left ventricular function post

myocardial infarction has become a question of major importance due to the proved influence of

revascularization on those patients’outcome[15,16]. However, since a severe ventricular dysfunction is associated with a higher peri-treatment morbidity and mortality, especially when

performing coronary bypass surgery, an accurate classification of the patients between “high” and

“low” probability of benefiting from the revascularization is warranted before referring them to the

surgeon or the invasive cardiologist. Up to now, this preselection is based mainly upon the use of

PET when available, on dobutamine stress echocardiography or on different scintigraphic protocols

using 201

Tl[17]. 99mTc-sestaMIBI, despite its recognized properties of being a marker of cellular

viability[18] has not yet gained a well defined place in the clinical diagnosis of viability, apparently

underestimating its extent compared to the other techniques[3,19]. However, a relative agreement

exists regarding the relationship between severe sestaMIBI defects (<30% of the peak activity) and

myocardial scar on one hand[4], and between a sestaMIBI uptake of >60% to 70% of the maximum

and viable tissue on the other hand[3]. The regions with an uptake situated between these two thresholds constitute a grey zone in which more or less 50% of the segments will probably benefit

from revascularization therapy.

44

Fig 5. Short axis tomograms (upper pannel), vertical (left) and horizontal (right) long axis tomograms (mid

pannel) and bull’s eye representations (lower pannel) of sestaMIBI (upper rows) and BMIPP (lower rows) of

a patient with triple-vessel disease and a 4.5 years old inferior myocardial infarction (10%-colour scale).

Visually, an extended area of mismatching is noted in the whole LAD territory (despite a low-normal

sestaMIBI uptake thereby probably representing myocardial stunning), while a small amount of mismatching

is observed in the inferior and inferoseptal wall, corresponding to hibernating tissue within the infarcted

region (quantitatively measured: 16.4% of the surface of the RCA territory).

Radioiodinated fatty acids analogues such as 123

I-BMIPP have recently been proposed as an

interesting approach for metabolic imaging of the myocardium, improving the diagnostic accuracy

of the conventional scintigraphic studies to predict the presence of inotropic reserve during low-

dose dobutamine infusion[5] and the improvement in wall motion and/or left ventricular ejection

fraction[6,7] in patients with recent myocardial infarction.

It has been suggested that BMIPP could reflect both regional myocardial perfusion and free fatty

acid metabolism. Indeed, a >90%-agreement has been reported between the uptake of BMIPP and

flow tracers such as 201

Tl or the early uptake of 11C-palmitate [20,21], assuming that BMIPP could

be used as a flow tracer besides its property of metabolic marker. In our small group of patients, this

assumption is confirmed by the very high concordance observed between BMIPP and sestaMIBI

uptake.

However, BMIPP is primarily used as a metabolic tracer, since it has been postulated that regional

mismatches could be related to alterations of the usage of fatty acids as energy substrates for the

production of high energy phosphate in myocardial regions with an low oxygen supply[22]. The combined approach of perfusion (with either

201Tl or a

99mTc-flow tracer) and metabolism with

SPET has demonstrated a good concordance with 18F-FDG PET (despite a trend toward

45

underestimation of viability[9]) and has been found a valuable predictor of long term cardiac

events[23]. It seems to correlate better with the presence of jeopardized tissue in patients with

myocardial infarction than either low-dose dobutamine echocardiography or the analysis of the

uptake of sestaMIBI alone, showing a high positive and negative acurracy[7]. One of the possible factors encoutering for the lower diagnostic accuracy of SPET viability studies

compared to PET could be the use of qualitative or semiquantitative methods in many studies to

evaluate the tracer uptake or the degree of mismatching, and to relate it to the presence of

jeopardized tissue. Indeed, using a quantitative approach, a preliminary study has reported

encouraging results regarding the predictive value of a mismatching between 123

I-BMIPP and 201

Tl

and the wall motion recovery post cardiac bypass surgery[24]. In the current study, we describe an original approach to quantify the extent of normal, jeopardized

and scar myocardial tissue in terms of % of the total left ventricular surface and of each arterial

territory, using colour-coded polar maps and sestaMIBI and BMIPP as perfusion and metabolism

tracers. In keeping with recent data from the literature[3,4], the presence and degree of mismatching

between both tracers were analyzed in regions with a sestaMIBI uptake between 30% and 60% of

the expected normal value, and both the reproducibility of the method and the relationship between

significant mismatching and the coronary anatomy were evaluated in 15 patients with severe left

ventricular dysfunction due to old myocardial infarctions. This patient population was chosen to

determine if a quantitative approach of the mismatching could more accurately identify preserved

viability in regions with severe and chronic hypoperfusion than the visual analysis, because of the

higher frequency of discordant BMIPP/201

Tl uptake reported in recent (<4 weeks old) than older

infarction[8] suggesting that this method better identifies myocardial stunning than hibernation.

Using the 30-60% perfusion threshold, a good intra- and interobserver reproducibility was

demonstrated for the assessment of normal, jeopardized and scar tissue, with quite small standard

deviations and a better interobserver agreement than reported with visual analysis[25]. Regarding the presence and extent of mismatching in the regions representing jeopardized

myocardium, a high correlation between the measurements was noted for the left ventricle surface

globally as well as for each individual arterial territory, without significant relationship between the

amount jeopardized tissue and the measured differences. Using the second standard deviation value

of the interobserver difference as threshold of significancy for the presence of clinically significant

jeopardized tissue, a very good agreement with the presence of wall motion abnormalities and/or

coronary stenosis was found, confirming the results reported by Schad et al[26]. Interestingly,

unlike Tamaki et al[8], we were unable to identify a clear relationship between the age of the infarction, the administrated therapy (either thrombolysis, angioplasty or intravenous heparin) and

the presence and degree of mismatching, since we observed extensive mismatching even in very old

myocardial infarctions (> 3 years old), hence indicating that quantitative SPET imaging with

BMIPP and sestaMIBI can clearly detect myocardium at risk even years after the acute event.

The new quantitative method described here seems a potentially interesting approach to improve the

accuracy of the fatty acid/perfusion SPET imaging to identify patients with severe left ventricular

dysfunction who are most susceptible to benefit from a revascularization procedure. However, the

exact amount of mismatching (in terms of percentage of the left ventricular surface) necessary to

predict functional recovery post revascularization requires additional follow-up studies.

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Ann Nucl Med 1994; 8: 47-54.

10. Mertens J, Eersels J, Van Ryckeghem W. New high yield Cu(I) assisted I-123 radioiodination of

15(p-I-phenyl)-9-methyl pentadecanoic acid, a potential myocardial tracer. Eur J Nucl Med 1987;

13: 159-160.

11. Van Steelandt E, Dobbeleir A, Vanregemorter J. Compton scatter correction for scintigraphic

imaging. Proceedings of the 11th annual symposium of the Belgian Association of Hospital

Physicists. 1995; p23.

12. A.S. Hambye, A.Dobbeleir, E. Stulens, A. Vervaet, J. Vandevivere, P.R. Franken. 240°: why

not ? Nucl Med Commun 1996;17: 583-590.

13. Altman DG. Some common problems in medical research, method comparison studies. In:

Altman DG, ed. Practical statistics for medical research. 1st edition. London: Chapman & Hall;

1991: 396-403.

14. Iskandrian AS, Verani MS. Exercise perfusion imaging in coronary artery disease: physiology

aand diagnosis. In: Nuclear cardiac imaging: principles and aplications. 2d edition. Philadelphia:

FA Davis Company,1996: 97.

15. Gioia G, Powers J, Heo J, Iskandrian AS. Prognostic value of rest-redistribution tomographic

thallium-201 imaging in ischemic cardiomyopathy. Am J Cardiol 1995; 75: 759-762.

16. DiCarli MF, Davidson M, Little R, Khanna S, Mody FV, Brunken RC, Czernin J, Rokhsar S,

Stevenson LW, Laks H, Hawkins R, Schelbert HR, Phelps ME, Maddahi J. Value of metabolic

imaging with positron emission tomography for evaluating prognosis in patients with coronary

artery disease and left ventricular dysfunction. Am J Cardiol 1994; 73: 527-533.

17. Gimple LW, Beller GA. Myocardial viability. Assessment by cardiac scintigraphy. Cardiology

Clinics, 1994; 12: 317-332.

18. Piwnica-Worms D, Kronauge JF, Chiu ML. Uptake and retention of hexakis (2-

methoxyisobutyl isonitrile) Technetium (I) in cultured chick myocardial cells. Mitochondrial and

plasma membrane potential dependence. Circulation 1990; 82: 1826-1838.

47

19. Marzullo P, Sambuceti G, Parodi O, Gimelli A, Picano E, Giorgetti A, L’Abbate A. Regional

concordance and discordance between thallium-201 ans sestamibi imaging for assessing tissue

viability: comparison with postrevascularization functional recovery. J Nucl Cardiol 1995; 2: 309-

316.

20. Chouraqui P, Maddahi J, Henkin R, Karesh SM, Galie E, Berman DS. Comparison of

myocardial imaging with iodine-123-iodophenyl-9-methyl pentadecanoic acid and thallium-201-

chloride for assessment of patients with exercise-induced myocardial ischemia. J Nucl Med 1991;

32: 447-452

21. Kawamoto M, Tamaki N, Yonekura Y, Magata Y, Tadamura E, Nohara R, Matsumori A,

Sasayama S, Konishi J. Significance of myocardial uptake of iodine 123-labeled beta-methyl

iodophenyl pentadecanoic acid: comparison with kinetics of carbon 11-labeled palmitate in positron

emission tomography. J Nucl Cardiol 1994; 1: 522-528.

22. Takeda K, Saito K, Makino K, et al. Iodine-123-BMIPP myocardial washout during exercise in

normal and ischemic hearts. J Nucl Med 1997; 38: 559-563.

23. Tamaki N, Tadamura E, Kudoh T, Hattori N, Yonekura Y, Nohara R, Sasayama S, Ikekobu K,

Kato H, Konishi J. Prognostic value of iodine-123 labelled BMIPP fatty acid analogue in patients

with myocardial infarction. Eur J Nucl Med 1996; 23: 272-279.

24. Inubushi M, Kudoh T, Hattori N, Magata Y, Ohno N, Nishimura K, Tamaki N, Konishi T. I123-

BMIPP/Tl-201 mismatching predicts wall motion recovery after CABG: assessment with

quantitative analysis. Ann Nucl Med 1996; 10: S79.

25. Taillefer R, Iskandrian A, Verani M, Orlandi C, Davies G, Borer JA, Pippin J. Observer

variability in myocardial viability assessment with I123-IPPA: results from the multicenter IPPA

study. J Nucl Med 1996; 37: 184P.

26. Schad N, Wagner RK, Hallermeier J, Daus HJ, Vattimo A, Bertelli P. Regional rates of

myocardial fatty acid metabolism: comparison with coronary angiography and contrast

ventriculography. Eur J Nucl Med 1990; 16: 205-212.

48

3.2 Influence of high-energy photons on the spectrum of iodine-123 with low and

medium-energy collimators: consequences for imaging with 123I labelled compounds

in clinical practice.

André A. Dobbeleir1 , Anne-Sophie E. Hambÿe

1 and Philippe R. Franken

2 .

1Nuclear Medicine, Middelheim Hospital, Antwerp, and

2Nuclear Medicine, Free University of

Brussels (VUB), Belgium.

European Journal of Nuclear Medicine 1999; 26: 655-658.

Abstract. Using iodine-123 labelled radiotracers, the presence of 2.5% high energy photons causes

image deterioration due to increased scatter. To investigate the influence of these photons on image

quality, we measured the spectrum of 123

I with a medium energy (ME), a low energy all purpose

(LEAP) and a high resolution (LEHR) collimator. Even in air, using low energy collimators, a high

baseline activity was observed over the total energy detection range of the gamma camera. The 159

keV photopeak to scatter activity ratio dropped from 5.9 for ME to 3.6 and 2.9 for LE collimators.

Acquiring images with LEHR collimators with energy windows set at 159 keV and 500 keV

demonstrated that the 159 keV LEHR image is a combination of ME image of the object and of the

LEHR 500 keV image. Because of their important septal penetration and greater geometric

detection efficiency compared to the 159 keV photons of 123

I, the contribution of high energy

photons is dependent on the source-detector distance. For a small source placed in air, the scatter to

photopeak activities varied from 17.4% at 80 cm to 37.8% at 5 cm distance from a LEHR

collimator. Considering only the scatter problem, medium energy collimators are the best choice for 123

I studies. Using low energy collimators for high resolution tomography with 123

I labelled

compounds, scatter contribution from high energy photons has to be corrected for quantitative

analysis or when dual isotope studies are performed, whether or not simultaneously acquired.

Key words: iodine-123, high energy photons, spectral analysis, collimator.

49

Introduction

Iodine has become important as an isotopic label because the chemistry of iodination is versatile

and well understood. However, besides the 159 keV photons, high purity 123

I emits high energy

photons: 2.4% between 440 and 625 keV, and 0.15% between 625 and 784 keV. These high energy

photons cause septal penetration and scatter detected in the energy window of the 159 keV

photopeak. Therefore, some authors recommended to use medium-energy (ME) collimators,

especially when quantitation is required [1,2]. Analyzing the recent literature published in this

journal using 123

I labelled dopamine receptors, fatty acids or antibodies, we noted 15 studies over a

1 year period. A large variety of collimators were used, from medium energy (ME) and fanbeam

collimators to low energy high resolution (LEHR) and all purpose (LEAP) collimators. When semi-

quantitative or quantitative analysis has to be applied, ME collimators are preferred. Alternatively

when high spatial resolution is important for accurate quantification , as for neuroreceptor SPET,

LEHR collimators supported by scatter correction are used. However Messa et al. still correct for

collimator-septa penetration while using a specialised annular geometry CERASPET system and

ME collimators for quantitative analysis of dopaminergic receptors [123

I]Beta-CIT [3].

In myocardial viability studies, iodine-123 beta-methyl-p-iodophenyl-pentadecanoic acid (BMIPP),

a free fatty acid analogue, is the most frequently used tracer for metabolic SPET studies, a

discordant uptake with less BMIPP than perfusion being well correlated with viable tissue. LEAP

[4-8] or LEHR collimators are used [9-14] although higher noise level in the 123

I image can disguise

the reduction in fatty acid uptake related to perfusion. Special care must be paid to the methodology

when quantitative measurements are intended, in order to avoid image misinterpretation due to

differences in physical characteristics [15]. One solution consists in using medium energy [16]

instead of low energy collimators, despite a certain loss of resolution [1]. Alternatively, low energy

collimators can be used, if a scatter correction is applied [17,18].

In a previously published series of 10 patients with myocardial infarction, we measured after

sequential studies 12.1% higher background activity for 123

I-BMIPP than for 99m

Tc-sestamibi using

a LEAP collimator. Performing dual window scatter correction , mean difference in activity

between technetium and 123-iodine in the infarcted area increased from 0.4% without background

correction to 6.4% after scatter subtraction, increasing dramatically the number of viable territories

[19]. In an attempt to clarify the image degradation with iodine-123 and low energy collimators, we

performed a few phantom studies.

Materials and methods

All data were acquired with a Trionix Triad 88 triple headed gamma camera using LEHR, LEAP

and ME collimators. Table 1 presents the specifications of these collimators for 99m

Tc according to

the manufacturer, as well as resolution measurements for 123

I determined in our department. The

Trionix collimators has been fabricated from lead foil by Precision (Tennessee, USA).

In a first time, the spectrum of 123

I in air was measured sequentially for each collimator with the

source at 10 cm from the same detector. A 2-ml volume source containing 74 MBq (2.0 mCi) of 123

I

was used. For each acquisition, the photopeak window was placed between 143 and 175 keV and

the scatter window just below, between 116 and 142 keV. As a comparison, the same measurements

were repeated in air for 99m

Tc, with the photopeak window between 126 and 154 keV and the

scatter window between 100 and 125 keV. The ratio photopeak to scatterpeak activity was

calculated in order to compare the signal to noise ratio for each collimator. To eliminate the

eventual effect of intrinsic detector performance, this study was repeated for the three detectors.

In a second time, the 2-ml volume 123

I source was placed in air at the center of the three detector

gamma camera, at an equal distance of 20 cm from each detector, and three simultaneous planar

images were obtained. The first detector was equipped with a LEHR collimator and the photopeak

was set at 159 keV. The second detector was equipped with a ME collimator with the same energy

50

window as the first, whereas for the third detector, also fitted with a LEHR collimator, the 20%

photopeak window was placed at 500 keV.

Finally the influence of distance on septal penetration for the 3 collimators was investigated. The

spectra of 123

I in air was measured for the 2-ml volume source placed at variable distances (5, 10,

20, 40 and 80 cm) of each of the 3 collimators. This was repeated for each detector. Scatter to

photopeak ratio was calculated as an indication of background observed in clinical studies.

Table 1. Collimator specifications for

99mTc according to the manufacturer

and measured data for 123I between brackets.

System resolution

in mm @ 10 cm

FWHM FWTM

Sensitivity

cpm / µCi

Septal

Penetration

LEAP 9.5 (9.9) 17.1 (18.3) 281 0.4 %

LEHR

7.1 (7.4) 13.0 (14.5)

132

0.2 %

MEAP

9.7 (10.1) 16.5 (17.1)

165

1.5% (67Ga)

Results

As expected, the spectra for 99m

Tc were very similar with the 3 types of collimators. The photopeak

to scatter ratio was close to 14 to 1 (14:1) in air regardless of the used collimator. The mean values

for the three detector/collimator combinations are presented in Table 2.

The spectra of iodine-123 acquired in air without scatter medium for each kind of collimator are

shown in Figure 1. The position and width of the photopeak (143-175 keV) and scatter window

(116-142 keV) are superimposed on the spectra. A small influence of the high energetic photons is

visible on the spectrum using medium energy collimator. For the low energy collimators , the high

energetic peak becomes more important in comparison to the 159 keV photopeak, and even in air a

large amount of scatter is present over the total energy range. The mean photopeak to scatter ratio is

5.9:1 with ME collimator and drops to 3.6:1 with LEAP collimator and to 2.9:1 with LEHR

collimator (Table 2).

The influence of high energy photons on the image quality is illustrated in Figure 2, showing an

image of the 123

I source in air acquired with ME and LEHR collimators; the photopeak was set at

159 keV. The third image is obtained with the LEHR collimator and a 20% energy window set at

500 keV. The 159 keV photopeak images are overexposed to attract the attention to the differences

in septal penetration between ME and LEHR collimators. The difference in scatter activity observed

at 159 keV between the two collimators resemble the scatter distribution observed at 500 keV. The

counts measured in a large region drawn over the source acquired using the LEHR collimator

amounted to 71 kcounts in the 500 keV and 1.49 Mcounts in the 159 keV image ( ratio 500 keV /

159 keV = 4.8% ), while the activity over the total 40-20 cm field of view raise to 1.00 Mcounts for

500 keV and 2.15 Mcounts in the 159 keV photopeak image (ratio 500 keV / 159 keV = 46.5%). In

the 159 keV image with the ME collimator 1.70 Mcounts was measured in the region over the

source and 1.81 Mcounts for the total field of view, an increase of only 6.5% compared to 44% with

the LEHR collimator. The cross-shaped artefact seen in both images with the LEHR collimator

represents penetration of the high energy photons through the thinner septa.

51

In Figure 3, the influence of distance on septal penetration by the high energy photons is depicted

for a 123

I point source in air using LEHR collimator. This figure clearly demonstrates that scatter

from the high energetic photons is distance-dependent, the closer to the collimator the more

important the scatter to photopeak ratio, ranging from 17.4% for 80 cm to 37.8% for 5 cm distance.

In Table 3, the scatter fraction for each distance and each collimator is presented.

Table 2. Activity ratio of photopeak on scatter window for

ME, LEHR and LEAP collimators for 123I in comparison

to a 99m

Tc source. Mean value for the three detectors

ME LEHR LEAP

99mTc in air

13.8 : 1

14.1 : 1

14.0 : 1

123I in air

5.87 : 1

2.88 : 1

3.60 : 1

Fig. 1. The spectra of iodine-123 in air with medium energy all purpose (ME) and high

resolution (HR) low energy collimators. The position and width of the photopeak

(143-175 keV) and scatter window (116-142 keV) are also shown.

52

Fig 2. The difference in scatter at 159 keV between LE and ME collimators is shown to be related to the

high-energy 123I photons.

Fig 3. Influence of source-collimator distance on septal penetration by high-energy photons, for a

123I source

in air using LEHR collimator. The distances considered are 5, 10, 20, 40 and 80 cm.

2 78 153 229 304 380 456 keV

Spectra159 keV

High energy photons

5 cm

80 cm distance

Discussion

We demonstrated that with 123

I and low energy collimators a larger contribution of scatter is

observed from sources closer to the detector. On the images of Figure 2, it can be seen that the

photons detected around 159 keV are the sum of true 159 keV photons and scattered photons from

the high energies. For the true 159 keV photons, those passing through the holes of the collimator

are only the ones travelling perpendicular to the detector. Changing the distance will only have a

53

Table 3. Ratio scatter on photopeak 123I activity (in %) for

3 collimators and variable distance in air between source

and gamma camera. Mean value for the three detectors.

Colli-

mator

5 cm 10 cm 20 cm 35 cm 80

cm

LEHR

37.8

34.7

29.0

22.5

17.4

LEAP

30.0

27.7

22.7

17.9

15.3

ME

18.2

17.1

16.8

15.4

15.1

small effect on the number reaching the crystal. On the contrary, due to septal penetration, high

energetic photons behave themselves as if the gamma camera was without a collimator and the

number of photons detected decrease by the inverse of the square of the distance. Despite the small

proportion of high energetic photons (about 2.5%), their greater geometric detection efficiency

compared to 159 keV photons make their relative contribution in the detected photons very

important if the distance between the camera and the object is small. This can explain why De

Geeter et al. [1] measured a relative sensitivity for a LEHR compared to a ME collimator of 0.74 for 99m

Tc whereas for 123

I a value of 1.53 was obtained. They used a plastic dish placed directly on the

collimator surface. Another-distance dependent effect is the changing effective path length through

the septa of the collimator depending on the angle of incidence of the photon and thus modifying

attenuation of high energy photons in the lead of the collimator. From the point of view of scatter,

using a low energy high resolution collimator for 123

I imaging is the worst solution because of a

poor photopeak to scatter ratio (2.9:1). Due to a higher photopeak sensitivity and almost equal

septal penetration, the low energy all purpose collimator has a slightly better ratio (3.6:1). Using

the medium energy collimator, the septal penetration becomes very low and the ratio raises to 5.9:1.

Since the observed results are collimator-dependent, slight differences could be expected with

collimators from other manufactures, mainly depending on the septal length and thickness.

Furthermore, changing the position and width of the scatter window will provide different

photopeak to scatter ratios. Although, this will not change the general findings observed when using

low-energy collimators for imaging with 123

I radioiodinated tracers.

In summary, the influence of high energy photons on the image depends on collimator specificities

and geometric factors (organ-detector distance). Considering only the scatter problem, medium

energy collimators are the best choice for 123

I studies. However for neuroreceptor studies, where

high spatial resolution is important to avoid partial volume artefacts for accurate quantification,

LEHR parallel or fanbeam collimators are prefered. For quantitative analysis or when comparing a 123

I-labelled compound to another isotope scatter correction is important when low energy

collimators are used.

References

1. De Geeter F, Franken PR, Defrise M, Andries H, Saelens E, Bossuyt A. Optimal collimator

choice for sequential iodine-123 and technetium-99m imaging. Eur J Nucl Med 1996; 23: 768-774.

2. Macey DJ, DeNardo GL, Denardo S, Hines HH. Comparison of low- and medium-energy

collimators for SPECT imaging with iodine-123-labelled antibodies. J Nucl Med 1986; 27: 1467-

1474.

54

3. Messa C, Volonte M, Fazio F, Zito F, Carpinelli A, d'Amico A, Rizzo G, Moresco R, Paulesu E,

Franceschi M, Lucignani G. Differential distribution of striatal [123

I]Beta-CIT in Parkinson's disease

and progressive supranuclear palsy, evaluated with single-photon emission tomography. Eur J Nucl

Med 1998; 25: 1270-1276.

4. Ito T, Tanouchi J, Kato J, et al. Recovery of impaired left ventricular function in patients with

acute myocardial infarction is predicted by the discordance in defect size on 123

I -BMIPP and 201

Tl-

SPET images. Eur J Nucl Med 1996; 23: 917-923.

5. Tamaki N, Tadamura E, Kudoh T, et al. Prognostic value of iodine-123-labelled BMIPP fatty

acid analogue in patients with myocardial infarction. Eur J Nucl Med 1996; 23: 272-279.

6. Tadamura E, Kudoh T, Hattori N, Inubushi M, Magata Y, Konishi J, Matsumori A, Nohara R,

Sasayama S, Yoshibayashi M, Tamaki N. Impairment of BMIPP uptake precedes abnormalities in

oxygen and glucose metabolism in hypertrophic cardiomyopathy. J Nucl Med 1998; 39: 390-396.

7. Kawai Y, Tsukamoto E, Nozaki Y, Kishino K, Kohya T, Tamaki N. Use of 123

I -BMIPP single-

photon emission tomography to estimate areas at risk following successful revascularization in

patients with acute myocardial infarction. Eur J Nucl Med 1998; 25: 1390-1395.

8. Yoshida S, Ito M, Mitsunami K, Kinoshita M. Improved myocardial fatty acid metabolism after

coronary angioplasty in chronic coronary artery disease. J Nucl Med 1998; 39: 933-938.

9. Vanzetto G, Janier M, Fagret D, Cinotti L, Andre-Fouet X, Comet M, Machecourt J. Metabolic

myocardial assessment with iodine 123-16-iodo-3-methyl hexadecanoic acid in recent myocardial

infarction: comparison with thallium-201 and fluorine-18 fluorodeoxyglucose. Eur J Nucl Med

1997; 24: 170-178.

10. Takeishi Y, Chiba J, Abe S, Tonooka I, Komatani A, Tomoike H. Heterogeneous myocardial

distribution of iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in patients

with hypertrophic cardiomyopathy. Eur J Nucl Med 1992; 19: 775-782.

11. Nakata T, Hashimoto A, Kobayashi H, Miyamoto K, Tsuchihashi K, Miura T, Shimamoto K.

Outcome significance of thallium-201 and iodine-123-BMIPP perfusion-metabolism mismatch in

preinfarction angina. J Nucl Med 1998; 39: 1492-1499.

12. Kobayashi H, Kusakabe K, Momose M, Okawa T, Inoue S, Iguchi N, Hosoda S.

Evaluation of myocardial perfusion and fatty acid uptake using a single injection of iodine-123-

BMIPP in patients with acute coronary syndromes. J Nucl Med 1998; 39: 1117-1122.

13. Taki J, Nakajima K, Matsunari I, Bunko H, Takata S, Kawasuji M, Tonami N. Assessment of

improvement of myocardial fatty acid uptake and function after revascularization using iodine-123-

BMIPP. J Nucl Med 1997; 38: 1503-1510.

14. Takeishi Y, Fujiwara S, Atsumi H, Takahashi K, Sukekawa H, Tomoike H. Iodine-123-BMIPP

imaging in unstable angina: a guide for interventional strategy. J Nucl Med 1997; 38: 1407-1411.

15. Tamaki N, Kawamoto M, Yonekura Y, et al. Regional metabolic abnormality in relation to

perfusion and wall motion in patients with myocardial infarction: assessment with emission

tomography using a iodinated branched fatty acid analog. J Nucl Med 1992; 33: 659-667.

16. Franken PR, Dendale P, De Geeter F, Demoor D, Bossuyt A, Block P. Prediction of functional

outcome after myocardial infarction using BMIPP and sestamibi scintigraphy. J Nucl Med 1996;

37: 718-722.

17. Gilland DR, Jaszczak RJ, Turkington TG, Greer KL, Coleman RE. Volume and activity

quantification with iodine-123 SPECT. J Nucl Med 1994; 35: 1707-1713.

18. Takeda K, Saito K, Makino K, Saito Y, Aoki S, Koji T, Matsumura K, Nomura Y, Kitano T,

Nakagawa T. Iodine-123-BMIPP myocardial washout and cardiac work during exercise in normal

and ischemic hearts. J Nucl Med 1997; 38: 559-563.

19. Dobbeleir A, Hambye AS, Franken PR. Influence of the methodology on the presence and

extent of mismatching between 99m

Tc-MIBI and 123

I -BMIPP in myocardial viability studies. J Nucl

Med 1999; 40: (in press).

55

3.3 Influence of the methodology on the presence and extent of mismatching between 99m

Tc-MIBI and 123I-BMIPP in myocardial viability studies.

André A. Dobbeleir1 MSc, Anne-Sophie E. Hambye

1 MD and Philippe R. Franken

2 MD, PhD.

1Nuclear Medicine, Middelheim Hospital, Antwerp, and

2Nuclear Medicine, Free University of

Brussels, Brussels, Belgium.

Journal of Nuclear Medicine 1999; 40: 707-714.

Abstract

Discordant uptake (mismatching) of 123

I-BMIPP less than 99m

Tc-MIBI is a good predictor of

myocardial viability. However, methodological factors can influence the assessment of the presence

of mismatching because of differences in background activity between the tracers. In the present

study, we investigated the influence of methodological parameters on the mismatching between

BMIPP and MIBI in patients with chronic ischemic heart disease.

Methods. Polar maps were created to quantify the extent of mismatched tissue measured in 10

patients with myocardial infarction according to different methods for data processing: no

correction, substraction of the background activity measured in the left ventricle cavity, and dual

window scatter correction. Mismatching was expressed in % of the surface of the left ventricle

globally as well as for each arterial territory using a BMIPP uptake of at least 10% less than MIBI

as threshold. The results of dobutamine stress echocardiography and the evolution of the regional

contractility at 6 months follow-up were used as references.

Results. Mean background activity in the ventricle cavity was 9.3% of the maximum activity for

MIBI and 21.4% for BMIPP before, and 2.8% and 8.3% after scatter correction. Fourteen arterial

vascular territories demonstrated baseline wall motion abnormalities, of which 9 with contractile

reserve under dobutamine. Significant mismatching was found in 5/14 regions without correction,

9/14 after scatter correction and 13/14 after background substraction. Compared to the evolution of

resting regional contractility at follow-up, optimal results were found when using the scatter

corrected data. Without correction, mismatching between BMIPP and MIBI was partially disguised

because of the higher noise level in the iodine images. On the contrary, substraction of background

measured by means of a single ROI overestimated the magnitude of mismatching due to the

heterogeneous background distribution in the ventricular cavity.

Conclusion. Quantifying the presence and extent of mismatching between MIBI and BMIPP in

chronic ischemic heart disease, significant differences in the detection of viability are noted

according to the acquisition and processing methods used. Scatter correction of the acquisition data

is the most accurate and liable method for identifying viable myocardium.

Key words: iodine-123-BMIPP, chronic ischemic myocardium, myocardial viability,

quantification.

56

Using 99m

Tc-MIBI for evaluation of myocardial viability, a normal uptake is a good predictor of

functional recovery but a decreased uptake clearly underestimates tissue viability (1). Furthermore,

the lower limit of normal with this tracer is not precisely defined and fluctuates between 50% and

60% (2,3).

Due to an early metabolic switch from beta-oxydation to glycolysis to preserve the

production of high energy phosphates in hypoxic myocardium, single-photon emission computed

tomography (SPECT) with radioiodinated free fatty acid analogues has been proposed as an

alternative to 18F-Fluorodeoxyglucose for imaging cardiac metabolism (4), a mismatching with fatty

acid uptake more severely reduced than the flow reliably identifying jeopardized but viable

myocardium (4-7).

However, comparing the tissue uptake of radiopharmaceuticals labeled with different

isotopes requires a special attention for the acquisition parameters. Particularly, the use of 123

I-

labeled compounds can lead to an underestimation of the defect contrast, due to the emission of

2.5% high energy photons (440-625 keV). When using low-energy collimators, these photons cause

septal penetration and scatter, partly detected in the 159 keV photopeak window. This phenomenon

results in an increased background level in the 123

I image, that can disguise partly or completely the

reduction in fatty acid uptake related to the perfusion tracer, or even result in an increased fatty

acid/perfusion uptake as recently reported by Sloof et al in chronic ischemic heart disease (8). To

overcome this problem when acquiring 123

I-imaging, one solution consists in using medium-energy

instead of low-energy collimators, despite a certain loss of resolution (9). Alternatively, low-energy

high-resolution collimators can be used, even for quantitative 123

I SPECT imaging, if a scatter

correction is applied (10).

The present study aimed at clarifying the influence of methodology on the quantitative

assessment of mismatching between iodine-123-beta-methyl iodophenyl pentadecanoic acid

(BMIPP) and 99m

Tc-MIBI. For this purpose, we quantified the presence and degree of mismatching

in ten patients with prior transmural myocardial infarction, using different methodological

approaches and a previously described quantitative method (11), and compared the results to the

findings of dobutamine stress echocardiography. We used low-energy all-purpose instead of high

resolution collimators because the amount of septal penetration is similar with both kinds of low-

energy collimators when 123

I-labeled compounds are used, but the photopeak sensitivity is higher

with the all purpose, resulting in a significant improvement of the signal/noise ratio.

Materials and methods

Study design

Ten patients with old transmural myocardial infarction (median: 3 months, range: 1 month-

10years) were included. Within a week, coronary angiography, dobutamine stress

echocardiography, radionuclide angiography, BMIPP and MIBI studies were obtained (the last two

with a 3-day interval).

Using echocardiography, the left ventricle was divided into 8 segments. The anterobasal,

anterolateral and anteroseptal segments were ascribed to the left anterior descending artery (LAD),

the posterolateral to the left circumflex artery (LCX), and the diaphragmatic, posteroseptal and

posterobasal to the right coronary artery (RCA), while the apex was attributed to the LAD unless a

dominant RCA or LCX was reported. In each arterial territory, wall motion was analyzed at rest and

during intravenous infusion of 5 and 10 µg/kg.min dobutamine and graded as normal, slightly,

mildly or severely hypokinetic, or a/dyskinetic. Viability was defined as an increase in wall motion

of at least one grade in a segment with resting abnormalities.

After completion of the tests, revascularization was performed within the month in 6

patients in whom it was technically feasible, the remaining being conservatively treated. Follow-up

data was obtained 6 to 7.5 months later.

57

All patients received written information about the study and gave informed consent. The

study protocol had been approved by the Commission of Medical Ethics of the Hospitals of

Antwerp.

Scintigraphic imaging protocol

Radioiodination of BMIPP was realized at the Free University of Brussels using 123

I (p,5n) and the

Cu(I)-assisted isotopic exchange reaction developed by Mertens (12).

123

I-BMIPP was intravenously injected in resting condition at a mean dose of 159 MBq (4.3

mCi) after at least 6h fasting. Potassium perchlorate was administered to the patients 15 min before

injection to block thyroidal uptake of free iodine. SPECT started 30 min postinjection using a triple-

head gamma camera (Triad, Trionix Lab, Twinsburg, USA), detector size 40*20 cm, equipped with

all-purpose low-energy collimators. Ninety projections (30/head) of 60 sec duration were acquired

over a 360° non-circular body contour orbit, using a 128*64 matrix. A scatter image was obtained

in a second window just under the photopeak according to the method of Jaszczak (13). The

photopeak image was set at 159 keV with a window between 143 and 175 keV, and the scatter

image acquired between 116 and 142 keV.

Resting 99m

Tc-MIBI SPECT was started at a mean time of 80 min postinjection of 925 MBq

(25 mCi) using a similar protocol as for the BMIPP, but with 40 sec acquisition time per projection

and different photo- and scatterpeak characteristics (photopeak set at 140 keV with a window

between 126 and 154 keV; scatter window between 100 and 125keV).

Determination of the k fraction for dual window scatter correction

In SPECT, scatter compensation consists in substracting a fraction k of the compton image C(x,y)

from the photopeak image P(x,y) to obtain a scatter compensated image I(x,y) = P(x,y) - k*C(x,y).

The value of this k factor depends on the acquisition geometry, the energy resolution of the camera,

the energy settings and the size of the object (14).

Using the previously described collimators and energy window settings, the projection

version of the dual window scatter correction was implemented by performing weighted

substractions with an experimentally determined k value directly on the projection images, before

reconstruction (15).

Experimental determination of this k value was performed as follows. Using the same

window settings and collimators that would be used for the patients studies, the scatter substraction

fraction was calculated for 99m

Tc and 123

I and different source geometries. Scatter correction was

performed on planar images since SPECT data consist of a set of planar images and quantitative

distortions will propagate in the tomographic studies.

Four different source geometries were tested for both isotopes: a small point source, a 5 cm

diameter-1 cm thick cylinder, a 10 cm diameter-2 cm thick cylinder and a large 10 cm diameter-10

cm thick cylinder. Images were acquired in air and with increasing depths of attenuating medium: 4,

8, 12, 16 and 20 cm of water.

When the logarithm of the counts are plotted against depth, the resulting straight line has a slope

equal to the attenuation coefficient for broad beam geometry, and after accurate elimination of

scatter, for narrow beam geometry (16). Therefore, k was iteratively changed for each source and

the subsequent scatter corrected counts were fitted to the single monoexponential function up to the

attenuation coefficient corresponded to the values for water for the two isotopes (0.15 cm-1 for

99mTc and 0.146 cm

-1 for

123I).

Processing and analysis of the scintigraphic data

The extent of viable tissue was evaluated for 4 different types of processing: 1°) Without correction.

2°) After background substraction performed as follows: a 1-cm2 region of interest (ROI) was

drawn at the basal part of a 1 cm thick midventricular long axis slice on both MIBI and BMIPP

images and the activity measured within these ROI’s was subtracted from the data before bull's eyes

were created. 3°) Using a dual window scatter correction with k values of 0.7 for 99m

Tc and 1.0 for

58

123I. 4°) With the same scatter correction method but a substraction constant k=1.3 instead of 1.0 for

123I. These 2 values of k for

123I, corresponding respectively to the point source and the to 10 cm

diameter-10 cm height phantom, had been found the minimum and maximum correction fractions

in the experimental measurements.

The three standard orthogonal tomograms were obtained after filtered backprojection and

appropriate reorientation of the images using a Butterworth prefilter (cutoff frequency 0.75 cyc/cm

for MIBI and 0.6 cyc/cm for BMIPP, order 5) and a Ramp-backprojection filter, and polar maps

were created.

Quantification of the mismatching

Color-coded polar maps allowing a quantitative analysis of the relative proportion of normal,viable

and scar tissue for the left ventricle globally and for each arterial territory were created according to

a previously described method (11). By quantifying the magnitude of viable tissue measured by the

four processing methods, the influence of methodology on the quantitative assessment of

mismatching between 123

I-BMIPP and 99m

Tc-MIBI could be evaluated.

These polar maps, comparing the MIBI and BMIPP images, are obtained as follows. The

lower limit of normal MIBI uptake is defined as 60% of the normal local value (2) and represented

in red, while scar tissue, defined as a MIBI uptake of <30%, is represented in blue. In between these

two limits, MIBI is compared to BMIPP to evaluate the presence and degree of mismatching. Green

is used for matched regions, meaning regions were the difference between BMIPP and MIBI uptake

is <10%, yellow for regions with a mismatching of BMIPP 10-20 % less than MIBI, and orange

corresponds to segments with a >20% mismatching, both considered as jeopardized but viable

tissue. The extent of mismatched tissue is considered significant if it amounts to at least 4.8 % of

the global left ventricular surface, 6.0 % of the LAD region, 5.8 % of the LCX and 7.8 % of the

RCA surface (11).

At baseline, the presence of viability by scintigraphy was compared to the findings of the

dobutamine stress echocardiography for the four processing methods. At follow-up, it was related to

the evolution of resting regional contractility assessed by echocardiography.

Results

Determination of the k fraction for scatter correction

The optimum k values for scatter correction measured for the four different sources geometries are

reported in Table 1. As expected according to the literature, smaller k values were found for larger

objects (15).

Table 1. Substraction coefficients for the dual energy window scatter correction method

Phantom 99m

Tc k fraction 123I k fraction

Point source 0.80 1.3

Cylinder D= 5 cm

H= 1 cm

0.75 1.2

Cylinder D= 10 cm

H= 2 cm

0.70 1.1

Cylinder D= 10 cm

H= 10 cm

0.70 1.0

Measurement of intraventricular cavity and infarcted area activities

Mean intraventricular activity was measured on both MIBI and BMIPP vertical midventricular long

axis slices. For MIBI, mean activity for the 10 patients was 9.3% of the maximum activity,

59

compared to 21.4% for BMIPP. After scatter correction, mean activity dropped to 2.8% for MIBI

and 8.3% for BMIPP with a k value of 1.0, indicating a slight undercorrection for the latter.

Mean tissue activity within the infarcted area for the 10 patients was measured by placing a

1-cm2 ROI over the central part of the infarcted region. The differences in mean measured activities

according to the correction method used are reported in Table 2 and are particularly prominent with

BMIPP, the mean difference in uptake between MIBI and BMIPP amounting to 0.4% without

correction, 6.4% after scatter correction and up to 12.8% after background substraction. Using this

last method, negative values of BMIPP uptake of -15.4% and -11.5% were found in two patients,

both with an extended anterior infarction. In these patients, a high basal to apical background

gradient was observed in the left ventricular cavity, responsible for this overcorrection.

Figure 1 shows the short axis, vertical long axis and bull's eyes MIBI and BMIPP images of a patient with an

history of severe heart failure (ejection fraction: 15%) due to a at least 1-year old silent anterior infarction. In

this region, MIBI uptake was almost normal (59% of the maximum activity and BMIPP uptake only slightly

reduced (55% of the maximum activity without correction). Applying scatter correction, the mean BMIPP

activity dropped to 43%, versus 39% with background substraction (respectively 16% and 20% less than

perfusion), hence making the mismatching more obvious. Six months after bypass surgery, the patient was

symptom-free, his ejection fraction had raised to 31%, and regional improvement was noted by

echocardiography.

60

Table 2: Mean activity in the infarcted area according to the correction method (in %).

MIBI BMIPP Difference

No correction 28.7 28.3 0.4

Background substraction 21.7 8.9 12.8

Scatter correction 22.1 15.7 6.4

Figure 2 shows the short axis, vertical long axis and bull's eyes MIBI and BMIPP images of a patient with a

14-week old anterior infarction and an ejection fraction of 39% at baseline. Without correction, BMIPP

uptake was >10% higher than MIBI (53.2% versus 40.9%) in the anterior and apical regions. After scatter

substraction, the activities measured in the infarcted area were almost equal for both tracers: 37.2% for MIBI

and 38.7% for BMIPP. At 6 months follow-up, the ejection fraction decreased by 2.5% and regional wall

motion remained unchanged.

Quantification of the mismatching according to the correction method

Analysis was focused on the 14 arterial territories showing resting wall motion abnormalities by

echocardiography. Using MIBI alone and a 60%-uptake as threshold for viable tissue (2), these

regions should have been considered nonviable because all of them had less than 60% MIBI uptake.

Comparing the BMIPP to the MIBI uptake in these regions, significant mismatching was observed

in 5/14 territories without correction, in 9 with both k=1.0 and 1.3 scatter correction factors and in

13 with background subtraction (Table 3). Interestingly, none of the regions supplied by nonstenotic

arteries showed significant mismatching. According to previous results based upon inter-observer

reproducibility, mismatching was considered significant if it involved at least 6.0 %, 5.8 % and 7.8

% of the surface perfused by the LAD, LCX and RCA arteries respectively (11). The extent of

61

mismatching measured by the different processing methods is represented in Figure 3 for the 14

arterial territories. This graph clearly illustates the influence of methodology on the magnitude of

viable tissue.

Table 3: Extent of mismatching in each arterial territory (in % of the surface) for the different

correction methods. Significant surface is represented in bold characters.

LAD: left anterior descending artery. LCX: left circumflex artery. RCA: right coronary artery.

No: no correction. Bg: background substraction. Scat 1.0:scatter correction with k value of 1.0 for BMIPP.

Scat 1.3: scatter correction with k value of 1.3 for BMIPP.

Arterial territories

LAD LCX RCA

No Bg Scat

1.0

Scat

1.3

No Bg Scat

1.0

Scat

1.3

No Bg Scat

1.0

Scat

1.3

Pat 1 0.5 14.1 8.4 10.8 0 0 0 0 0 0 0 0

Pat 2 0 0 0.6 3.1 0 23.8 12.4 9.2 0 2 1.7 0

Pat 3 1.7 14.1 3.4 5.5 0 0 0 0 0.2 3.9 1 1.6

Pat 4 21 36.6 35.2 39.3 0 0 0 0 0 1.9 1.9 2.2

Pat 5 1 4.6 0.8 5 14.3 67.2 15.2 42.1 4 37.4 27.7 30.8

Pat 6 0 9.1 0.7 0.8 0 0 0 0 0 2.3 0 0

Pat 7 0 7.3 3.2 4.5 0 1.1 1.3 0 0 0 0 0

Pat 8 15.8 37.5 30.2 32.7 9.1 22.3 15.3 17.2 14.2 31.9 25.3 28.4

Pat 9 1.8 27.9 14.6 22.3 0 0 0 0 0 0 0 1.3

Pat

10

0 1.5 0 0 0.3 11.2 0.6 1.8 0.4 7.2 5.2 5.4

When the two k values for scatter correction with 123

I were compared, a small difference in

the % mismatched surface was noted. However this did not modify the classification of the

concerned territories as either significantly mismatched or not.

As a comparison, dobutamine stress echocardiography demonstrated evidence of contractile

reserve in 9 territories.

At follow-up, echocardiographic improvement was noted in all revascularized regions,

versus in 1 nonrevascularized (Table 4). Accuracy of the different processing methods to predict the

evolution of regional contractility at follow-up was 64% when no correction was applied, 93% for

scatter correction and 79% for the background correction (versus 93% for dobutamine stress

echocardiography).

Discussion

When the uptake of 99m

Tc-labeled sestamibi and 123

I-BMIPP are quantitatively compared in the

setting of myocardial viability assessment, special attention must be paid to the acquisition

parameters. Indeed, comparing the data without correction underestimates the magnitude of viable

myocardium, and appliance of a background correction overestimates it. Dual window scatter

correction constitutes the optimal approach, predicting functional outcome with the same accuracy

as dobutamine stress echocardiography in patients with chronic ischemic heart disease and

myocardial infarction.

62

Figure 3: Extent of the mismatched surface for the 14 arterial territories (in %) according to the different

correction methods. No: no correction. Bg: background substraction. Scat 1.0: scatter correction with k value

of 1.0 for BMIPP. Scat 1.3: scatter correction with k value of 1.3 for BMIPP

Free fatty acid metabolism and its relationship to myocardial viability studies

In myocardial viability assessment, a normal uptake of sestamibi, usually defined as at least 60% of

the peak activity (2) identifies residual viable tissue with a high accuracy. However, a decreased

uptake is a rather poor predictor of myocardial scar, and additional metabolic studies are required to

differentiate poorly perfused but still viable from fibrotic tissue. Radioiodinated free fatty acids,

suitable for SPECT imaging, are a useful tool for metabolic imaging. Their uptake, depending

primarily upon regional blood flow (17) and regulated by a membrane fatty acid-binding protein, is

followed by the ATP-dependent initial steps of the native fatty acids enzymatic activation to acyl-

coenzyme A (18), before they are esterified to triglyceride and incorporated in the endogenous lipid

pool.

Using BMIPP, prolonged myocardial retention time is obtained thanks to the presence of a

methyl-group precluding direct beta-oxidation. However, a significant proportion of the BMIPP-

CoA is beta-oxided after an intermediate alpha-oxidation step (19), and only a small amount of the

extracted BMIPP is backdiffused. In pathological conditions with impaired myocardial oxygen

supply, alteration of the usage of fatty acids as energy substrate for the production of high energy

phosphate results in a increased backdiffusion of BMIPP, decreased tissular concentration of

BMIPP and alpha-oxidized metabolites, and hence mismatching with the flow tracers.

In patients, this pattern of uptake with BMIPP less than perfusion has been found a good predictor

of myocardial viability, while a matched decreased uptake of both tracers reliably identified

myocardial scar (4-7). Reverse mismatching (BMIPP higher than perfusion) is less frequently

reported and its significance unclear. It could be associated with unstable conditions (20).

0

10

20

30

40

50Bg Scat 1.0 Scat 1.3No

Extent (%)

Method

m=24.8

m=5.9

m=14.1m=17.9

63

Table 4: Echocardiographic and scintigraphic findings in the 14 arterial territories with resting wall motion

abnormalities.

LAD: left anterior descending artery. LCX: left circumflex artery. RCA: right coronary artery.

H: hypokinesis. A: akinesis. D: dyskinesis. Dobutamine stress test: (+) = contractile response under

dobutamine; (-) = unchanged wall motion. No: no correction. Bg: background substraction.

Scat: scatter correction. MIBI/BMIPP: (+) = mismatching; (-) = matched decreased uptake.

CABG: coronary artery bypass grafting. PTCA: percutaneous transluminal coronary angioplasty.

Involved

artery

Baseline

wall

motion

Dobuta

mine

stress

MIBI/BMIPP Treatment Follow-up

wall motion

Scat No Bg

Patient 1 LAD H (+) (+) (-) (+) PTCA Normalized

Patient 2 LCX A (-) (+) (-) (+) CABG Improved

Patient 3 LAD A (-) (-) (-) (+) Medical Unchanged

Patient 4 LAD A (+) (+) (+) (+) PTCA Improved

Patient 5 RCA

LCX

A

A

(+)

(+)

(+)

(+)

(-)

(+)

(+)

(+)

CABG Improved

Improved

Patient 6 LAD severe H (+) (-) (-) (+) Medical Improved

Patient 7 LAD D (-) (-) (-) (+) Medical Unchanged

Patient 8 LAD

RCA

LCX

severe H

severe H

mild H

(+)

(+)

(+)

(+)

(+)

(+)

(+)

(+)

(+)

(+)

(+)

(+)

CABG Improved

Improved

Improved

Patient 9 LAD A (+) (+) (-) (+) CABG Improved

Patient 10 RCA

LCX

D

A

(-)

(-)

(-)

(-)

(-)

(-)

(-)

(+)

Medical Unchanged

Unchanged

Influence of the methodology on the pattern of distribution of BMIPP related to perfusion:

mismatching versus reverse mismatching.

Using low-energy collimators for cardiac imaging with 123

I-radioiodinated free fatty acids, the

magnitude of septal penetration varies from one study to the other depending on the surrounding

activity, even when high-purity 123

I is used. This must be kept in mind especially when the uptake

of BMIPP must be quantitatively compared to that of a perfusion tracer. Indeed, the heterogeneous

distribution of the resultant background might mask the presence of mismatching or even result in a

"reverse mismatching" with BMIPP uptake higher than the perfusion.

This feature, recently reported by Sloof et al in a significant number of patients with chronic

ischemic heart disease, incited these authors to suggest that the mismatching with BMIPP less than

perfusion might be more typical for the (sub)acute phase of a myocardial infarction while a reverse

mismatching, mirroring the findings observed with 18F-fluorodeoxyglucose, should be more

frequently associated with viability in the chronic phase of the disease (8). However, in their paper,

the authors observed a spread of BMIPP uptake from 20% higher to 10% lower than thallium.

Furthermore, they considered a 7% to 8% difference in uptake as threshold of significancy, in order

to take into account the differences in attenuation between the 2 isotopes as recommended by

Tamaki (21). Since we found 12% more background activity in the left ventricle cavity with BMIPP

due to septal penetration of high energy photons, it is likely that this might at least partially explain

the higher BMIPP than thallium uptake they noted.

Indeed, although reverse mismatching has been reported in a small number of patients, it

seems related to unstable conditions (20) rather than to the delay between the acute event and the

64

tests since Tamaki found no reverse mismatching but a decreased BMIPP uptake relative to 201

Tl in

29/50 consecutive patients with chronic infarction (22).

Influence of the methodology on the presence and extent of viable myocardium

In our patients, the mean tissue activity within the infarcted area for the 10 patients was very similar

for both tracers when no correction for the higher noise level in the BMIPP images was applied

(mean BMIPP uptake 0.4% lower than MIBI). After scatter correction, the difference increased to

6.4%.

Our results demonstrate that methodological factors can influence the image interpretation

when comparing data obtained by using isotopes with different physical characteristics. In

myocardial viability assessment, comparing 123

I-BMIPP and 99m

Tc-sestamibi without correcting for

the differences in signal-to-noise ratio, scatter and attenuation results in an underestimation of the

magnitude of mismatching, partially disguised by the higher background in the iodine images,

especially in regions with low uptake.

Conversely, measuring the background activity by means of a single region of interest located at the

basal part of the myocardium to apply a background subtraction overcorrects the BMIPP images,

particularly in patients with extended apical defects, hence worsening the specificity. Indeed,

because of the heterogeneous distribution of background activity within the ventricle, the activity in

low count regions is influenced by the surrounding tissue activity when applying filtered

backprojection (23), and one single ROI placed on the base of the ventricle is not representative for

the real distribution of background activity within the whole ventricular cavity, as shown by the

negative values of BMIPP uptake found in two of our patients.

Scatter correction is thus the method of choice when the uptake of BMIPP must be quantitatively

compared to a perfusion tracer. In our small group of patients, it demonstrated the same accuracy as

dobutamine stress echocardiography.

Regarding the perfusion tracer of choice, the value of 99m

Tc-labeled compounds for

assessing myocardial viability remains controversial compared to 201

Tl (24). However, we should

recommend 99m

Tc-labeled agents for quantitative comparison with 123

I-BMIPP, because of the small

difference in attenuation between 123

I and 99m

Tc.

Using the dual window method, the value of the substraction factor k is difficult to

determine from phantom studies because it depends on the distribution of activity, and different

approaches result in slightly different values (13). Based upon phantom studies showing that scatter

substraction factors of 1.0 and 1.3 were the lowest and highest possible values for 123

I, we applied

these two values to 123

I-BMIPP imaging in patients. Using a scatter factor k=1.0 for BMIPP, the

mean left ventricular background activity remained higher than in the MIBI images corrected for

scatter with a factor k=0.7, indicating a slight undercorrection. However, when quantifying the

mismatching between MIBI and BMIPP with k=1.0 and 1.3 for 123

I, the difference in the %

mismatched surface was small and had no influence on the classification of a region as either viable

or not. Triple window scatter correction avoids the scatter factor determination (25).

In the present study, BMIPP and MIBI were acquired sequentially with an interval of 3

days. Acquiring two different energies simultanously would likely cause errors in this quantitative

analysis because of cross-talk from one energy window into the other (6). Using small asymmetric

energy windows and correcting for cross-talk, Madsen et al (26) concluded in a phantom study that

the true difference in regional tracer uptake should exceed 10 % to get reliable results. Since a

difference of ±10% uptake between both tracers is defined as mismatching, hence viable tissue,

simultanous acquisitions are not appropriate.

Low-energy all-purpose instead of high-resolution collimators were used in this work, to

improve the signal-to-noise ratio after scatter correction. Further optimization of the method could

be achieved by using medium-energy collimators for 123

I-BMIPP and low-energy collimators for 99m

Tc-MIBI with the same resolution.

65

Conclusion

When quantifying the mismatching between 123

I-BMIPP and 99m

Tc-MIBI in myocardial viability

assessment, special attention must be paid to the acquisition parameters. Indeed, direct comparison

between the two tracers without any correction results in an underestimation of the presence of

mismatching while background substraction frequently overestimates the amount of viable tissue.

Compared to dobutamine stress echocardiography in a small group of patients, quantification of

scatter corrected images was the most optimal method for identifying the presence of viable

myocardium.

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67

3.4 Clinical applications.

BMIPP Imaging to Improve the Value of Sestamibi Scintigraphy for Predicting Functional Outcome in Severe Chronic Ischemic Left Ventricular Dysfunction. Anne-Sophie E. Hambye, André A. Dobbeleir, A. Vervaet, Paul A. Van den Heuvel and Philippe R. Franken. Nuclear Medicine and Cardiology, Middelheim Hospital, Antwerp, and Nuclear Medicine, Free University of Brussels (VUB), Brussels, Belgium.

Journal of Nuclear Medicine 1999; 40: 1468-1476.

Mismatching between BMIPP and perfusion accurately predicts functional outcome after acute myocardial infarction. The

current investigation aimed at evaluating the value of this method to predict the evolution of global function according to

the applied treatment in patients with chronic ischemic heart disease. Methods: Twenty patients with infarction and

chronic left ventricular dysfunction were studied (median infarction age: 12 weeks, range: 2 weeks-15 years).

Radionuclide angiography, 2D-echocardiography and BMIPP and gated sestamibi scintigraphy were obtained at rest

before and >6 months after treatment (revascularization in 13 and conservative therapy in 7). In 7 patients, radionuclide

angiography was repeated after 1 year. Results: On a patient basis, mismatching with BMIPP less than sestamibi was

noted in 15 patients at baseline. Eleven of these 15 patients demonstrated significant functional improvement at follow-

up, versus only one of the 5 with a matched decreased uptake. Hence, the combined sestamibi/BMIPP was 73% positive

and 80% negative predictive of functional outcome, with a global accuracy of 75%. On a segmental basis, using an

optimal threshold of uptake defined by ROC curve analysis, sestamibi was only 63% accurate to predict regional

outcome. Adding BMIPP improved the accuracy to 80% (p=0.001).

At follow-up, significant mismatching was still noted in 7 patients in the revascularized group, and 1 in the medically

treated. It was associated with a further increase in ejection fraction at one year follow-up only in the revascularized

group. Conclusion: In patients with chronic left ventricular dysfunction post-infarction, a mismatching with BMIPP less

than sestamibi reliably identifies jeopardized but viable myocardium, and predicts functional recovery with an accuracy

similar to that reported in the (sub)acute phase of the infarction.

68

Mid-ventricular short axis (SA), vertical long axis (VLA), and bull’s eye (BE) images of a 45-year old male patient with a 37 week-old anteroseptal infarction associated with extended akinesis (9 segments). Baseline EF amounted to 37% and 8/9 segments were mismatched. Six months after CABG, EF did not significantly change (39%) although the patient was clinically symptom free. On scintigraphy, 6/9 segments with baseline dysfunction were still mismatched despite an increased sestamibi and BMIPP uptake. At one year, EF amounted to 44%.

69

Quantification of Sestamibi and BMIPP Uptake for Predicting Functional Outcome in Chronically Ischemic Dysfunctional Myocardium. A.S. HAMBYE, A. VERVAET, A. DOBBELEIR Nuclear Medicine, Middelheim Hospital, Antwerp, Belgium.

Nuclear Medicine Communications, 1999; 20: 737-745. Summary

In chronic ischemic heart disease, little is known about the usefulness of free fatty acid scintigraphy for assessing

viability. To investigate this, we quantified the uptake of 99Tc

m-sestamibi and

123I- BMIPP at rest twice with 6 months

interval in 20 patients with chronic ischemic left ventricular dysfunction and infarction. Depending on the relative

distribution of both tracers, 4 patterns of uptake were observed and named normal, mismatched, matched and scar. The

proportion of the left ventricle surface corresponding to each pattern was expressed in % of the total surface using a

polar map. In the meantime between the 2 series of tests, patients were either addressed for revascularization or

conservatively treated.

The quantitative results were compared to those of dobutamine stress echocardiography (DSE) in arterial territories with

resting contractile dysfunction and correlated to the evolution of regional and global function at follow-up.

At baseline, 25 arterial territories were analyzed. Using sestamibi, on average 1/3 of their surface was considered as

normally perfused. No clear association was found between the % normally perfused surface and the DSE findings.

Adding BMIPP and using a value of >7% of the arterial surface with BMIPP lower than sestamibi (mismatch) as cutoff of

significance for viability, 14/18 mismatched regions were considered viable by DSE, and 6/7 with <7% mismatched

surface or matching were not.

On a patient basis, 15 patients were viable, of whom 13 were revascularized (16 territories). At follow-up, global function

improved in 11 of the 15 viable patients, all in the revascularized group. Regional improvement was noted in 11/16

revascularized territories, and was associated with a significant increase in sestamibi and BMIPP uptake and in the %

normally perfused myocardial surface. In the 5 patients without significant viability, no functional deterioration or changes

in the quantitative parameters were observed under medical treatment.

These results suggest that quantitative analysis of sestamibi and BMIPP uptake is a reliable method to objectivate the

presence of myocardial viability in chronic ischemic heart disease and to predict functional improvement after

revascularization.

Evolution with time of the percent uptake of sestamibi and BMIPP in the regions with wall motion abnormalities by echocardiography relative to the treatment used.

Sestamibi uptake (%) BMIPP uptake (%)

Baseline

Follow-up

Mean

difference

P-value

Baseline

Follow-up

Mean

difference

P-value

Revascularized territories (n=16) 47.2±11.4 53.0±12.0 5.8±5.7 0.004 38.5±13.2 47.8±14.7 9.3±6.9 <0.001

Conservatively treated territories (n=9) 41.0±10.9 40.6±13.4 -0.4±8.8 0.86 40.1±9.6 39.2±12.7 -0.8±6.8 0.77

*Values are expressed as the mean ± standard deviation.

70

Predicting Functional Outcome by quantification of sestamibi and BMIPP after acute myocardial infarction. Anne-Sophie E. Hambye, Ann Vervaet, André A. Dobbeleir, Paul Dendale and Philippe R. Franken. Nuclear Medicine, Middelheim Hospital, Antwerp, and Nuclear Medicine and Cardiology, Free University of Brussels (VUB), Brussels, Belgium.

European Journal of Nuclear Medicine 2000; 27: 1494-1500.

Iodine-123 15-(p-iodophenyl)-3-R,S-methyl-pentadecanoic acid (BMIPP) can be used to image myocardial fatty acid

regional distribution and utilization with single-photon emission tomography (SPET). By visual analysis, a mismatching

with regional uptake of BMIPP less than that of a perfusion tracer has been show to predict myocardial viability and

functional improvement after restoration of flow in patients with myocardial infarction. The current study aimed to

evaluate a newly developed quantitative method of analysis of sestamibi and BMIPP uptake for the prediction of

functional recovery after revascularization in patients with acute infarction. BMIPP and gated sestamibi SPECT studies at

rest were obtained before and >3 months after revascularization in 18 patients with recent infarction. A color coded polar

map was generated from the comparison of sestamibi and BMIPP uptake. Depending on the relative distribution of the

two tracers, different patterns of uptake were identified and their extent expressed as percentages of the surface of the

whole left ventricle and of the three main coronary artery territories. At follow-up, recovery was defined as ≥5% increase

in ejection fraction compared to baseline. Receiver-operating characteristic curve analysis was performed to analyse the

data. At baseline, significant correlations were found between ejection fraction and the % surface with decreased

sestamibi or BMIPP uptake (r=-0.68, p=0.001, and r=-0.72, p<0.0001 respectively). When combining both tracers,

ejection fraction was significantly associated with extent of myocardium showing decreased sestamibi uptake with lower

BMIPP uptake (mismatching; r=-0.68, p=0.001). At follow-up, significant functional recovery was found in 13/18 patients.

By ROC curve analysis, the optimal pattern of distribution predicting recovery was a mismatching with uptake of

sestamibi <70% and uptake of BMIPP at least 10% lower. For this parameter, optimal cut-off of extent was 10% of the

whole left ventricle surface (sensitivity 69%, specificity 80%, accuracy 72%) and 25% of the infarct related arterial

territory (sensitivity 77%, specificity 80%, accuracy 78%). The areas under the curve were 79% for the left ventricle

surface and 72% for the individual arterial territories. These results suggest that in patients with acute infarction,

quantitative analysis of sestamibi and BMIPP could offer an objective and reproducible method for estimating the severity

of cardiac dysfunction and predicting the evolution of ejection fraction after revascularization.

Optimal

cut-off

(% surface)

Sens./

Spec. pair

(%)

AUC

(SEE)

(%)

Normal sestamibi uptake

80

54/40

32 (14)

Normal BMIPP uptake 55 69/40 52 (14)

NPDFA 10 46/40 32 (16)

DPDFA-mismatch 10 69/80 79 (12)

NPDFA+DPDFA-mismatch 25 62/60 46 (19)

DPDFA-match

5 62/60 65 (16)

Optimal % left ventricle surface predicting ≥5%

increase in ejection fraction at follow-up for each

distribution pattern of sestamibi and BMIPP, and their respective sensitivity/specificity pairs and

area under the curve (AUC) with the corresponding

standard error of the estimate (SEE) calculated by ROC curve analysis. The best parameter is

indicated in italics.

NPDFA: normal perfusion, decreased fatty acid uptake

DPDFA: decreased perfusion, decreased fatty acid uptake

71

4. Perfusion of the brain.

4.1 Quantification in SPECT using non-invasive methods.

A. Dobbeleir, R.A. Dierckx, J. Vandevivere, P.P. De Deyn.

Departments of Nuclear Medicine and Neurology, Middelheim Hospital Antwerp and Nuclear

Medicine, University Hospital Ghent, Belgium.

In SPECT in Neurology and Psychiatry. Editors De Deyn, Dierckx, Alavi and Pickut. 1997 John

Libbey & Company Ltd.

Summary

Development of dedicated tomographic equipment, in the early eighties, led to the regional

quantification of cerebral blood flow. Using the inert radioactieve gas Xenon-133, Lassen and co-

workers measured the cortical blood flow in ml/min. After the introduction of I-123 IMP and Tc-99m

HMPAO, during the late eighties, kinetic models were developed in several centres using acquired data

from conventional nuclear medicine equipment. However, due to the necessity of arterial sampling for

quantitation, visual interpretation of the tomographic images is still the method of choice in clinical

practise.

Using Tc-labeled tracers and high resolution tomographic gamma cameras, tracer uptake of the main

brain structures can be analyzed. Regions with reduced tracer uptake are visually detected by

comparing to the cerebellar or contralateral uptake. Semiquantitative analysis is performed by

comparing activity ratios of different regions. Many different methods for defining the regions of

interest have been applied, like fixed size regions, functional cortical regions and circumferential

profiles. 3D translation and rotation techniques are used to combine neuroanatomic and functional

images for delineation of the brain structures. Visual interpretation and semiquantification are widely

used.

An hypothetical volume calculation method was presented by Mountz. Assuming that the contralateral

brain region remains uninvolved, this solid method takes into account the severity of hypoperfusion

and extent of the lesion. We used this method in order to express acute ischaemic infarction as

millilitre of zero perfusion.

A non-invasive method for quantitative assessment of brain perfusion was presented by Matsuda. Our

group presented a simple method, using calibrated point sources as a scaling factor, whereby the

tomographic slices are displayed as regional Tc-99m HMPAO brain uptake per cm3 brain tissue in

proportion of the injected lipophilic dose. This method was used to test the influence of several

parameters such as heart rate, weight, height, brain volume, age and drug activation on the HMPAO

brain uptake. Hence, evaluation of global alterations in neurological disorders may be considered.

Introduction

Many neurological disorders are associated with a decrease of perfusion. Since several decenia

attempts at quantification of brain function have been made. In 1945, Kety and Schmidt 1 measured

absolute cerebral blood flow, using inhalation of nitrous oxide in low concentrations. As shown by the

Fick 2 equation, arterial and venous blood samples are needed.

QBRAIN(T) = FLOW * (AC - VC) dt , in which

QBRAIN = amount of substance delivered to the brain, AC = arterial concentration and VC = venous

concentration

72

Several models, especially for PET studies, have been derived from this equation. For absolute

quantification, several presumptions are made in the kinetic blood flow models. In SPECT, absolute

quantification is mainly used to validate semi-quantification methods for specific patient groups.

Cerebral blood flow

Due to the introduction of I123-amphetamine and certainly Tc99m-HMPAO at the end of the eighties

and the use of high resolution tomographic scanners the interest in the regional distribution of the brain

perfusion increased tremendously. The first pass extraction of HMPAO was explained by Nickel 3 in a

simple circulation model.

ABRAIN = Ainject * (1 - Rlung) * (CBF/CO) * Rbrain , in which

ABRAIN = activity trapped in the brain, Ainject = total injected activity, Rlung = retention factor of the lung,

CBF = cerebral blood flow, CO = cardiac output and RBrain = retention factor of the brain

After intravenous injection of a known activity of Tc99m-HMPAO the tracer flows through the right

heart, the lung and the left heart chambers. Within the lung a small part of the activity is trapped due to

diffusion to the lung tissue. This fraction is indicated as the retention factor of the lung. Afterwards, in

the aorta the blood flow splits into the brain circulation and the systemic circulation. Therefore, only

the fraction of activity given by the ratio of cerebral blood flow on cardiac output reaches the brain.

The amount of activity, the brain uptake, retained in the brain depends on the extraction and retention

fraction of the brain.

Again to quantitate the retention fraction in the brain arterial and venous blood samples are needed. A

technique avoiding these blood samples is necessary for clinical applications. Generally for practical

reasons it is also considered that the retention fraction is constant over the brain and that the HMPAO

SPECT image represents mainly a distribution of blood flow.

Absolute quantification

The first non-invasive absolute quantification method was

proposed by Lassen, Kanno, Celsis and co-workers 4,5.

Their method is based on the inhalation and expiration of the inert gas Xe133. Four 1 minute

sequential tomographic images of the cross-section of the brain were obtained using a dedicated

tomograph. The shape of the arterial input function is recorded using a separate detector placed over

the right lung. This was the only non-invasive method until recently. The technical disadvantages

are the need for a dedicated expensive fast rotating single photon tomograph and the poor resolution

of the low energetic Xenon isotope.

Besides arterial sampling methods, compartimental models have been developed by predicting the

blood flow from a linear relationship with a calculated index like the absolute quantification method of

Matsuda 6. This method, most applied worldwide at this moment, uses the brain input and aortic arch

curves to calculate a brain perfusion index which is correlated to blood flow. Detailed explanation is

given in another chapter.

Visual and semi-quantitative analysis

Quantification remains difficult in routine practice. Therefore most physicians evaluate the distribution

of blood flow in the brain by visual interpretation. In an attempt to be more sensitive, reducing the

variation coefficient by refering to a stable region, many semi-quantitative methods using

Tc99m-HMPAO have been described over the past few years 7. Operator defined or automatic left to

right ratios have been used. The activity in functional regions has been studied. In order to delineate

73

more precisely the anatomic structures, SPECT images have been matched to CT or NMR images. The

volume of the defect has been calculated comparing to the contralateral healthy structures.

Figure 1. Hofmann brain phantom. First and third row represent planar images of slices through the phantom.

Second and fourth row are tomographic reconstructions.

Significant improvement in image resolution has been achieved by using multidetector systems and

high resolution fanbeam collimators 8. When comparing images made with a single detector to a multi-

detector system, physicians had to adapt their visual interpretation due to a dramatic improvement of

reconstructed resolution, from about 15 mm to about 8 mm providing functional detailes never

observed before. The images became close to the ones observed with PET systems.

The group of Matsuda at the Kanazawa University in Japan presented the first high resolution

functional brain atlas 9. Major topographical reference points could be defined and a comparison was

made with the MRI data 10.

Meanwhile progres was also made in computerspeed permitting reconstruction or reprojection methods

which were too time consuming a few years ago 11. Three-dimensional display utilizing volume

rendering facilitates understanding of spatial relationships and anatomo-functional correlation 12.

In smaller structures, a relative hypoperfusion is observed. This is not necessary a physiological

phenomenon, but is associated to the tomographical resolution of the gamma camera and is well

74

known as partial volume effect. For this reason, visually or quantitatively structures of the left

hemisphere are compared to the same structures in the right hemisphere.

In figure 1 a Hofmann brain phantom is presented. The first and third row represents planar images of

slices through the phantom. The second and fourth row are tomograpic reconstructions of the phantom.

Due to a worse resolution, the images of the tomographic reconstruction are less sharp and a drop of

activity is observed in smaller structures 13.

In figure 2 a circumferential profile of the phantom in a basal ganglia slice is presented. Although the

same radioactivity is present everywhere, different activities of the cortex are observed. Frontal cortical

activity is higher then in the other cortical regio's. This corresponds to the regio in the phantom where

the cortex has the largest diameter. This means also that normal distribution of the tracer in the brain

depends of the resolution of the acquisition system. A mental picture of normality and pictures of

different disease states are therefore mandatory. Gender differences in brain uptake were described by

Podreka in a large group of normal subjects 14.

Figure 2. A circumferential maximum value profile of a Hofmann phantom in a basal ganglia slice

normalized to the mean activity. 90° corresponds to frontal activity.

That's why some centers try to establish a normal database of regional cerebral uptake 15. Sectorial

regions of interest were drawn on brain slices of normal volunteers in order to obtain strict reference

values to be used in interindividual and intergroup clinical comparisons. The activity in each region is

generally compared the the contralateral activity and to the cerebellar activity. A mean and SD value

can be obtained for each region. Most of the cortical normal values are situated at a level of about 80 to

85 % of the cerebellar activity. The spread was in general around 5 % exept in the fronto-orbital

region where it was about 10 %. In all similar studies, for example in Alzheimer patients, the

assumption has to be made on clinical grounds that the cerebellar activity in patients is normal since

the cerebellum is needed as reference region. In the same way the mean activity in the whole slice or

even in the whole brain is used as reference. Automatic transformation of 3D images into a stereotaxic

Talairach atlas for establishing a normal database and patient comparison has been achieved 16.

Effective volume determination

Defect volumes can be calculated. ROIs have to be drawn over the lesion on all slices involved. These

ROIs are mirrored to the contralateral homologous region. The total functional volume loss, expressed

as an imaginary volume of zero perfusion can then be calculated. This method, first used by Mountz 17,

75

takes into account the pixel volumes, number of slices and the activity difference at each slice between

the normal and in our case ischaemic hemisphere.

We used this method in patients suffering from unilateral acute ischemic infarction 18. By expressing

the infarction as millilitre zeroperfusion, this semiquantification method simultaneously takes into

account the extent and degree of hypoperfusion. SPECT defects may be measured in an accurate and

reproducible way. Moreover this study showed a significant correlation between the volume

zeroperfusion and the neurologic deficit on admittance as scored on the Orgogozo scale.

Brain uptake quantification

We have developed an absolute quantification method 19, not to quantify blood flow, but to quantify

exactly what is seen on the images: the regional brain uptake of Tc99m-HMPAO being the product of

blood flow and retention of the brain. We studied the influence of individual body surface, brain

volume and heart rate fluctuation on the brain uptake 20. The influence of these factors were

investigated in 33 healthy volunteers. Afterwards, they were applied to 13 patients suffering from

probable dementia of Alsheimer's type, in order to correct for interindividual variation 21. An equation

has been tested to calculate from known point source activities a factor K. Multiplying SPECT slices

on pixel by pixel base by this factor provides image values expressed as 10-6 of the injected lipophilic

dose per ml brain tissue.

This allows intra or interindividual comparison between different Tc99m HMPAO studies. In healthy

volunteers with similar heart rate at injection in the two studies, a mean deviation of 7.2% in cerebellar

uptake was observed between repeated acquisitions 19. On the contrary testing the reproducibility of the

method on healthy volunteers, we noted a significant influence of the heart rate at injection time. This

could be expected since the brain uptake is inversely proportional to the cardiac output.

Table 1 shows the cerebellar uptake of the total group of 33 healthy volunteers, 18 men, 15 women and

13 Alzheimer patients. The mean uptake at basal heart rate indicated in the first column varies from

43.1 for men to 75.2 for the Alzheimer patients. The second column shows the brain uptake corrected

for the body surface. The value 49.9 for men becomes closer to the uptake value of 66.2 for the

Alzheimer patients, who had a much smaller body weight. The third column shows the results after the

correction for body surface and brain volume index. In each of these groups, the cerebellar uptake

becomes very close to about 52 10-6 of the injected dose per ml brain tissue, with a similar standard

deviation of about 7.

Table 1. Cerebellar uptake (mean and standard deviation) in healthy volunteers and DAT patients at rest

heart rate, corrected for a body surface factor of BS/1.73 and corrected for body surface and a brain volume

factor of BV/1350.

76

Figure 3. Regional brain uptake rBU in healthy volunteers and DAT patients, after cumulative corrections for

heart rate, body surface and brain volume, plotted versus age. The decline of cerebellar uptake with age

becomes negligible rBU = 54.7 – 0.04 x age.

In figure 3 the cerebellar uptake of 33 healthy volunteers and 13 Alzheimer patients, after cumulative

corrections for heart rate, body surface and brain volume are plotted versus age. As seen on this graph

the decline of the cerebellar uptake with age becomes negligible.

Normalized brain uptake values allow extension of the application of the quantification method from

longitudinal studies to group comparisons. This study proved that the cerebellum is a practical and

reliable region to choose as a reference in patients with Alzheimer's dementia.

Discussion

The aim of quantification is to provide a reliable and reproducible numerical measure of brain

perfusion in different regions and time windows. Since absolute quantification is difficult and time

consuming in daily practise, absolute quantification is certainly important for identifying stable

regions at different disease state, regions which afterwards can be used in semi-quantitation as

control or reference regions. In those cases semi-quantitation is advisable since possible

measurement errors are smaller. However in cases, where a overall change of blood flow can be

expected like carotic obstruction or in stimulation studies, the more difficult and susceptive to errors

absolute quantification method is mandatory.

References

1. Kety SS, Schmidt CF.(1945): The determination of cerebral blood flow in man by use of nitrous

oxide in low concentrations. Am J Physiol. 143,53-66.

2. Fick A. (1870): Uber die Messung des Blutquantums in den Herzventrikeln. Verhandl Phys Med

Ges Wurzburg. (Translated Hoff HE, Scott HJ, N Engl J Med 1948. 239, 476-483).

3. Nickel O, Nagele-Wohrle B, Ulrich P, Eisner D, Roesler A, Grimm W and Hahn K.(1989):

RCBF-quantification with 99mTc

HMPAO-SPECT: Theory and first results. Eur J Nucl Med. 15,1-8.

77

4. Kanno I, Lassen NA.(1979): Two methods for calculating regional cerebral blood flow from

emission computed tomography of inert gas concentrations. J Comput Assist Tomogr. 3, 1, 71-76.

5. Celsis P, Goldman T, Henriksen L and Lassen NA.(1981): A method for calculating regional

cerebral blood flow from emission computed tomography of inert gas concentrations. J Comput Assist

Tomogr. 5, 5, 641-645.

6. Matsuda H, Tsuji S, Shuke N, Sumiya H, Tonami N, Hisada K.(1992): A quantitative approach to

technetium-99m hexamethylpropylene amine oxime. Eur J Nucl Med. 19, 195-200.

7. Mountz J.(1991): Quantification of the SPECT Brain Scan. Nuclear Medicine Annual, Raven Press,

New York. 67-98.

8. Dobbeleir A, Dierckx R, Vandevivere J. (1991): High spatial resolution SPECT using a three-head

rotating gamma camera and super fine lead fanbeam collimators. Eur J Nucl Med.18, 8, 600.(abstract)

9. Matsuda H, Oskoie SD, Kinuya K, Tsuji S, Sumiya H, Tonami N, Hisada K. (1990): Tc-99m

HMPAO brain perfusion tomography atlas using high resolution SPECT system. Clin Nucl Med. 15,

428.

10. Dierckx R, Dobbeleir A, Martin JJ, De Deyn PP. (1993): Tc-99m HMPAO tomography using a

three-headed SPECT system equipped with lead fan-beam collimators. Clin Nucl Med. 18, 532-

534.

11. Wallis J, Miller T.(1990): Volume rendering in three-dimensional display of SPECT images. J

Nucl Med. 31, 1421-1430.

12. Dierckx R, Dobbeleir A, Borggreve F, De Deyn PP, Vandevivere J. (1991): Three-dimension

reconstruction of brain perfusion. Eur J Nucl Med. 18, 597.(abstract)

13. Kim H, Zeeberg B, Fahey F, Bice A, Hoffman E and Reba R.(1991): Three-dimensional SPECT

simulations of a complex three-dimensional mathematical brain model and measurements of the

three-dimensional physical brain phantom. J Nucl Med. 32, 1923-1930.

14. Podreka I, Goldenberg G, Baumgartner C, Lang W, Steiner M, Schmidbauer M, Suess E, Bruecke

T, Asenbaum S, Deecke L.(1989): HMPA0 brain uptake in young normal subjects: gender differences

and hemispheric asymmetries. J Cereb Blood Flow Metab. 9 Suppl 1, 202. (abstract)

15. De Sadeleer C, de Metz K, Somers G, Bossuyt A.(1994): Relative quantification of Tc99m

HMPAO SPECT based on sectorial regions of interest in normal volunteers. Eur J Nucl Med. 21, 8,

781.(abstract)

16. Vanhove C, Monte C, Colaert H, Demonceau G.(1994): Standardised atlas for brain studies. Eur J

Nucl Med. 21, 8, 773.(abstract)

17. Mountz J.(1989): A method of analysis of SPECT blood flow image data for comparison with

computed tomography. Clin Nucl Med. 14, 192-196.

18. Dierckx R, Dobbeleir A, Pickut B, Timmermans L, Dierckx I, Vervaet A, Vandevivere J, Deberdt

W, De Deyn PP.(1995): Technetium-99m HMPAO SPET in acute supratentorial ischaemic infarction,

expressing deficits as millilitre of zero perfusion. Eur J Nucl Med. 22, 5, 427-433.

19. Dobbeleir A, Dierckx R.(1993): Quantification of Tc-99m HMPAO brain uptake in routine clinical

practice using calibrated point sources as an external standard: phantom and human studies. Eur J Nucl

Med. 20, 684-689.

20. Dierckx R, Dobbeleir A, Maes M, Pickut B, Vervaet A, De Deyn PP.(1994): Parameters

influencing SPET regional brain uptake of Tc-99m HMPAO measured by calibrated point sources as

an external standard. Eur J Nucl Med. 21, 514-520.

21. Dobbeleir A, De Deyn PP, Dierckx R.(1994): The cerebellum as reference region: comparison

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Eur J Nucl Med. 21, 10, S5.(abstract)

78

4.2 Quantification of technetium-99m hexamethylpropylene amine oxime brain

uptake in routine clinical practice using calibrated point sources as an external

standard: phantom and human studies

A. Dobbeleir, R. Dierckx

Nuclear Medicine Department, Middelheim Hospital, Lindendreef 1, B-2020 Antwerp, Belgium

European Journal of Nuclear Medicine 1993; 20: 684-689.

Abstract. Quantitative methods for calculation of regional cerebral blood flow with technetium-

99m hexamethylpropylene amine oxime (99m

Tc-HMPAO) have been proposed. These methods are

very labour intensive and therefore are not useful in routine practice. We describe a simple

alternative method, using calibrated point sources as a scaling factor, whereby the tomographix

slices are displayed as regional 99m

Tc-HMPAO brain uptake per cm3 brain tissue in 10

-6 of the

injected lipophilic dose. The method was validated on Jaszczak and Hoffman phantoms using a

three-detector system with HR parallel and HR fan-beam collimators. Under the optimal conditions

described in this paper, the measured to real activity ratio was 1.00 (SD = 0.06). The reproducibility

of the cerebellar uptake in a group of ten normal volunteers and five patients was studied. Intra-

individually a mean deviation of 12.6% was observed for the total group. For those persons with a

heart rate difference of less than 5 units between the two studies, a mean deviation of 7.2% was

obtained. Quantitative 99m

Tc-HMPAO brain uptake images can be useful for longitudinal studies,

especially for follow-up, activation and pharmacological studies.

Key words: Technetium-99m hexamethylpropylene amine oxime – Quantification – Phantom

studies – Brain – Human studies

Introduction

Several authors [1-3] have shown that technetium-99m hexamethylpropylene amine oxime (99m

Tc-

HMPAO) distribution reflects regional cerebral blood flow (rCBF). In recent years, various

methods have been proposed for the quantification of rCBF on the basis of 99m

Tc-HMPAO uptake

[4-7]. All these methods are very elaborate and not applicable on a routine basis. A non-invasive

method for the quantitative assessment of brain perfusion using 99m

Tc-HMPAO was presented by

Matsuda et al. [8]. Although brain uptake is influenced by various parameters such as cardiac output

[5], retention fraction [9], and lipophilic and hydrophilic fraction [10], a simple quantification of the

regional brain uptake (rBU) of 99m

Tc-HMPAO may be useful for follow-up, pharmacological and

activation studies. A simple quantification method to convert brain counts into brain uptake is

presented, using calibrated point sources as an external standard. This method, which avoids the

need for regular phantom calibration of the single-photon emission tomography (SPET) system,

was tested on phantoms, and human reproducibility studies are also described.

Materials and methods

Reference sources.

Four point sources of 5 µCi (185 kBq) 99m

Tc were made by pipetting 5 µl of a 1mCi/ml (37

MBq/ml) solution, using a capillary precision pipette, onto scarcely absorbent paper and dried. The

point sources with a diameter of 3 mm and an activity precision of 2% were prepared in less than 10

min. The exact activity of the 1 ml solution was measured in an ionisation chamber. The four point

sources were fixed along the orbitomeatal axis of each patient before performing the 99m

Tc-

79

HMPAO SPET study. We used a three-detector system (Trionix, Triad) with a detector size of 40 x

22 cm and an energy window of 20%. For phantom studies 5-µl point sources of varying activities

were fixed on the Jaszczak of Hoffman phantom.

Phantom studies.

The spheres (internal diameter 33.5, 28, 22, 16, 13.5 and 10.5 mm) of the Jaszczak Deluxe phantom

were filled with a known concentration of about 3 µCi/ml (111 kBq/ml). Point sources of 1, 2, 4 and

6 µCi (37, 74, 148 and 222 kBq) were fixed on the Jaszczak phantom. The phantom was filled with

a low activity, about 0.1 µCi/ml (3.7 kBq/ml), in order to permit visualisation of the physical

boundary of the phantom. A total of 12 tomographic acquisitions, each of 120 angular views, were

performed on the three-detector system. Acquisition arrays were 128 x 128 and 64 x 64 for the

ultra-high-resolution parallel (UHRP) collimators and 256 x 128 and 128 x 64 for the super-fine

fan-beam (SFFB) collimators. When using the parallel collimators a zoom factor of 1.6 was applied

because of the rectangular shape of the detector. Reconstruction was performed in a 128 x 128 or 64

x 64 array depending on the acquisition array, resulting in a pixel size of 2.2 and 4.4 mm for the

UHRP collimators and 1.8 and 3.6 mm for the SFFB collimators. The acquisitions were repeated

for a total acquisition time of 10, 20, or 30 min. The projection data were reconstructed by filtered

backprojection using a Butterworth filter with a cutoff frequency of 0.7 cyc/cm and roll-off 5.

Chang’s first-order attenuation correction was applied using an attentuation coefficient of 0.12 cm-1.

Circular ROIs, 21-29 mm in diameter depending on the collimator and acquisition array, were

drawn over the point sources. The ROIs were applied on a number of slices with a total axial

distance equal to the ROI diameter. The adjacent slices were used for background substraction. The

diameter necessary to include the total point source activity had been determined previously (Table

1). Total point source activity was calculated applying the ROI on multiple slices and substracting

the ROI activity (background) of the first and last slices of the cylinder, corrected for the volume

ratio, from the total cylinder activity. Background substraction using adjacent slices was done to

eliminate blurred activity from the phantom or brain tissue into the point source region. The mean

activity in a 5 x 5 mm ROI in the centre of the spheres was measured and the activity/cm3

calculated, taking into account the pixel size and the measured and real activity of the point sources.

The same method was used for a three-dimensional Hoffman phantom [11] except that point

sources of 2, 4, 8 and 12 µCi (74, 148, 296 and 444 kBq) were used. The phantom was scanned at

least 6 h after filling and all activities are given at scan time. A 20-min acquisition (40 images of 30

s each, three detectors) was performed using the UHRP ans SFFB collimators. The activities in

cerebellum and frontal cortex (highest activity in the phantom) were measured.

Human studies: reproducibility of 99m

Tc-HMPAO brain uptake.

Ten normal volunteers (age range 24-52 years) and five patients (age range 54-72 years) were

studied. Two acquisitions were performed for each individual within a period of 1 week. The total

study period was 2 months. The protocol was approved by the local Ethics Committee and informed

consent was obtained. Using a previously fixed butterfly needle, 20 mCi (740 MBq) 99m

Tc-HMPAO

was administered to the patient sitting in a quiet and dimmed room, with eyes open and ears

unplugged. To ensure proper formulation of HMPAO, the manufacturer’s package insert was

followed, which implies one vial per patient. The injection was given less than 10 min after

preparation. In these conditions the injected lipophilic fraction can be estimated as 90% of the

injected dose [12]. Heart rate at the time of injection was noted. 5µCi (185 kBq) point sources were

fixed along the orbitomeatal axis and 120 images of 60 s were acquired using the three-detector

system and SFFB collimators starting 20 min after injection. After reorientating the slices parallel to

the orbitomeatal axis by means of the point sources, ROIs were drawn over the point sources and

the total point source counts were calculated as previously described. The mean of the four point

source counts was calculated. Knowing the pixel size (Z) in cm, the mean total point source counts

(CS), the activity of the point sources (AS), the injected liphophilic fraction (ID) and the delay

between the measurement in the ionisation chambre of the source activity and the injected dose (T),

80

and adding a multiplication factor to obtain whole numbers, a factor K is calculated: K=AS.e-

0.00193.T.10

6/CS.ID.Z

3. Multiplying SPET slices on a pixel-by-pixel basis by factor K gives image

values expressed in 10-6 of the injected dose per cm

3 brain tissue. The mean cerebellar uptake in a

11-mm-square ROI centered on the peak pixel value was compared in the two acquisitions. The

cerebellum was chosen since it is often used as a reference region in semi-quantitative analyses.

Results

Reference sources

Typical point source activities and the influence of ROI diameter in patient acquisitions are shown

in Table 1. The data show a greater influence of blurred activity of brain tissue in the ROI at the

meatus than at the canthus region. This difference in blurred activity is almost completely

eliminated after substraction of the background activity in the adjacent slices. For individual

sources a deviation of less than 5% of the mean value was observed in all patients. From Table 1 we

considered an ROI with a diameter of 21 mm large enough to include all the activity from the point

source when using the fan-beam collimator, a 128 x 128 reconstruction array and a Butterworth

filter. A similar approach showed the necessary ROI diameter to be 29 mm when using the parallel

collimator and a 64 x 64 reconstruction array.

Table 1. Influence of ROI diameter on measured point source activities (kcounts) for a fan-beam collimator

and 128 x 128 array patient study. Data are presented for the cylindrical volume, the adjacent slices and the

background substracted activity (bg substr.) ROI

diameter

(mm)

6 x 3.6 mm

slices

2 x 3.6 mm

slices

bg

subtr.

6 x 3.6 mm

slices

2 x 3.6 mm

slices

bg

subtr.

Canthus, right Canthus, left

14.6 146.7 2.7 138.5 145.0 2.1 139.0

16.7 165.4 2.9 156.5 160.0 2.6 152.3

18.5 177.1 3.5 166.9 170.2 3.0 161.0

20.6 184.8 4.0 172.8 176.2 3.5 165.6

22.4 190.0 5.3 174.4 183.3 3.7 172.3

24.5 192.6 5.3 176.3 184.8 4.9 170.0

Meatus, right Meatus, left

14.6 170.5 6.7 150.4 157.4 3.6 146.4

16.7 188.8 10.5 157.2 174.8 5.2 159.4

18.5 204.8 12.6 166.9 189.0 6.5 169.4

20.6 220.2 13.1 180.9 200.5 8.4 175.1

22.4 223.8 14.7 179.9 208.6 12.0 172.6

24.5 237.4 18.5 182.0 213.7 12.7 175.7

Phantom studies

In Table 2 the ratio of measured to real concentration in the centre of the largest sphere (chosen to

exclude any partial volume effect) is shown as a function of point source activity for the two

collimators, with 64 x 64 and 128 x 128 reconstruction arrays and 10-30 min acquisition time.

When the parallel collimator was used, the point source activity had only a minor influence except

in the 128 x 128 array at 10-min acquisition time for the lowest source activities. Excluding these

low pixel count acquisitions, the mean ratio of measured to real activity was 1.00 (SD=0.06). Using

the fan-beam collimator, the concentration in the spheres of the Jaszczak phatom was overestimated

at low pixel density due to underestimation of the point source activity. For the high pixel density

acquisitions a mean ratio of 1.00 (SD=0.04) was measured.

81

Table 2. Ratio of measured to real concentration, for different point source activities, in the centre of the

33.5-mm hollow sphere of the Jaszczak phantom filled with 3 µCi/ml (111 kBq/ml) 99m

Tc

Point source activity

37 kBq 74 kBq 148 kBq 222 kBq

Parallel 64x64 array

10 min acq. 1.04 1.10 1.00 1.02

20 min acq. 1.02 0.99 0.98 0.95

30 min acq. 0.95 0.98 0.98 0.95

Parallel 128 x 128 array

10 min acq. 1.19 1.15 0.99 1.07

20 min acq. 1.08 1.06 0.95 1.01

30 min acq. 1.02 1.08 0.97 1.05

Fan-beam 64 x 64 array

10 min acq. 1.08 1.12 1.00 1.03

20 min acq. 1.13 1.14 1.01 1.01

30 min acq. 0.98 1.00 0.93 0.98

Fan-beam 128 x 128 array

10 min acq. 2.52 1.83 1.24 1.30

20 min acq. 1.22 1.17 0.98 1.04

30 min acq. 1.19 1.12 1.00 1.06

Table 3. Ratio of measured to real concentration in the centre of the hollow spheres of the Jaszczak phantom

filled with 3 µCi/ml (111 kBq/ml) 99m

Tc, demonstrating the partial volume effect

Sphere diameter (mm)

33.5 28.0 22.0 16.0 13.5 10.5

Parallel 64 x 64 array 0.98 0.95 0.88 0.62 0.49 0.30

Parallel 128 x 128 array 1.03 0.99 0.94 0.60 0.48 0.27

Fan-beam 64 x 64 array 1.03 0.96 0.91 0.70 0.49 0.33

Fan-beam 128 x 128 array 1.02 1.01 1.00 0.83 0.66 0.42

The influence of sphere diameter on the ratio of measured to real concentration in the centre of the

hollow spheres (mean value of three acquisitions) is shown in Table 3. The partial volume effect is

larger for the parallel collimator than for the fan-beam collimator since the FWHM (reconstructed

in air, radius 12.5 cm) is 10.1 mm for the former compared to 7.3 mm for the latter.

Table 4 shows the results of the measured to real concentration for the cerebellar region of the

Hoffman phantom. Again, high point source activity is necessary for the fan-beam acquisitions,

whereas at high source activity compared to organ activity, the point source is slightly

overestimated after reconstruction for the parallel collimator. In this respect, Galt et al. [13]

described activity overestimation due to the cutoff frequency when comparing high- and low-

activity sources. We presumed that for the cerebellar region of the Hoffman phantom the partial

volume effect was negligiable. Lower activities due to a partial volume effect are observed in

different regions of the cortex, as shown by the circumferential maximum value profile in Fig. 1.

Human studies: reproducibility of 99m

Tc-HMPAO brian uptake

The reproducibility of the point source activity in repeated human studies is shown in Table 5. A

mean deviation of 2.4% is observed intra-individually. The interval between the two studies in each

volunteer was restricted to less than 1 week in an attempt to avoid changes in the sensitivity of the

gamma camera. Due to the reproducibility of the point source method, this technique of data

calibration with sources can be applied for SPET studies, correcting for the changes in sensitivity of

the gamma camera over time. The individual cerebellar uptake values are presented in Table 6. A

mean deviation of 12.6% (SD=10.3%) in cerebellar uptake is observed intra-individually. The

82

correlation coefficient between the first and second acquisition was 0.80 (Fig. 2). Six volunteers and

four patients had a less than 5-unit difference in heart rate between the two studies (Table 6). The

mean deviation in cerebellar uptake for those individuals was 7.2% (SD=4.1%), and the correlation

coefficient was 0.94 (Fig. 3). Probably due to stress, four volunteers and one patient had a

significant higher heart rate (mean 28%) and a lower cerebellar uptake (mean 21%) in the first

investigation than in the second. Unlike in the case of rCBF, interindividual comparison with regard

to percentage of brain uptake is not possible, mainly due to differences in cardiac output or body

surface area

Table 4. Ratio of measured to real concentration in the Hoffman phantom filled with 3 µCi/ml (111 kBq/ml) 99m

Tc for different point source activities and a total acquisition time of 20 min. The concentration was

measured in a 5 x 5 mm ROI corresponding to the area of highest activity in the cerebellar region of the

phantom (largest hot region in phantom, where no partial volume effect is expected)

Point source activity

74 kBq 148 kBq 296 kBq 444 kBq

Parallel 64 x 64 array 1.02 0.97 0.97 0.93

Parallel 128 x 128 array 1.00 0.97 0.94 0.90

Fan-beam 64 x 64 array 1.16 1.14 1.03 0.97

Fan-beam 128 x 128 array 1.40 1.21 1.07 1.00

Fig. 1. Circumferential maximum value profile of a Hoffman phantom in a basal ganglia slice normalised to

the mean activity. 90° corresponds to frontal activity.

Table 5. Reproducibility of point source activity, in counts/µCi, for repeated HMPAO brain studies in ten

volunteers.

Volunteer Acquisition 1 Acquisition 2

1 29199 27536

2 31132 30674

3 30990 31177

4 31476 30885

5 28940 29230

6 33910 32751

7 31709 32065

8 32498 33512

9 33067 31833

10 31850 31970

83

Fig. 2. Reproducibility of HMPAO uptake in the cerebellum (10-6/cm

3.ID) in ten volunteers and five patients.

A correlation coefficient of 0.80 was obtained (uptake 2=1.10 x uptake 1)

Table 6. Reproducibility of cerebellar uptake in 10

-6 of injected dose per cm

3 brain tissue for repeated

HMPAO brain studies in ten normal volunteers and five patients

Uptake 1 Uptake 2 % change Heart rate 1 Heart rate 2

Volunteer 1 72.2 65.0 -10.5 74 74

Volunteer 2 42.0 39.7 -5.7 60 60

Volunteer 3 38.6 44.1 13.4 68 68

Volunteer 4 51.0 53.3 4.5 76 72

Volunteer 5 66.6 68.6 3.0 76 80

Volunteer 6 33.3 31.9 -4.4 58 63

Volunteer 7 49.4 60.2 17.6 84 70

Volunteer 8 37.3 55.2 38.7 80 68

Volunteer 9 47.9 55.0 13.8 74 56

Volunteer 10 41.6 56.2 30.0 108 72

Patient 1 36.2 37.1 2.4 77 72

Patient 2 53.3 51.2 -4.0 82 86

Patient 3 48.2 55.0 13.1 88 88

Patient 4 49.7 54.7 9.6 104 105

Patient 5 10.1 46.9 15.6 96 80

Discussion

Point sources were used as an external standard to convert counts from the camera into

concentrations of activity in the brain. In order to use the optimal point source activity, similar

once-only phantom work is necessary when employing a single detector system or different

collimators. Since the correct calibration is strictly dependent on ROI extension and background

substraction, the ROI diameter and axial distance (number of slices) should be adapted to the

resolution of the system. The use of point sources for calibration introduces a supplementary

measurement error compared to the cylindrical uniform phantom technique. On the other hand,

tomographic sensitivity variations of the gamma camera, even during scan, do not influence the

point source method because of the use of the target organ on point source ratio. Regular, possible

daily, calibration using the cylindrical uniform phantom is necessary. Since a relatively high

number of counts have to be acquired at a relatively low count rate to avoid any influence of the

84

non-linearity response of the gamma camera, implementing the cylindrical uniform phantom

method in routine practice might be more cumbersome.

Fig.3. Reproducibility of HMPAO uptake in the cerebellum (10

-6/cm

3.ID) in six volunteers and four patients

in whom no significant heart rate difference was observed between the two investigations. A correlation

coefficient of 0.94 was obtained (uptake 1=1.02 x uptake 2)

Despite the greater point source activity dependence for correct estimation of the phantom

concentrations, in patient studies we preferred the SFFB and 128 x 128 reconstruction array because

of the minimal partial volume effect. An acquisition time of 40 min was then needed [14]. From the

results obtained with the Hoffman and Jaszczak phantoms we deduced that point sources of

approximately 5µCi (185 kBq) were optimal. For a parallel collimator the point source activity is

less critical. The filter cutoff frequency was not the cause of overestimation of the fan-beam data at

low source activity. For these data a negligible difference was observed when a Butterworth filter

was applied, varying the cutoff frequency from 0.5 to 1.7 cyc/cm. Overestimation of fan-beam data

at low point source activity with a short acquisition time is probably due to the rebinning process,

the transformation from fan-beam to parallel data, before backprojection. The phantom studies seem

to indicate that there is a minimum count density below which the rebinning algorithm cannot be

used. This should be verified by comparing different computer systems. Reprojecting the fan-beam

data without rebinning eliminated the underestimation of the point sources. However, this method is

not preferred because of high statistical noise in the reconstructed slices. The same effect might

explain higher contrast between grey and white matter in fan-beam reconstructed images.

Kojima et al. described the effect of spatial resolution on quantification [15]. Due to a partial

volume effect, we could only recover real activity in spheres larger than 20 mm using SFFB and

larger than 25 mm using UHRP collimators. Similar results were presented by Szabo et al. [16] for

high-resolution SPET with a three-detector system. This partial volume effect explains the

underestimation in the circumferential profile of the Hoffman phantom, as previously described by

Kim [17]. This can be a major problem in comparing different patients because of different

physiology in respect of not only rBu but also rCBF. Nevertheless, providing tomographic slices in

rBU values might be useful, intra-individually, for activation studies, follow-up and

pharmacological studies. Since no internal reference region is needed, clinically the scope of

indications may be extended and methodological discussions on the choice of reference region are

unneccessary [18]. In order to reduce the cost, by splitting the vial, the lipophilic fraction should be

investigated for absolute quantification. Good intra-individual reproducibility was obtained in cases

of constant heart rate, although large interindividual differences were obtained, as previously

described by Prodreka et al. [19]. The influence of heart rate on rBU is currently being studied in a

larger patient group. It has been shown that the brain extraction of HMPAO is lower at higher flow

85

[20]. Measurement of the absolute uptake might be useful in order to determine the retention factor

for the linearisation correction method of Lassen et al. [20].

To conclude: Although the results are based on a three-detector system with high-resolution

collimators and a relatively small rotation radius, the quantification method should be applicable to

most SPET systems after careful phantom work. Different results can be expected for small brain

structures using a one-detector system with lower resolution collimators and a larger rotation radius.

The major advantage of the described method is its simplicity for routine clinical use, the same

sources being used daily for all patient acquisitions and the final result being represented in terms of

regional brain uptake.

Acknowledgements.

The authors wish to thank Dr. Vandevivere, Head of the Nuclear Medicine Departement, for

providing the opportunity to develop this method and Prof. De Deyn, Head of the Departement of

Neurology, for moral support and addvice. They are also grateful to the technicians of the

department for their collaboration in performing the patient studies.

References

1. Sharp PF, Smith FW, Gemmell HG, et al. Technetium-99m HMPAO stereoisomers as

potential agents for imaging regional cerebral blood flow: human volunteer studies. J Nucl

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2. Costa DC, Ell PJ, Cullum ID, Jarritt PH. The in vivo distribution of 99Tc

m HMPAO in

normal man. Nucl Med Commun 1986:7:647-658.

3. Nowotnik DP, Canning LR, Cumming SA, et al. Development of a TC-99m-labelled

radiophamaceutical for cerebral blood flow imaging. Nucl Med Commun 1985;6:499-506.

4. Matsuda H, Oba H, Seki H, et al. Determination of flow and rate constants in a kinetic

model of 99m

Tc-hexamethyl-propylene amine oxime in the human brain. J Cereb Blood

Flow Metab 1988;8:61-68.

5. Nickel O, Nägele-Wöhrle B, Ulrich P, et al. rCBF-quantification with 99m

Tc-HMPAO-

SPECT: theory and first results. Eur J Nucl Med 1989;15:1-8.

6. Pupi A, De Cristofaro M, Bacciotttini L et al. An analysis of the arterial input curve for

technetium-99m-HMPAO: quantification of rCBF using single-photon emission computed

tomography. J Nucl Med 1991;31:1501-1506.

7. Murase K, Tanada S, Fujita J, et al. Kinetic behavior of technetium-99m-HMPAO in the

human brain and quantification of cerebral blood flow using dynamic SPECT. J Nucl Med

1992;33:135-143.

8. Matsuda H, Tsuji S, Shuke N, et al. A quantitative approach to technetium-99m

hexamethylpropylene amine oxime. Eur J Nucl Med 1992;19:195-200.

9. Szabo Z, Monsein LH, Maruki et al. Quantitative imaging of CBF with Tc-99m HMPAO

[abstract]. Eur J Nucl Med 1991;18:667.

10. Nakamura K, Tukatani Y, Kubo A, et al. The behavior of 99m

Tc-hexamethyl

propyleneamineoxime (99m

Tc-HMPAO) in blood and brain. Eur J Nucl Med 1989;15:100-

107.

11. Hoffman EJ, Cutler PD, Digby WM, Maziotta JC. 3-D phantom to simulate cerebral blood

flow and metabolic images for PET. IEEE Trans Nucl Sci 1990;37:616-620.

12. Hung JC, Corlija M, Volkert WA, Holmes RA. Kinetic analysis of technetium-99m d,I-

HMPAO decomposition in aqueous media. J Nucl Med 1988;29:1568-1576.

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13. Galt JR, Grant SF, Alazraki NP. Effect of system resolution on quantitative measurements

of the cerebral cortex and cerebellum and Spect brain images [abstract]. J Nucl Med

1991;32:728.

14. Dobbeleir A, Dierickx R, Vandevivere J. High spatial resolution Spect using a three-head

rotating gamma camera and super fine lead fan-beam collimators [abstract]. Eur J Nucl Med

1991;18:600.

15. Kojima A, Matsumoto M, Takahashi M, et al. Effect of spatial resolution on Spect

quantification values. J Nucl Med 1989;30:508-514.

16. Szabo Z, Seki C, Rhine J, et al. Effect of spatial resolution on absolute quantification with

high resolution Spect [abstract]. Eur J Nucl Med 1991;18:604.

17. Kim HJ, Zeeberg B, Fahey F, et al. Three-dimensional Spect simulations of a complex

three-dimensional mathematical brain model and measurements of the three-dimensional

physical brain phantom. J Nucl Med 1991; 32:1923-1930.

18. Syed G. Eagger S, Toone D, et al. Quantification of regional cerebral blood flow (rCBF)

using 99Tc

mHMPAO and SPECT: choice of the reference region. Nucl Med Commun

1992;13:811-816.

19. Podreka I, Goldenberg G, Baumgartner C, et al. HMPAO brain uptake in young normal

subjects: gender differences and hemispheric asymmetries. J Cereb Blood Flow Metab

1989;9 Suppl 1:202.

20. Lassen N, Andersen A, Friberg L, Paulson O, The retention of 99Tc

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human brain after intracarotid bolus injection: a kinetic analysis. J Cereb Blood Flow Metab

1988;8(Suppl):S13-S22.

87

4.3 Clinical applications.

Parameters influencing SPET regional brain uptake of technetium-99m hexamethylpropylene amine oxime measured by calibrated point sources as an external standard. R.A. DIERCKX, A. DOBBELEIR, M. MAES, B.A. PICKUT, A. VERVAET, P.P. DE DEYN. Nuclear Medicine and Neurology , Middelheim Hospital and Born-Bunge Foundation Antwerp, Belgium. Psychiatry, University Hospitals of Cleveland, USA.

European Journal of Nuclear Medicine, 1994; 21: 514-520. Abstract

Using calibrated point sources as external standard to convert single-photon emision tomography (SPET) brain counts

into absolute values of regional brain uptake (rBU) of technetium-99m hexamethylpropylene amine oxime (HMPAO), the

relative contribution of different parameters to inter-individual variability of cerebellar rBU was examined in 33 healthy

volunteers. Stepwise regression analysis identified body surface as the most important factor underlying inter-individual

variability (P<0.001), when compared with brain volume. In the normal volunteer population presented, age decrement of

rBU corrected for body surface and brain volume equalled

60.05-0.20xage. Based on the data of eight normal volunteers, including four test-retest studies with heart rate (HR)

differences greater than 5 units and four test-retest studies with doubling of heart rate after bicycle exercise, influence of

heart rate may be expressed by the equation ∆rBU=0.35 ∆HR. Clinically, estimation of the relative influence of different

factors allows normalization and extension of the applicability of the rBU quantification method used from longitudinal

studies to group comparisons. Interestingly, results of the Daily Stress Inventory Scale and a subjective rating scale

suggest the absence of a significant influence of minor stress on rBU. When using one vial per patient, chromatography

may be omitted in clinical routine practice and lipophilicity may be estimated as 90% of the injected dose, if administered

within 10 min after preparation. Finally, sensitivity of the quantification method was tested in eight volunteers using

acetazolamide brain activation and showed a mean increase in cerebellar rBU of 30.2%, varying between 14.1% and

75.9%.

Group rBU at rest heart rate rBU BS corrected rBU BS+BV corrected

Global (n=33)

48.4±9.7

52.1±7.75

52.0±7.27

Men (n=18) 43.1±7.56 49.9±8.4 51.6±8.68

Women (n=15)

54.8±8.12 54.7±6.18 52.5±5.45

Summary of rBU (mean±stan- dard deviation) in men and women separ- ately and in the whole group, rBU at rest heart

rate, rBU after correction of body surface

and rBU after cumulative correc- tions for body surface and brain volume

rBU (mean±standard deviation) in 10-6 of the injected lipophilic dose per cm3 brain tissue; n,

number of volunteers; BS, body surface (index per 1.73 m2); BV, mean brain volume of 1350 ml

88

Validation of the cerebellum as a reference region for SPECT quantification in patients suffering from dementia of the Alzheimer type.

B.A. PICKUT, R.A. DIERCKX, A. DOBBELEIR, K. AUDENAERT, K. VAN LAERE, A. VERVAET, P.P. DE DEYN. Neurology and Nuclear Medicine, Middelheim Hospital and Born-Bunge Foundation Antwerp, Belgium. Nuclear Medicine and Psychiatry, University Hospital Gent, Belgium. Psychiatry Research: Neuroimaging Section 1999; 90: 103-112. Abstract

In longitudinal brain studies of dementia of the Alzheimer type (DAT), the cerebellum is often used as a reference region

for single photon emission computed tomography (SPECT) quantification, which assumes no significant regional

influence of physiological fluctuations or pathology. With the use of absolute quantification in DAT patients, reproducibility

of cerebellar uptake of technetium-99m-d,l- hexamethylpropyleneamine oxime (HMPAO) was tested and compared with

the mean absolute cerebellar tracer uptake in DAT patients and healthy control subjects. In 13 DAT patients SPECT

studies were repeated within 2 weeks to assess reproducibility of cerebellar regional brain uptake (rBU). With calibrated

point sources as scaling factors, cerebellar activity was expressed as rBU of HMPAO per cm3 brain tissue in percent of

the injected lipophilic dose of 740 MBq (20 mCi). Also, mean cerebellar rBU in patients suffering from DAT was

calculated and compared with a previously established database obtained in healthy volunteers. Repeated SPECT

studies within a 2-week interval in clinically stable patients resulted in a mean rBU increase of 6.8±10.3% in the second

study as compared with the first. A similar shift was previously reported in healthy volunteers. Mean cortical cerebellar

rBU values in DAT patients and in the healthy reference population concurred, after cumulative corrections for body

surface and for a mean brain volume of 1350 ml (obtained in healthy control subjects), showing respective mean values

of 53.9±7.4 and of 52.0±7.3 x 10 –6 of the injected lipophilic dose 740 MBq (20 mCi) of HMPAO per cm

3 brain tissue . A

unidirectional shift in mean absolute cerebellar uptake values occurs between repeat examinations in DAT patients

similar to previous findings in a group of healthy volunteers. The origin of this phenomenon remains elusive but deserves

further study with regard to SPECT (semi)quantification in DAT patients. Most interestingly, the presented findings

suggest that the use of HMPAO SPECT in DAT patients the cerebellum remains scintigraphically uninvolved.

Demographic data, MMSE scores, and individual cerebellar regional brain uptake in 13 patients with dementia of the Alzheimer type (DAT), respectively, at resting heart rate and after cumulative corrections for body surface and for a mean brain volume of

1350 ml (determined in healthy volunteers)

Patient number

Gender/age MMSE score

rBU1 rBU2 BS index

rBU2- corr1

BV (in cm3)

rBU2- corr2

1 F/68 11 83.8 85.4 0.75 63.9 1150 54.4

2 F/76 12 62.5 73.9 0.89 65.8 1220 59.5

3 F/83 16 70.1 72.9 0.84 61.2 1060 48.1 4 F/67 22 98.3 124.7 0.72 90.4 920 61.6

5 F/72 16 72.6 72.8 1.00 72.8 1037 55.9

6 F/74 19 72.6 82.9 0.89 73.8 1125 61.5 7 F/73 7 81.8 78.7 0.92 72.4 1194 64.0

8 F/78 5 58.9 71.1 0.77 54.7 1053 42.7

9 F/84 13 60.4 61.3 0.90 55.2 1060 43.3 10 F/83 15 62.2 64.4 0.87 56.0 1105 45.8

11 M/78 25 46.1 43.0 1.18 50.7 1274 47.8

12 M/78 19 78.2 75.7 0.95 71.9 1092 58.1 13 M/82 17 57.7 70.8 1.02 72.2 1086 58.1

Notes. rBU, regional (cerebellar) brain uptake, 10-6 of the injected lipophilic dose 740 MBq (20 mCi) of Tc-99m HMPAO per

cm3 brain tissue; rBU1, rBU for first examination; rBU2, rBU for repeat study; BS, body surface, index per 1.73 m2; BV, brain volume in cm3; rBU2 corr1, regional brain uptake for repeat study corrected for BS; rBU2 corr2, regional brain uptake for repeat

study corrected for BS and BV of 1350 ml.

89

5. Dopamine transporter imaging in the human brain.

Quantification of Iodine-123-FPCIT SPECT with a resolution independent technique.

Andre A. Dobbeleir

1,3, Anne-Sophie E. Hambye

2, Ann M. Vervaet

1 and Hamphrey R. Ham

3.

1Nuclear Medicine, Middelheim Hospital, Antwerp, Belgium

2Nuclear Medicine, CHU-Tivoli, La Louvière, Belgium

3Nuclear Medicine, University Hospital Ghent, Ghent, Belgium

Submitted.

Abstract Accurate quantification of small-sized objects by SPECT is hampered by the partial volume effect.

The present work evaluates the magnitude of this phenomenon with iodine-123 in phantom studies,

and presents a resolution-independent method to quantify striatal 123

I-FP-CIT uptake in patients.

Methods: First, five syringes with internal diameters varying between 9 and 29mm and an

anthropomorphic striatal phantom were filled with known concentrations of iodine-123 and imaged

by SPECT using different collimators and radii of rotation. Data were processed with and without

scatter correction. From the measured activities, calibration factors were calculated for each specific

collimator.

Second, a resolution-independent method for FP-CIT quantification using large regions of interest

was developed and validated in 34 human studies (controls and patients) acquired in 2 different

hospitals, by comparing its results to those obtained by a semi-quantitative striatal-to-occipital

analysis. Taking the injected activity and decay into account, the measured counts/volume could be

converted into absolute tracer concentrations.

Results: For the fan-beam, high resolution and medium energy collimators, the measured

maximum activity in comparison to the 29 mm-diameter syringe was respectively 38%, 16% and

9% for the 9 mm-diameter syringe and 82%, 80% and 30% for the 16 mm syringe, and not

significantly modified after scatter correction. For the anthropomorphic phantom, the error in

measurement in % of the true concentration ranged between 0.3-9.5% and was collimator

dependent. Medium energy collimators yielded the most homogeneous results.

In the human studies, inter-observer variability was 11.4% for the striatal-to-occipital ratio and

3.1% for the resolution-independent method, with correlation coefficients >0.8 between both. The

resolution-independent method was 89%-sensitive and 100%-specific to separate the patients

without and with abnormal FP-CIT uptake (accuracy: 94%). Also the quantification in % of the

injected activity was well correlated with both the striatal-to-occipital and the resolution-

independent ratios.

Conclusion: Partial volume effect severely affects the quantification of FP-CIT uptake and results

in a rather large inter-observer variability. Measurement of striatal and non-specific activity in large

regions of interest circumvents this problem and provides stable and reproducible resolution-

independent results, allowing a direct comparison between data acquired with different imaging

systems or even in different hospitals.

Keywords: dopamine transporters, Parkinson’s disease, 123

I-FP-CIT, partial volume effect, SPECT,

quantification, anthropomorphic striatal phantom.

90

Introduction

Parkinson’s disease is a degenerative process of the dopaminergic neurons in the caudate and

putamen nuclei of the substantia nigra, resulting in progressive cellular loss (1-3).

The cocaine-like radioligand, iodine-123-FP-CIT ([123

I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane) developed by Neumeyer et al binds with high affinity to the striatal

dopamine transporters (DAT) in humans (4), and several studies have demonstrated the value of

FP-CIT brain SPECT imaging in the work up of patients with movement disorders (5-16).

Though the primary evaluation of a FP-CIT scan relies on the visual analysis, many authors

recommend a quantitative approach besides the visual to increase the objectivity of interpretation,

especially in doubtful cases (17-19).

Usually, this quantification consists in measuring the ratio of striatal (specific) to occipital (non

specific) FP-CIT uptake using manually drawn and/or positioned regions of interest (ROIs).

Due to the rather small size of these regions however, quite large variations in the measured ratios

have been reported, questioning the robustness and reliability of the technique. Even in normal

subjects, Seibyl et al found values for the putamen and caudate ratios between 1.9 and 6.3 (17).

Using SPECT, the low spatial resolution of the gamma camera and its consequent partial volume

effect hampers an accurate measurement of the count density in small-sized objects.

In FP-CIT studies, the small size of the human striatum has the effect that quantification is

influenced by the ROIs size and positioning, and therefore observer-dependent (17-19). In a recent

publication, Fleming and al have demonstrated that the influence of partial volume effect, and the

resulting variability in quantifying the radioactive content of small objects, can however be largely

reduced by using comfortable ROIs to measure the total uptake in an object rather than its activity

concentration (20).

FP-CIT imaging is gaining increasing importance in the differential diagnosis of patients with

movement disorders, and the availability of a reliable, reproducible and simple index to quantify

FP-CIT uptake should probably be of value to set up multi-centric studies.

Therefore, we designed the present work first to evaluate the magnitude of the partial volume effect

and its potential negative consequences in iodine-123 SPECT imaging. For this purpose, phantoms

of various sizes were filled with known concentration of radioactivity and imaged by SPECT with

different collimators and radii of rotation to quantify the influence of the system resolution on the

results. Processing was done without or with scatter subtraction to analyze the possible effects of

scatter.

Second, we developed a resolution-independent method for striatal FP-CIT quantification, based

upon the use of large ROIs to circumvent the partial volume effect. This method was validated in a

retrospective study using human data acquired in two different hospitals, by comparing its results to

those obtained by a semi-quantitative striatal-to-occipital analysis.

Materials and methods

Phantom studies

Syringes:

Five syringes of 2, 5, 10, 20 and 50 ml (internal diameter: 9, 13, 16, 20 and 29 mm respectively)

were filled with the same concentration of iodine-123 (1.30 MBq/ml - 35 µCi/ml). In total, 45

SPECT acquisitions were performed in air at a radius of rotation of 13.5, 15.0 and 16.5 cm with a

Triad triple-head gamma camera (Trionix, Ohio, USA) equipped with either fan-beam, high

resolution or medium energy collimators. Hundred and twenty images (3x40) of 4 seconds with a

pixel size of 3.56 mm were acquired using the triple energy window method described by Ichihara,

with the photopeak set at 143-175 kev (159 ± 10%) and the scatterpeaks at 125-141 keV and 180-

196 keV (21). The triple energy window method attempts to correct for both scatter and septal

penetration generated by the high energy photons of iodine-123 (22).

91

Each photopeak and scatter corrected acquisition was prefiltered with a Butterworth filter (order 6,

cut-off 1.0 cyc/cm) and 3.56 mm-thick transaxial slices were reconstructed. A linear profile of the

activity through the transaxial slices was measured to determine the maximum. All the maximum

activities were extrapolated to the initial time of filling to correct for radioactive decay.

With its 29 mm internal diameter, the 50 ml syringe is more than twice the SPECT resolution.

Therefore, it was considered as unaffected by the partial volume effect and used as a reference to

assess the magnitude of partial volume effect in the smaller syringes.

Additionally, from the known activity in each syringe and the total counts measured in the

transaxial slices, the gamma camera sensitivity factor for each collimator could be calculated with

and without scatter correction, allowing to transform the measured counts into MBq.

Anthropomorphic phantom:

An anthropomorphic striatal phantom was used to investigate the magnitude of the partial volume

effect and the reliability of the measured striatal activity. The investigations were performed in

cascades.

First, only the left and right striatum (both 11 ml) were filled with 555 and 407 kBq (15 and 11 µCi)

iodine-123. SPECT acquisition was performed using the same triple energy window, with the 3

previously described collimators but with 40 sec/image at a radius of 15 cm. Second, the remaining

brain structures were filled with 7.40 MBq (200 µCi) iodine-123 in 1300 ml and the phantom was

rescanned. The true contrast ratio between striatum and brain was measured afterwards in a well-

counter. Finally, the filled brain was incorporated in the skull and a 50 cm long catheter filled with

740 kBq (20 µCi) 99m

Tc was fixed around the skull at the canthomeatal level before repeating the

acquisition.

For the processing, each photopeak and scatter corrected acquisition was prefiltered using a

Butterworth filter (order 6, cut-off 1.0 cyc/cm) and 3.56 mm-thick transaxial slices were

reconstructed. Linear attenuation correction was performed on the second and the third sets of data

within an ellipse drawn around the brain or on the catheter fixed on the skull. Attenuation

coefficients of respectively 0.11 cm-1 for the brain, 0.12 cm

-1 for the brain + skull, and 0.15 cm

-1

after scatter correction were applied.

Human studies

Acquisition:

Thirty-four FP-CIT studies acquired in two different hospitals were retrospectively analyzed,

including 6 healthy volunteers (medical staff) and 28 patients referred to the nuclear medicine

department because of clinically unclear differential diagnosis between essential tremor and

Parkinson’s disease. By visual analysis of the FP-CIT study, 10 patients were considered as normal

and 18 patients as having significant abnormalities of the dopaminergic system. To validate the

resolution-independent quantification, the 10 patients with a visually normal FP-CIT scan and the 6

healthy volunteers were considered as the control group (mean age 62.9 y; range 39-90) while the

18 with a pathological test constituted the patients group (mean age 64.7 y; range 31-81).

Each subject received an intravenous injection of 148-222 MBq (4-6 mCi) [I123

]FP-CIT (Amersham

Cygne, Eindhoven, The Netherlands). Prior to the injection, potassium iodide or natrium

perchlorate was orally administered to block the thyroid uptake of free iodine. SPECT acquisition

was performed on a the Triad triple-head gamma camera equipped with fan-beam collimators or on

a MultiSPECT3 triple-head gamma camera (Siemens, Illinois, USA) equipped with low energy

high resolution collimators. Fourty views/head of 45 second each were acquired with a 20%

symmetric energy window centred around 159 keV (total scan duration: 30 minutes). Before

imaging, four skin markers containing 148 kBq (4 µCi) iodine-123 were taped at the level of the

canthomeatal line, two on each side of the subject’s head. They were used for posthoc reorientation

of transaxial images, and delineation of the ellipse around the brain for attenuation correction. In

92

some patients, these markers were replaced by a 50 cm long catheter filled with 740 kBq (20 µCi) 99m

Tc.

Raw data (pixel size: 3.56 mm) were transferred to a SunBlade 1500 Link Medical computer

system (Link Medical, Hampshire, UK) and reconstructed with a Butterworth prefilter (order 6, cut-

off 1.0 cyc/cm) and a ramp reconstruction filter. After reorientation parallel to the canthomeatal

plane, transaxial slices were corrected for attenuation using Chang’s algorithm on an ellipse fitted

on the catheter or through the skin markers. A linear attenuation factor of 0.12 cm-1 was used (17).

No scatter correction was applied.

Data analysis:

First, the 3 axial slices with the highest striatal activity were manually selected and summed

(classical semi-quantification). ROIs were manually drawn around the nucleus caudate, the

putamen, and on the occipital cortex as the non-specific binding area, and a semi-quantitative

striatal-to-occipital ratio (V”3) was calculated as:

V”3 = (caudate or putamen activity - occipital activity) / occipital activity.

Second, larger ROIs were drawn to obtain a resolution-independent semi-quantification. For this

purpose, 13 slices enclosing the whole striatum were summed (total thickness 4.6 cm), on which

two large ROIs were drawn: a 200 cm3 “striatal” ROI over the striatum (normal volume 20 cm

3),

and an elliptical ROI enclosing almost the whole brain (brain ROI).

The following parameters were then calculated.

(1) A resolution-independent striatal uptake, similar to the specific uptake size index recently

presented by Fleming (20): by subtracting the striatal ROI activity from the brain ROI, an operator-

insensitive non specific brain activity was obtained. After normalisation for the ROI size, the non

specific brain activity was subtracted from the striatal ROI activity to obtain the total striatal

activity. The resolution independent striatal uptake ratio was obtained by dividing the total striatal

activity by the mean brain activity/cm3.

Bg = Brain _ striatum

ROIind = Striatumcts – ( Bg

cts x Striatum

cm3/Bg

cm3 )

Bgcts / Bg

cm3

(2) The total striatal uptake, expressed as a percentage of the injected activity: using the gamma

camera sensitivity factor (specific for the collimator considered and total scan time), the total

striatal activity was transformed to real activity expressed in MBq. The striatal uptake in % of the

injected activity was then calculated, left and right striatum uptake obtained from the total striatal

uptake, and left and right activity measured in large mirrored ROIs on the background corrected

striatal image.

For display purposes, a density image of the striatum was generated from the total uptake values

expressed in % of the injected activity per cm3 striatal tissue. A colour-coded scale was used, each

colour corresponding to a specific range of percentage of the injected activity.

Reproducibility study:

To calculate the reproducibility of striatal uptake measurement for both the striatal-to-occipital ratio

and the resolution-independent method, the 34 data sets were processed by 2 observers

independently, starting from the raw acquisition. The inter-observer variability was expressed as the

mean ± S.D. of the absolute differences in % between the two observers.

93

Results

Phantom studies

The magnitude of the partial volume effect is reported in Table 1 for the different types of

collimators. Expressed as a fraction of the maximum activity of the 50ml-syringe, the measured

activity varied from 9%-40% for the 2 ml-syringe up to 50-100% for the 20ml-syringe and was

clearly collimator dependent, the best results being measured with the fan-beam collimators and the

worse with the medium energy. Scatter subtraction did not significantly improve the accuracy of the

measurements, as can be expected when imaging a small source with little scatter material. On the

other hand, increasing the scan radius of rotation from 13.5 to 16.5 cm resulted in an additional

mean maximum activity loss of respectively 6.0%, 4.9% and 3.9% with the medium energy, high

resolution and fan-beam collimators.

Table 1. Influence of the partial volume effect for the different collimators, without and with scatter

subtraction. The maximum activity of the linear profile through the transaxial slices of the 2, 5, 10 and 20 ml

syringes is expressed in % of the maximum activity of the 50 ml-syringe used as the reference.

Fan-beam High resolution

Medium energy

Syringe

volume

Internal

diameter Max

counts

Max cnts

- scatter

Max

counts

Max cnts

- scatter

Max

counts

Max cnts

- scatter

2 ml 9 mm 38 40 16 17 9 9

5 ml 13 mm 63 67 33 36 17 17

10 ml 16mm 82 88 80 84 30 31

20 ml 20 mm 98 100 81 84 50 51

50 ml 29 mm 100 100 100 100 100 100

From the ratio between the measured total counts in the syringe and the true activity for a scan

duration of 30 minutes, gamma camera sensitivity factors could be calculated without and with

scatter correction for the each type of collimator. The values of the different sensitivity factors are

given in Table 2.

Table 2: Gamma-camera sensitivity factors (in counts/µCi.scan) for the different collimators, without and

with scatter correction (scan duration: 30 minutes).

Fan-beam High resolution Medium energy

Non

corrected

Scatter

corrected

Non

corrected

Scatter

corrected

Non

corrected

Scatter

corrected

Sensitivity

6770

6176

7511

6760

9127

8411

94

Using the anthropomorphic phantom, the most homogeneous results were obtained with the

medium energy collimators, all ratios between measured and true striatal activity remaining within a

3 % error regardless of whether the striatum was imaged alone, with brain activity or with skull

attenuation (Table 3). With the other sets of collimators, the error amounted to 3.6% at the very

most when scanning the striatum alone, but increased up to a maximum of 9.5 % after addition of

activity in the other brain structures (Table 3).

Table 3: Ratio (in %) between the measured and the true activity in the anthropomorphic striatal phantom for

the different collimators, without and with scatter correction.

Fan-beam High resolution Medium energy

Non

corrected

Scatter

corrected

Non

corrected

Scatter

corrected

Non

corrected

Scatter

corrected

Striatum alone 103.6 102.8 102.9 100.3 98.2 97.9

Striatum + brain 107.4 96.0 109.5 100.5 97.2 98.1

Striatum + brain

+ skull

103.9 101.5 99.1 106.8 98.5 102.5

In a well counter, the true contrast ratio between left striatum and brain was 7.7. Measured on the

images, its value was 3.5 for the fan-beam and 3.0 for the high resolution collimator in the centre of

the left striatum, and dropped to 2.5 and 2.0 respectively within a 1 cm diameter ROI drawn on the

central slice. A partial volume factor of a magnitude of 3 seems therefore a good approximation for

the count loss.

Human studies

Using the striatal-to-occipital ratio, mean±SD absolute inter-observer variability was 11.4±16.9 %

(3.6±3.1 % in the control group and 21.4±22.4 % in the patients group due to the much lower

uptake), versus only 3.1±1.8 % with the resolution-independent striatal-to-brain method.

The results of the three different methods for striatal uptake measurement are presented in Table 4.

Globally, as well the striatal-to-occipital ratio as both resolution-independent methods (striatal-to-

brain activity/cm3 and in % of the injected activity) allowed a good separation between controls and

patients. Two of the 18 patients (11%) had values within the normal range with the striatal-to-brain

methods (Figure 1), resulting in a sensitivity of 89%, a specificity of 100% and an accuracy of 94%.

With the method expressing the uptake as a percentage of the injected activity, only one patient was

not correctly classified but 3 controls had values at the lower range (sensitivity: 94%, specificity:

81%, accuracy: 88%) (Figure 2). The best separation between controls and patients was obtained

after normalisation for the body weight (sensitivity: 94%, specificity: 100%, accuracy: 97%)

(Figure 2).

95

Figure 1. Striatal activity divided by the mean brain activity/cm3 in the summed 13 slices using the resolution

independent method. The total striatal activity is shown on the left graph, and the individual left and right

activity at the right. For each graph, the normal subjects are at the left and the Parkinson patients at the right.

total striatum/mean brain activity

0,0

50,0

100,0

150,0

200,0

250,0

normal subjects patients

striatum / mean brain activity

0,0

20,0

40,0

60,0

80,0

100,0

120,0

left striatum

right striatum

patientsnormal subjects

Figure 2. Plots of the total, left and right striatal uptake expressed in % of injected dose, without (top graphs)

and with normalization (bottom graphs) for the patient’s weight.

For each graph, the normal subjects are at the left and the Parkinson patients at the right.

total uptake-raw data

0,000

0,200

0,400

0,600

0,800

1,000

1,200

normal subjects patients

left - right uptake raw data

0,000

0,100

0,200

0,300

0,400

0,500

0,600

left uptake

right uptake

normal subjects patients

total uptake weight normalised

0,000

0,200

0,400

0,600

0,800

1,000

1,200

normal subjects patients

left - right weight normalised

0,000

0,100

0,200

0,300

0,400

0,500

0,600

left uptake

right uptake

normal subjects patients

By regression analysis, the three methods were nicely correlated with each other (Figure 3). For the

right and the left striatum respectively, the correlation coefficients were 0.86 and 0.82 between the

striatal-to-occipital ratio and the striatal-to-brain method, 0.77 and 0.71 between the striatal-to-

occipital ratio and the striatal uptake expressed in % of the injected activity, and 0.94 and 0.90

between the two resolution-independent methods.

A display of the results measured by the three methods in a healthy volunteer is shown in Figure 4.

96

Table 4. Striatal activity measured in normal subjects and Parkinson patients with the different methods. The

mean specific striatal to non specific uptake is given in the first two columns, the resolution independent

method (left and right striatal activity divided by the mean brain activity/cm3) in the two median columns and

the uptake in % of injected dose, normalised for the patient weight, in the last two columns.

Name V”3 left V”3 right ROI ind left ROI ind right uptake left uptake right

Subject 1 2,56 2,48 95,8 89,3 0,464 0,433

Subject 2 2,31 2,15 75,2 80,8 0,358 0,385

Subject 3 1,84 1,80 77,6 64,5 0,385 0,320

Subject 4 2,88 2,90 94,3 91,2 0,379 0,366

Subject 5 2,04 2,20 85,1 78,3 0,373 0,343

Subject 6 2,03 1,85 90,4 78,1 0,498 0,432

Subject 7 2,24 1,93 74,2 80,3 0,332 0,359

Subject 8 2,33 2,24 74,0 76,2 0,292 0,301

Subject 9 2,43 2,40 108,2 99,9 0,526 0,486

Subject 10 2,58 2,55 78,4 73,4 0,309 0,289

Subject 11 2,13 2,18 81,6 80,4 0,370 0,365

Subject 12 1,68 1,52 86,0 71,8 0,442 0,369

Subject 13 2,31 2,28 75,4 70,1 0,358 0,333

Subject 14 2,06 1,93 79,4 75,8 0,359 0,343

Subject 15 1,96 2,13 70,1 74,2 0,316 0,334

Subject 16 2,80 3,04 76,8 98,8 0,281 0,361

mean 2.26 2.22 82.7 80.2 0.378 0.364

S.D. 0.33 0.39 10.1 9.9 0.071 0.051

range 1.68–2.88 1.52–3.04 70.1–108.2 64.5–99.9 0.281–0.526 0.289–0.486

Patient 1 0,88 1,08 47,8 61,2 0,133 0,170

Patient 2 0,69 0,61 40,9 45,4 0,143 0,159

Patient 3 0,31 1,12 11,2 60,5 0,053 0,290

Patient 4 0,44 0,74 35,4 47,3 0,172 0,230

Patient 5 0,38 0,39 37,8 39,2 0,160 0,166

Patient 6 1,27 1,31 52,9 58,9 0,227 0,252

Patient 7 1,87 1,76 64,7 54,0 0,297 0,248

Patient 8 0,27 0,37 38,5 42,1 0,147 0,161

Patient 9 0,77 0,96 54,2 65,0 0,235 0,282

Patient 10 0,83 0,88 57,5 46,7 0,253 0,205

Patient 11 0,60 0,71 44,0 50,7 0,156 0,180

Patient 12 1,94 2,08 82,3 82,7 0,271 0,273

Patient 13 0,68 0,67 64,8 60,5 0,299 0,279

Patient 14 0,85 1,03 50,6 55,0 0,234 0,254

Patient 15 0,76 1,07 32,2 56,7 0,150 0,264

Patient 16 1,64 1,86 83,0 88,1 0,394 0,419

Patient 17 0,63 0,77 37,7 50,2 0,202 0,269

Patient 18 0,87 1,38 72,2 16,6 0,300 0,069

mean 0.87 1.04 50.4 54.5 0.213 0.232

S.D. 0.50 0.48 18.4 15.8 0.082 0.075

range 0.27–1.94 0.37–2.08 11.2–83.0 16.6–88.1 0.053–0.394 0.069–0.419

97

Figure 3. Regression between the traditional method with manually drawn ROIs and the resolution

independent method at the top. Regression between the traditional method and the striatal uptake in % of

injected dose at the bottom (X-axis = V”3 traditional method)

V'3 - ROI independent left striatum

R = 0.86

0,0

20,0

40,0

60,0

80,0

100,0

120,0

0 1 2 3 4

V'3 - ROI independent right striatum

R = 0.82

0,0

20,0

40,0

60,0

80,0

100,0

120,0

0 1 2 3 4

V'3 - % uptake I.D. left striatum

R = 0.77

0,000

0,100

0,200

0,300

0,400

0,500

0,600

0 1 2 3 4

V'3 - % uptake I.D. right striatum

R = 0.71

0,000

0,100

0,200

0,300

0,400

0,500

0,600

0 1 2 3 4

Discussion

In quantitative SPECT studies of small objects, accurate measurement of the radioactive content is

significantly influenced by the partial volume effect, and the degree of reduction of the measured

compared to true activity is highly dependent upon the resolution of the gamma camera-collimator

system.

When imaging syringes of various diameters by SPECT with different types of collimators, we

found that the underestimation of the measured activity for iodine-123 was lowest with the fan-

beam collimators, and that scatter correction did not significantly modify the influence of partial

volume effect. For this part of the work, we used a 50ml syringe as a reference, assuming that with

its internal diameter of more than twice the SPECT resolution, it should not be significantly

affected by partial volume effect. For lower resolution collimators however, this assumption could

be partially incorrect so that our results might not be completely reproduced using another system.

When imaging the human striatum with 123

I-FP-CIT, its small size (about 1 cm) makes an accurate

quantification of the true activity by SPECT particularly sensitive to partial volume effect and

dependent upon the system and collimator resolution. The highest resolution collimator is therefore

the most appropriate choice. However, even with fan-beam collimators, we estimated the magnitude

of underestimation of activity for the striatum to be about 3 in an anthropomorphic brain phantom.

The influence of partial volume effect probably at least partly explains the fluctuations in count

density observed at different anatomical levels of the striatum in the same individual, as the real

diameter of a human striatum decreases from 12 mm at the head of the caudate nucleus to 6 mm at

the tail of the putamen, and also the differences in normal striatal-to-occipital values between

98

SPECT and PET (1.9 to 3.8 for 123

I-FP-CIT (17-19) versus >7.8 for the PET dopamine transporter

ligand 18F-FECNT (23)).

Since the importance of partial volume effect depends on the system resolution, multi-centric

studies with FP-CIT using quantitative or even semi-quantitative indices are difficult to carry out,

and reference normal values from one centre cannot be used in another without caution.

To circumvent the influence of partial volume on the measurement of activity in small organs,

Fleming et al have recently shown that the determination of the total uptake in the whole organ with

large regions of interest instead of small ROIs drawn around the target alone constitutes an

interesting approach (20).

The method presented in this paper uses two very large regions of interest. Knowing that the

volume of the human striatum is about 20 cm3 and the real concentration of dopaminergic

radioligands 8 to 9 times higher in the striatum than in the remaining brain tissue, the total striatal to

the mean brain activity/cm3 values between 150 and 200 obtained in our normal subjects seem

consistent.

This method offers several advantages compared to the classical striatal-to-occipital ratio usually

found in the literature. Being significantly larger than the SPECT resolution, the ROIs are not

subjected to partial volume effect so that the striatal-to-brain ratio is gamma-camera, acquisition

and reconstruction independent, allowing a direct comparison between results from different

centres, without the need for any special soft- or hardware adjustment.

Thanks to their large size, the placement of the ROIs becomes less critical, resulting in an important

reduction of the inter-observer variability compared to the traditional striatal-to-occipital method

while keeping its performance in separating normal subjects from Parkinson’s patients.

Using adequate calibration factors, the total count rate can be expressed in MBq, hence in

percentage of the injected activity. In our study, the striatal uptake expressed in percentage of the

injected activity was well correlated with both the classical striatal-to-occipital ratio and the

resolution-independent striatal-to-brain method, but slightly less accurate in differentiating normal

subjects from Parkinson’s patients. Normalisation for the body weight allowed a better separation

between both groups.

However, besides calibration errors, physiological differences between patients might interfere in

the calculation of the absolute uptake, and this absolute quantification is more complex than the

intermediate results of the resolution-independent method presented here, which could be easily

implemented in most centres.

In the anthromorphic striatal phantom, we were able to measure the activity with an error of less

than 10 % compared to the true value, and even smaller after scatter correction.

In the patients studies however, data were not corrected for scatter or septal penetration. Applying

these corrections might change the ratio between the striatum and brain background. This needs

further investigation.

Conclusion

In small objects, partial volume results in a dramatic underestimation of the true radioactive content,

making an accurate quantification of the activity concentration a little hazardous. In a quantitative

anthropomorphic phantom study, the magnitude of partial volume effect was of the order of 3 for

FP-CIT striatal uptake, and was collimator and processing-dependent. The classically used striatal-

to-occipital ratio can therefore hardly be applied for multi-centric studies or even to define widely

usable normalcy rates.

Our resolution-independent method uses very large regions of interest and is thus not influenced by

the partial volume effect. Well correlated with the classical ratio but providing a better inter-

observer variability, and easy to implement in a nuclear medicine department, it offers a

reproducible, reliable and simple way to separate the patients with a normal or pathological FP-CIT

scan, and should be helpful to compare quantitatively the results between different imaging systems

and even different centres.

99

Figure 4. Normal subject: At the top left a density image of the striatum is expressed in % of the

injected dose per ml with an appropriate colour scale. At the bottom the traditional (striatum –

occipital) / occipital image is represented. Values for striatal activity divided by the mean brain

activity/cm3, % of the injected dose and traditional ratio’s are shown.

Acknowledgments

The authors would like to express their gratitude to Amersham-Health Belgium (part of GE

Healthcare) for providing the anthropomorphic striatal phantom, and to Philippe Delsarte and Rudi

Vandermeiren for the technical assistance.

The authors have indicated they have no conflict of interest.

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2. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine

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4. Neumeyer JL, Wang S, Gao Y, Milius RA, Kula NS, Campbell A, Baldessarini RJ, Zea-

Ponce Y, Baldwin RM, Innis RB. N-ω-fluoroalkyl analogs of (IR)-2β-carbomethoxy-3β-(4-

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5. Lorberboym M, Djaldetti R, Melamed E, et al. 123I-FP-CIT SPECT imaging of dopamine

transporters in patients with cerebrovascular disease and clinical diagnosis of vascular

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6. Schwartz M, Groshar D, Inzelberg R, Hocherman S. Dopamine-transporter imaging and

visuo-motor testing in essential tremor, practical possibilities for detection of early stage

Parkinson's disease. Parkinsonism Relat Disord. 2004;10:385-9.

7. Ceravolo R, Volterrani D, Gambaccini G, et al. Presynaptic nigro-striatal function in a group

of Alzheimer's disease patients with parkinsonism: evidence from a dopamine transporter

imaging study. J Neural Transm. 2004;111:1065-73.

8. Catafau AM, Tolosa E. Impact of dopamine transporter SPECT using 123I-Ioflupane on

diagnosis and management of patients with clinically uncertain Parkinsonian syndromes.

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9. Walker Z, Costa DC, Walker RW et al. Striatal dopamine transporter in dementia with Lewy

bodies and Parkinson disease: a comparison. Neurology. 2004;62:1568-72.

10. Winogrodzka A, Bergmans P, Booij J et al. [123I]FP-CIT SPECT is a useful method to

monitor the rate of dopaminergic degeneration in early-stage Parkinson's disease. J Neural

Transm. 2001;108:1011-9.

11. Booij J, Speelman JD, Horstink MW, Wolters EC. The clinical benefit of imaging striatal

dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic

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threshold of disease in Parkinson's disease. Synapse. 2001;39:101-8.

13. Benamer HT, Patterson J, Wyper DJ et all. Correlation of Parkinson's disease severity and

duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord. 2000;15:692-8.

14. Benamer TS, Patterson J, Grosset DG, et al. Accurate differentiation of parkinsonism and

essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-

CIT study group. Mov Disord. 2000;15:503-10.

15. Tissingh G, Booij J, Bergmans P, et al. Iodine-123-N-omega-fluoropropyl-2beta-

carbomethoxy-3beta-(4-iod ophenyl)tropane SPECT in healthy controls and early-stage,

drug-naive Parkinson's disease. J Nucl Med. 1998;39:1143-8.

16. Booij J, Tissingh G, Boer GJ, et al. [123I]FP-CIT SPECT shows a pronounced decline of

striatal dopamine transporter labelling in early and advanced Parkinson's disease. J Neurol

Neurosurg Psychiatry. 1997;62:133-40.

17. Seibyl JP, Marek K, Sheff K, et al. Iodine-123-β-CIT and iodine-123-FPCIT SPECT measurement op dopamine transporters in healthy subjects and Parkinson’s patients. J Nucl

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18. Booij J, Habraken J, Bergmans P et al. Imaging of dopamine transporters with iodine-123-

FPCIT SPECT in healthy controls and patients with Parkinson’s disease. J Nucl Med 1998;

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19. Habraken J, Booij J, Slomka P, et al. Quantification and visualization of defects of the

functional dopaminergic system using an automatic algorithm. J Nucl Med 1999; 40:1091-

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radiopharmaceutical uptake. Phys Med Biol 2004; 49:227-234.

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21. Ichihara T, Ogawa K, Motomura N, et al. Compton scatter compensation using the triple-

method for single and dual-isotope SPECT. J Nucl Med 1993; 34:2216-2221.

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iodine-123 with low- and medium-energy collimators: consequences for imaging with 123

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labelled compounds in clinical practice. Eur J Nucl Med 1999; 26:655-658.

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dopamine transporter ligand 18F-FECNT. J Nucl Med 2003; 44:855-861.

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6. Summary and future directions.

Part I deals with cardiac studies. In chapter 2, methods aimed at evaluating left ventricular ejection fraction are described.

In the first part, the performance capacities and limitations of a single crystal digital gamma camera are evaluated with respect to the high count rate required for an accurate measurement of ejection fraction by first pass radionuclide angiography. Using the ultrashort half-lived 191Irm, the high yield of the generator (120 mCi - 4400 MBq) provided more than 1 million real counts per second whereas the measured camera saturation was 420 kcps. Compared to a large field of view detector system, a small field of view (20 cm) has the advantage to have less activity in the field of view reducing the non-linearity problem. Using an 191Os reference source, we were able to correct for the non-linearity up to 320kcps. Applied to patient studies, a maximum count rate of 250 kcps was measured during the left ventricular phase, with a system resolution loss of 2-3 mm in fast mode. Repeated LVEF determination at 2 min-intervals in 50 patients was highly reproducible with a mean

difference of 2.08±1.55 EF units (r=0.97). Furthermore, the simultaneous use of 191Irm and of 201Tl permitted a combined evaluation of myocardial perfusion and function both at rest and during exercise.

In the second part, the performances of different software for left ventricular ejection fraction (LVEF) and volume measurements by gated myocardial tomography are studied, and the influence of modifying acquisition and reconstruction parameters are evaluated, especially in patients with small hearts. In patients with a normal-sized heart, the different commercially available software for quantitative gated SPET was well correlated. Changes in matrix size had little influence on LVEF and volumes whereas smoothing significantly modified the volume measurements. In small-sized hearts on the other hand, LVEF at the higher range were frequently observed. The results of quantitative gated SPET were software, matrix size and smoothing dependent. Probably more realistic, significantly lower LVEF and larger volumes were found by increasing the matrix size or sharpening the filter.

Chapter 3 deals with the quantification of perfusion and metabolism in the specific context of myocardial viability assessment.

The first part reports the development and clinical validation of a quantification whereby the activity of the myocardial perfusion tracer 99mTc -sestamibi and the free fatty acid metabolism tracer 123I-BMIPP was quantified on a pixel-to-pixel basis. Based upon the difference in uptake between sestamibi and BMIPP, the presence and extent of normal, viable and scar myocardium was expressed in % of the surface of the left ventricle as a whole and of the three main coronary arteries separately and visually displayed using colour-coded polar maps. This analysis was applied to patient studies. Inter-observer difference in the % viable myocardial surface was rather small, amounting to 1.5% at most. Moreover, a good concordance was found between the presence of decreased sestamibi and BMIPP uptake and a significant stenosis on coronary angiogram. In the second part the influence of high-energy emitting photons on the spectrum of iodine-123 was quantified for low- and medium-energy collimators in phantom studies.

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In the third part this scatter influence was shown in patient studies. The newly developed quantification with colour-coded polar maps was applied to calculate the extent of viable tissue, defined as a mismatched uptake with BMIPP uptake lower than sestamibi. Since the contribution of scatter in the iodine images is not negligible, its potential influence on the calculated amount of viable tissue was measured by quantifying sestamibi and BMIPP uptake without correction, after background subtraction, and with scatter correction. Echocardiographically assessed changes in segmental wall motion at six months after treatment was used as the gold standard. The evolution of contractile function was correctly predicted in 64% of the segments without correction, 79% after background subtraction and 93% after scatter correction. The fourth part contains the abstracts of the articles that we have published about the clinical applications of myocardial perfusion/metabolism imaging in patients with chronic ischemic heart disease post-infarction. From these clinical studies, it seems that 99mTc -sestamibi alone is a suboptimal tracer to identify myocardial viability in patients with chronic ischemic heart disease post-infarction, even when a quantitative analysis is applied. Adding a metabolic tracer such as 123I-BMIPP significantly improves the diagnostic accuracy, and the combination of sestamibi and BMIPP imaging is able to identify myocardial viability in chronic ischemic heart disease with an accuracy similar to that reported in the literature for 18F-FDG PET, or for the combined BMIPP/sestamibi study in the acute or subacute phase of a myocardial infarction. However, due to the influence of high energy photons in the iodine-123 imaging, scatter correction is recommended and special attention must be paid to the used collimator.

Part 2 deals with brain studies. In Chapter 4, an absolute quantification method of the brain perfusion is described. Methodologically, because of the clinical need for an absolute SPECT parameter, a simple approach was developed using calibrated point sources as scaling factor, to display tomographic images as regional 99mTc HMPAO brain uptake (rBU) per cm3 brain tissue in percent of the injected lipophilic dose. The method was validated on Jaszczak and Hoffman phantoms using a three detector SPECT system with parallel and fan-beam collimators. A mean reproducibility of 7.2 % was obtained in human studies. Application of the method in 33 healthy volunteers pointed to body surface as the most important factor explaining interindividual variability when compared to brain volume. The same study stressed the need in longitudinal studies for normalization of rBU to the rest heart rate and suggested the absence of significant influence of minor stress on regional 99mTc HMPAO brain uptake. The former evaluation of cerebellar rBU in a healthy population was extended to patients suffering from dementia of the Alzheimer type (DAT). rBU values in operator-defined cerebellar regions of interest may be considered highly symmetrical, reproducible and stable in time in healthy volunteers. Moreover, after cumulative corrections for body surface and brain volume a similar and reproducible, absolute cerebellar 99mTc HMPAO uptake value was found for the group of DAT patients and the group of healthy volunteers. The presented findings suggested that the cerebellum may be a good choice as reference region in SPECT analysis of DAT patients.

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In Chapter 5, dopamine transporters in the striatum are quantified. Parkinson’s disease is characterised by a severe degeneration of dopaminergic neurons in the substantia nigra, resulting in a loss of dopamine transporters in the caudate and putamen nuclei visualized with 123I-FP-CIT. Using SPECT, it is well know that semi-quantitative analysis of small organs like the striatum is hampered by the partial volume effect due to the low spatial resolution of the gamma camera. For source diameters < 12 mm, the count density was reduced by a factor 3 to 5. We devised a resolution independent method by calculating the total striatum activity divided by the mean brain activity per ml using two very large region of interests. Knowing that the volume of the human striatum is about 20 ml and the real concentration of dopaminergic system radioligands is 8 to 9 times higher in the striatum than in the remaining brain tissue, the total striatal to the mean brain activity/cm3 values between 150 and 200 obtained in our normal subjects seem consistent. Moreover using classical striatal and occipital ROIs, we obtained an inter-observer variability of 11.4 % compared to 3.1% using the resolution independent method. Additionally the total striatal uptake was expressed as percentage of injected dose using a gamma camera calibration factor. Globally, good separation was obtained between normal and Parkinsons using both, the conventional and our method. When corrected for the patient’s weight, striatal uptake expressed in percentage of the injected dose allowed a better separation between normal subjects and Parkinson’s patients compared to the conventional method. For more accurate anatomic localization of defects, we created two images for visual interpretation: a striatum/brain ratio image and an uptake image expressing the % of the injected dose per ml striatal tissue. The resolution independent method is gamma-camera, acquisition and reconstruction independent. Using this method, results from different centres can directly be compared without the need of any special soft- or hardware adjustment.

Future directions. The current trends in conventional nuclear instrumentation and data analysis can be divided in three main topics: image fusion, software development and new devices. The fusion of modalities becomes standard in clinical practice. Hybrid imaging systems SPECT equipment with X-ray tubes (CT) are on the market. Initial attempts to co-register functional and anatomical images acquired on two different machines failed to disclose the proper alignment and are too cumbersome on a routine basis (1). SPECT/CT improves the diagnostic accuracy of SPECT in various clinical situations (2) although misalignment artefacts between emission and transmission can still be present, especially in cardiac studies (3). A debate is still going on pro and contra attenuation correction for cardiac studies (4). However a CT based attenuation map improves semi-quantitative cardiac studies (5,6) and precise absolute quantification becomes realistic when including also scatter and collimator depth corrections in the iterative reconstruction methods (7,8). Attempts are also made to correct partial volume effect in small textures by anatomical information (9). Improvement of reconstruction algorithm’s remained a major topic on the IEEE meeting in Rome 2004. New software starts entering clinical practice. Three dimensional models of coronary artery tree created by biplane angiograms are aligned with 3D perfusion SPECT images (10). Motion-frozen gated images can be created using phase-to-phase motion vectors (11). Statistic parametric mapping (SPM), frequently used for brain research becomes a standard procedure (12).

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The major improvement in nuclear medicine is expected from new devices and material. The goal is to reduce the intrinsic spatial resolution and energy resolution (13,14). New detection materials with better physical characteristics than NaI concerning stopping power, energy resolution, light output, fragility and density will most likely replace NaI crystals (15). Position sensitive photo multiplier tubes (PSPMT) has become available which are coupled to pixellated NaI(Tl) crystals or new scintillation material like CsI(Tl) (16,17). It is expected that new imaging devices with several thousands of tiny crystals or semiconductor array detectors will improve the sensitivity and specificity of clinical studies (15,18). Increased detector sensitivity will permit dynamic tomographic studies and more precise quantitative data for compartimental analysis already performed for planar studies. Small surgical probes based on CZT semiconductors or PSPMT tubes become popular in surgery tracing regional metastases (19). It remains however questionable whether these small devices, now a day used for animal studies or as surgical probes, can be developed as large detectors for human studies at a reasonable price.

1. Keidar Z, Isreal O, Krausz Y. SPECT/CT in tumor imaging: technical aspects and clinical applications. Semin Nucl Med 2003; 33:205-18.

2. Schillaci O, Danieli R, Manni C, Simonetti G. Is SPECT/CT with a hybrid camera useful to improve scintigraphic imaging interpretation? Nucl Med Commun. 2004;25:705-10.

3. Fricke H, Fricke E, Weise R et al. A method to remove artifacts in attenuation-corrected myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-derived attenuation maps. J Nucl Med. 2004;45:1619-25.

4. Figaro E, Wackers F. Should SPET attenuation correction be more widely employed in routine clinical practice? Eur J Nucl Med 2002; 29: 409-415.

5. Grossman G, Garcia E, Bateman T et al. Quantitative Tc99m sestamibi attenuation-corrected SPECT development and multicenter trial validation of myocardial perfusion stress gender-independent normal database in an obese population. J Nucl Cardiol 2004; 11: 239-241.

6. Dondi M, Fagioli G, Salgarello M et al. Myocardial SPECT: what do we gain from attenuation correction (and when)? Q J Nucl Med Mol Imaging 2004; 48:181-7.

7. El Fakhri G, Buvat I, Benali H et al. Relative impact of scatter, collimator response, attenuation and finite spatial resolution corrections in cardiac SPECT. J Nucl Med 2000; 41: 1400-8.

8. Links J, Becker L, Rigo P et al. Combined corrections for attenuation, depth dependent blur and motion in cardiac SPECT: a multicenter trial. J Nucl Cardiol 2000; 7: 414-25.

9. Matsuda H, Ohnishi T, Asada T et al. Correction for partial volume effects on brain perfusion SPECT in healthy men. J Nucl Med 2003; 44: 1243-52.

10. Faber T, Santana C, Garcia E et al. Three dimensional fusion of coronary arteries with myocardial perfusion distributions: clinical validation. J Nucl Med 2004; 45: 745-53.

11. Slomka P, Nishina H, Berman D et al. “Motion-Frozen” display and quantification of myocardial perfusion. J Nucl Med 2004; 45: 1128-34.

12. Friston K, Ashburner J, Holmes A and Poline J-B. SPM: Statistical parametric mapping, software for functional neuroimaging. Welcome department of Cognitive Neurology, University College London.

13. Williams M, Goode A, Galbis-Reig V et al. Performance of a PSPMT based detector for scintimammography. Phys Med Biol 2000; 45: 781-800.

14. Loudos G, Nikita K, Uzunoglu N et al. Improving spatial resolution in SPECT with the combination of PSPMT based detector and iterative reconstruction algoritms. Comput Med Imaging Graph 2003; 27: 307-13.

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15. Fidler V. Current trends in nuclear instrumentation in diagnostic nuclear medicine. Radiol Oncol 2000; 34: 381-5.

16. Weisenberger A, Kross B, Majewski S et al. Dual low profile detector heads for a restraint free small animal SPECT imaging system. IEEE conference Rome 2004: p136.

17. Pani R, Pellegrini R, Cinti M et al. New devices for imaging in nuclear medicine. Cancer Biother Radiopharm. 2004;19:121-8.

18. Wieczorek H, Goedicke A, Shao L et al. Analytical model for pixellated SPECT detector concepts. IEEE conference Rome 2004: p142.

19. Blevis L, Reznik A. Intra-operative imaging probe using CZT. IEEE conference Rome 2004: p197.

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Samenvatting en toekomstperspectieven.

Deel 1 betreft hartstudies. In hoofdstuk 2 worden methoden ter bepaling van de linker ventriculaire ejectiefraktie beschreven.

In het eerste deel, wordt de prestatie en beperkingen van een kleinveld digitale gamma camera met betrekking tot hoge telcapaciteit voor accurate bepaling van de linker ventriculaire functie bij de eerste doorstroming voor radio-nucleaire angiocardiography beschreven. Het kort levend 191Irm (5sec) van een nieuwe hoge opbrengst 191Os/191Irm generator leverde meer dan 1 miljoen werkelijke slagen per seconde daar waar de gemeten verzadiging van de gamma camera 420kcps was. De kleine gezichtsveld (20 cm) gamma camera heeft het voordeel ten opzichte van een grootveld dat er minder activity gemeten wordt en dus ook het activiteits niet-lineaire probleem vermindert. Op een nauwkeurige manier verbeterden wij deze niet-lineaire respons van de gamma camera tot 320kcps door middel van een 191Os referentie bron. In patient studies was de maximum telsnelheid gedurende de linker ventriculaire faze 250 kcps. Het resolutieverlies van het systeem in snelle telmode was 2-3 mm. De reproduceerbaarheid van herhaalde LVEF bepalingen in 2 min-intervallen in 50 patienten

was r=0.97 and het gemiddelde verschil=2.08±1.55 EF eenheden. Verder, maakte het gebruik van 191Irm als merkstof voor linker ventriculaire angiography en 201Tl voor myocard perfusie en wandbeweging gelijktijdige bepalingen mogelijk, zowel in rust als gedurende inspanning. In het tweede deel wordt de prestatie van verschillende software programma’s bestudeerd en tevens de invloed van opnamemethode en reconstructieparameters op de ejectiefractie en hartvolumes, vooral bij patienten met een klein hart. In patienten met een hart van normaal volume, LVEF en volume, bepaald door middel van verschillende commerciële software voor kwantitatieve gated SPECT zijn vergelijkbaar. LVEF en volume zijn weinig gevoelig aan wijzigingen in de opnamematrix. Door smoothing (afvlakken) werd het volume aanmerkelijk gewijzigd maar niet de LVEF waarde. Bij kleine harten daarentegen, beïnvloeden zowel het gebruikte programma, de opname matrix als smoothing in belangrijke mate de resultaten van kwantitatieve gated SPECT. Hoge ejectiefraktie waarden worden dikwijls waargenomen. Een grotere matrix en scherpere reconstructie filter worden gesuggereerd om de accuraatheid van de commerciële software te verbeteren, voornamelijk bij patiënten met een klein hart. Hoofdstuk 3 handelt over de kwantificatie van perfusie en metabolisme in het specifieke kader van leefbaar hartweefsel. In het eerste deel beschreven we de ontwikkeling en klinische validering van een methode om de aktiveit van de perfusietracer 99mTc-sestamibi en de vetzuur metabolisme tracer 123I-BMIPP pixel per pixel te kwantificeren, aan de hand van kleur-gecodeerde polaire voorstellingen. Met als basis het opnameverschil tussen sestamibi en BMIPP, wordt de aanwezigheid en uitgebreidheid van normaal, leefbaar en littekenweefsel uitgedrukt in % van het linker ventrikel als geheel en voor de vaatgebieden van de 3 hoofdkransslagaders afzonderlijk berekend en in beeld gebracht. Deze analyse werd toegepast op patiëntengegevens. De inter-observer verschillen in het percentage mismatched oppervlak waren eerder klein, ten hoogste 1.5%. Bij vergelijking

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met de coronaire anatomie werd een goede overeenkomst vastgesteld tussen een verminderde traceropname en een significante vernauwing van de arterie.

In het tweede deel van dit hoofdstuk wordt de invloed van hoog energetische fotonen afkomstig van 123I op het gemeten spectrum gekwantificeerd met collimatoren voor lage energie en middelhoge energie in een fantoom studie.

In het derde deel wordt deze scatter invloed aangetoond bij patiënten. Voor deze studie maakten we gebruik van de nieuwe polaire kleur-gecodeerde voorstelling om de uitgebreidheid van leefbaar myocard te kwantificeren, gedefinieerd als mismatching met BMIPP opname lager dan sestamibi. Gezien de bijdrage van scatter in de jodium beelden en de mogelijke invloed op de berekende hoeveelheid leefbaar weefsel, werd de sestamibi en BMIPP opname berekend zonder correktie, met background en met scatter correktie. Echocardiografische veranderingen in wandbeweging 6 maanden na behandeling werd gebruikt als referentie. De accuraatheid om de evolutie van de regionale contractiliteit bij vervolgonderzoek te voorspellen, was als volgt: 64% indien geen correctie werd toegepast, 79% na correctie voor background en 93% na scattercorrectie.

Het vierde deel bevat de abstracten van de artikelen gepubliceerd betreffende klinische toepassingen van de gecombineerde studie van perfusie en metabolisme bij patiënten met chronische linker ventrikeldysfunctie na infarct. Uit deze studies blijkt dat de voorspellende waarde van scintigrafie met sestamibi alleen sub-optimaal is om leefbaar weefsel op te sporen, zelfs bij kwantitatieve analyse. Toevoeging van de resultaten van de 123I-BMIPP scintigrafie verbeterde de accuraatheid aanzienlijk en de combinatie van sestamibi en BMIPP beeldvorming gaf de mogelijkheid om leefbaar weefsel bij patiënten met chronische linker ventrikeldysfunctie op te sporen met dezelfde accuraatheid als met 18F-FDG vermeld in de literatuur. Tevens werden identieke resultaten bekomen als bij patiënten in de acute of subacute fase na een hartinfarct met dezelfde gecombineerde sestamibi/BMIPP methode. Wegens de invloed van hoog energetische fotonen in beelden van een jodium-123 gemerkt produkt zoals BMIPP is scatter correctie aanbevolen en dient aandacht besteed te worden aan de gebruikte collimator.

Deel 2 behandelt hersenstudies In hoofdstuk 4 wordt een absolute kwantifikatiemethode voor hersenperfusie beschreven. Methodologisch werd wegens de klinische vraag naar een absolute SPECT parameter, een eenvoudige benadering ontwikkeld, gebruikmakend van gekalibreerde puntbronnen als schalingsfactor, om tomografische beelden voor te stellen als regionale 99mTc HMPAO hersenopname per cm3 hersenweefsel in percent van de geïnjecteerde lipofiele dosis. De methode werd gevalideerd op Jaszczak en Hoffman fantomen, gebruikmakend van een 3-detector SPECT systeem met parallelle en fan-beam collimators. Een gemiddelde reproduceerbaarheid van 7.2% werd bekomen in een referentiepopulatie. Toepassing bij 33 gezonde vrijwilligers wees op lichaamsoppervlakte als belangrijkste factor in vergelijking met hersenvolume ter verklaring van de interindividuele variabiliteit. Dezelfde studie benadrukte tevens de noodzaak in longitudinale studies een normalisatie uit te voeren voor het hartritme in rust en suggereerde de afwezigheid van een significante invloed van lichte stress op de regionale 99mTc HMPAO hersenopname. De voorgaande evaluatie van cerebellaire rBU in een gezonde populatie werd uitgebreid tot patiënten lijdend aan demensie van het Alzheimer type (DAT). rBU waarden van cerebellaire operator-bepaalde regios van interesse kunnen worden beschouwd als symmetrisch, reproduceerbaar en stabiel in de tijd in gezonde vrijwillers. Bovendien werd

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na cumulatieve correcties voor lichaamsoppervlakte en hersenvolume een vergelijkbare en reproduceerbare, absoluut cerebellaire 99mTc HMPAO opname gevonden in de groep DAT patiënten en de groep gezonde vrijwilligers. De voorgestelde bevindingen suggereerden dat het cerebellum een goede keuze is als referentie regio voor de SPECT analyse van patiënten lijdend aan dementie van het Alzheimer type. Hoofdstuk 5: dopamine transporters in het striatum worden quantitatief bepaald. Parkinson’s ziekte wordt gekenmerkt door een hevige degeneratie van dopaminegevoelige neuronen in de grijze stof (dopaminergic neurons in the substantia nigra), met gevolg een verlies van dopamine transporters in nucleus caudata en putamen, in beeld gebracht met 123I-FP-CIT. Met SPECT, is het goed gekend dat semi-kwantitative analyse van kleine organen zoals het striatum belemmerd wordt door het partiëel volume effekt veroorzaakt door de slechte resolutie van de gamma camera. Voor bronnen met diameters < 12 mm werd een aktiviteit met een faktor 3 tot 5 te laag gemeten. Wij hebben een resolutie onafhankelijke methode ontwikkeld die erin bestaat de totale activiteit van het striatum te bepalen en te delen door de gemiddelde hersenaktiviteit, gebruik makend van twee grote interessezones. Wetende dat het volume van het menselijk striatum ongeveer 20 ml is en de werkelijke concentratie van de radioactieve tracer 8 tot 9 keer hoger is in het striatum dan in de rest van het hersenweefsel, is de gemeten verhouding van totale striatale op gemiddelde hersenactiviteit per ml van 150 tot 200 hiermee in overeenstemming. Met de klassieke striatale and occipitale ROIs, bekwamen we een inter-observator variabiliteit van 11.4 % in vergelijking met 3.1% met de resolutie onafhankelijke methode. Aanvullend hebben wij de totale striatale opname uitgedrukt in procent van de ingespoten dosis, gebruik makend van een gamma camera ijkingsfactor. Een goede scheiding werd bekomen tussen normale en Parkinson patiënten met de conventionele en onze methode. Met de methode waarbij de opname in het striatum uitgedrukt werd in procent van de dosis en na correctie door het gewicht van de patiënt werd een betere scheiding waargenomen dan met de conventionele methode. Voor meer accurate anatomische lokalisatie van defecten hebben wij twee bijkomende beelden ontworpen voor visuele interpretatie : een striatum/brain ratio beeld een een opnamebeeld uitgedrukt in % van de ingespoten dosis per ml striataal weefsel. De resolutie onafhankelijke methode is niet gamma camera, beeldopname of reconstructie afhankelijk. Met deze methode kunnen dan ook resultaten van verschillende centra onmiddelijk met elkaar vergeleken worden zonder soft of hardware aanpassingen.

Toekomstsperspectieven.

De huidige stroming in conventionele nucleaire instrumentatie en data analyse kan opgesplitst worden in drie belangrijke richtingen: beeldfusie, software ontwikkeling en nieuwe toestellen. De fusie van verschillende beeldvormende technieken wordt de norm in de klinische praktijk. Hybride SPECT camera’s uitgerust met X-straalbuizen (CT) worden verkocht. Initiële pogingen om functionele en anatomische beelden van twee verschillende toestellen te co-registreren onthullen de moeilijkheid om de strukturen in overeenstemming te brengen en zijn te arbeidsintensief voor routinematig gebruik (1). SPECT/CT verhoogt de diagnostieke accuraatheid van SPECT bij verschillende klinische onderzoeken (2). Nietemin blijven co-registratie artefacten tussen emmissie en transmissie beelden mogelijk, vooral bij hartstudies (3). Er is tevens nog discussie pro en contra attenuatiecorrectie bij hartstudies. (4) Daartegenover staat dat semi-quantitative gegevens verbeterd worden door middel van een CT attenuatie map (5,6) en preciese absolute

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kwantificatie wordt realistisch wanneer tevens scatter en collimator afhankelijke diepte correcties toegevoegd wordt aan de iteratieve reconstructie methode (7,8). Pogingen worden tevens ondernomen om het partiëel volume effect bij kleine strukturen te corrigeren met behulp van anatomische informatie (9). Verbetering van reconstructiealgoritmes was nog steeds een belangrijk onderwerp op de IEEE meeting in Rome 2004. Nieuwe software gaat deel uitmaken van de kliniek. Drie-dimentionele modellen van de kransslagaders verkregen door twee-dimentionele angiografie en 3D perfusie SPECT beelden worden op elkaar gepast (10). Bewegings-bevroren gated beelden kunnen verkregen worden met behulp van fase tot fase bewegingsvectoren (11). Statistische parametrische mapping (SPM), frequent gebruikt in hersenonderzoek wordt een standaard procedure (12). De belangrijkste vooruitgang in nucleaire geneeskunde dient te komen van nieuwe toestellen en materiaal. Het doel is de intrinsieke ruimtelijke resolutie en energieresolutie te verbeteren (13,14). Nieuw detectormateriaal met betere fysische karakteristieken dan NaI, wat betreft stralingsabsorptie, energieresolutie, licht opbrengst, breekbaarheid en densiteit, zal hoogstwaarschijnlijk NaI kristallen gaan vervangen (15). Positie gevoelige fotomultiplicatoren (PSPMT) worden gebruikt samen met pixelgrootte NaI(Tl) kristalen of nieuw scintillatie materiaal zoals CsI(Tl) (16,17). Men rekent erop dat nieuwe detectoren, bestaande uit duizenden kleine kristallen of een semi-conductoren matrix, de sensitiviteit and specificiteit van klinische studies zal verhogen (15,18). Verhoogde detector sensitiviteit maakt ook dynamische tomografische studies mogelijk en genereert meer nauwkeurige kwantitatieve gegevens als input voor compartimentele analyse reeds uitgevoerd met planaire beeldopnames. Kleine heelkundige sondes met CZT semi-conductoren of PSPMT worden gebruikt tijdens de operatie om lokale metastases op te sporen (19). Het blijft echter twijfelachtig, of deze kleine toestellen gebruikt voor dierproeven of als heelkundige sondes kunnen ontwikkeld worden tot grote detectoren, voor klinisch gebruik, tegen een aanvaardbare prijs.

1. Keidar Z, Isreal O, Krausz Y. SPECT/CT in tumor imaging: technical aspects and clinical applications. Semin Nucl Med 2003; 33:205-18.

2. Schillaci O, Danieli R, Manni C, Simonetti G. Is SPECT/CT with a hybrid camera useful to improve scintigraphic imaging interpretation? Nucl Med Commun. 2004;25:705-10.

3. Fricke H, Fricke E, Weise R et al. A method to remove artifacts in attenuation-corrected myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-derived attenuation maps. J Nucl Med. 2004;45:1619-25.

4. Figaro E, Wackers F. Should SPET attenuation correction be more widely employed in routine clinical practice? Eur J Nucl Med 2002; 29: 409-415.

5. Grossman G, Garcia E, Bateman T et al. Quantitative Tc99m sestamibi attenuation-corrected SPECT development and multicenter trial validation of myocardial perfusion stress gender-independent normal database in an obese population. J Nucl Cardiol 2004; 11: 239-241.

6. Dondi M, Fagioli G, Salgarello M et al. Myocardial SPECT: what do we gain from attenuation correction (and when)? Q J Nucl Med Mol Imaging 2004; 48:181-7.

7. El Fakhri G, Buvat I, Benali H et al. Relative impact of scatter, collimator response, attenuation and finite spatial resolution corrections in cardiac SPECT. J Nucl Med 2000; 41: 1400-8.

8. Links J, Becker L, Rigo P et al. Combined corrections for attenuation, depth dependent blur and motion in cardiac SPECT: a multicenter trial. J Nucl Cardiol 2000; 7: 414-25.

9. Matsuda H, Ohnishi T, Asada T et al. Correction for partial volume effects on brain perfusion SPECT in healthy men. J Nucl Med 2003; 44: 1243-52.

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10. Faber T, Santana C, Garcia E et al. Three dimensional fusion of coronary arteries with myocardial perfusion distributions: clinical validation. J Nucl Med 2004; 45: 745-53.

11. Slomka P, Nishina H, Berman D et al. “Motion-Frozen” display and quantification of myocardial perfusion. J Nucl Med 2004; 45: 1128-34.

12. Friston K, Ashburner J, Holmes A and Poline J-B. SPM: Statistical parametric mapping, software for functional neuroimaging. Welcome department of Cognitive Neurology, University College London.

13. Williams M, Goode A, Galbis-Reig V et al. Performance of a PSPMT based detector for scintimammography. Phys Med Biol 2000; 45: 781-800.

14. Loudos G, Nikita K, Uzunoglu N et al. Improving spatial resolution in SPECT with the combination of PSPMT based detector and iterative reconstruction algoritms. Comput Med Imaging Graph 2003; 27: 307-13.

15. Fidler V. Current trends in nuclear instrumentation in diagnostic nuclear medicine. Radiol Oncol 2000; 34: 381-5.

16. Weisenberger A, Kross B, Majewski S et al. Dual low profile detector heads for a restraint free small animal SPECT imaging system. IEEE conference Rome 2004: p136.

17. Pani R, Pellegrini R, Cinti M et al. New devices for imaging in nuclear medicine. Cancer Biother Radiopharm. 2004;19:121-8.

18. Wieczorek H, Goedicke A, Shao L et al. Analytical model for pixellated SPECT detector concepts. IEEE conference Rome 2004: p142.

19. Blevis L, Reznik A. Intra-operative imaging probe using CZT. IEEE conferencence Rome 2004:p197.

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7. List of publications.

1)Thyroid Research, 590-593 (December 1976)

Early thyroidal iodide and pertechnetate kinetics: new approach with a scintillation camera and a

computer.

Decostre P, Brooke P, Dobbeleir A, Erbsmann F.

2) European Journal of Nuclear medicine 2,173-177 (1977).

Measurement of separate kidney clearance by means of 99m-Tc-DTPA complex and a

scintillation camera.

A.Piepsz, A.Dobbeleir, F.Erbsmann.

3) Journal of Nuclear medicine (1977) Volume 18, Number 10.

Comments on Tc-99m DTPA scintillation camera renography.

A.Piepsz, H.R.Ham, A.Dobbeleir, F.Erbsmann.

4) Journal of Pediatrics. 1978 ; 5 : 769-74.

A simple method for measuring separate glomerular filtration rate using a single injection

of Tc-DTPA and the scintillation camera.

A.Piepsz, R.Denis, H.R.Ham, A.Dobbeleir, C.Schulman, F.Erbsmann.

5) Journal of Nuclear medicine (1981),Volume 22,Number 8.

Radionuclide quantitation of left-to-right cardiac shunts using deconvolution analysis.

H.R.Ham, A.Dobbeleir, P.Viart, A.Piepsz, A.Lenaers.

6) Radionuclides in Nephrology, 269-273, Grune and Stratton London 1982.

How to exclude renal obstruction in children ? Comparison of intrarenal transit times,

cortical times and the furosemide test.

A.Piepsz,H.R.Ham,A.Dobbeleir,M.Hall,F.Collier.

7) Nuclear medicine Communications 4 (1983); 276-281.

Background determination for 99m-Tc DTPA renal studies. A comparison between interpolative

background subtraction and surface ratio method.

A.Piepsz, A.Dobbeleir , H.R.Ham.

8) Nuclear medicine Communications 6 (1985); 477-483.

Influence of statistical noise on the determination of the single kidney 99m-Tc DTPA clearance.

A.Piepsz, A.Dobbeleir, H.R.Ham.

9) European Journal of Nuclear medicine. (1985) 11 : 17-21.

Evaluation of methods for qualitative and quantitative assessment oesophagal transit of liquid.

H.R.Ham, B.Georges, M.Guillaume, F.Erbsmann, A.Dobbeleir.

10) Nucl. Med. Comm. 8 (1987) 365-373 .

Measurement of right ventricular volumes from ECG gated steady state krypton-81m

angiocardiography.

P.R. Franken, P. Mols, E. Delcourt, A. Dobbeleir, B. Georges, H.R. Ham .

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11) Nuclear Medicine Communications 9, 603-612 (1988).

Assessment of vertebral mineral content by means of a single crystal scintillation camera.

J. Vandevivere, A. Dobbeleir, H.R. Ham, L. Williame.

12) J. Nuclear Medicine. Volume 30, 6 1989. (1025-1031)

Clinical Usefulness of Ultrashort-lived Iridium-191m from a Carbon-Based Generator System for

the Evaluation of the Left Ventricular Function.

P.R. Franken, A. Dobbeleir, H.R. Ham, C. Brihaye, M. Guillaume, F.F. Knapp, J. Vandevivere.

13) Clinical Nuclear Medicine. Volume 14, 12 1989.

Continuous anterior acquisitions in gastric emptying: comparison with the mean.

J. Roland, A. Dobbeleir, H.R. Ham, J. Vandevivere.

14) Nuclear Med. Comm. 10,1989.

Renal background.

A. Piepsz, A. Dobbeleir, H.R. Ham.

15) Nuclear Med. Comm. 11, 1990.

Effect of mild mental stress on solid phase gastric emptying in healthy subjects.

J. Roland, A. Dobbeleir, J. Vandevivere and H.R. Ham.

16) Eur. J. Nucl. Med. Volume 17, 130-133 1990.

Evaluation of reproducibility of solid-phase gastric emptying in healthy subjets.

J. Roland, A. Dobbeleir, J. Vandevivere and H.R. Ham.

17) J. Nuclear Medicine. Volume 31, 4 1990.

Effect of background correction on separate Tc99m-DTPA renal clearance.

A. Piepsz, A. Dobbeleir, H.R. Ham.

18) Eur. J. Nucl. Med. Volume 18, 83-86, 1991.

Technetium 99m mercaptoacetyltriglycine (Mag3) gamma camera clearance calculations:

methodological problems.

M. Tondeur, A. Piepsz, A. Dobbeleir, H.R. Ham.

19) Nuclear Med. Comm. 12, 27-34, 1991.

Performance of a single crystal digital gamma camera for first pass cardiac studies.

A. Dobbeleir, P.R. Franken, H.R. Ham, C. Brihaye, M. Guillaume, F.F. Knapp and J. Vandevivere.

20) Nuclear Med. Comm. 12, 473-484, 1991.

Comparison between exercise myocardial perfusion and wall motion using Tl201 and Ir191m

simultaneously.

P.R. Franken, A. Dobbeleir, H.R. Ham, R.Ranquin, S. Lieber, F. Van den Branden, P. Van den

Heuvel, C. Brihaye, M. Guillaume, F.F. Knapp and J.Vandevivere.

21) Clin Nucl Med 1992, 17: 378-389

Visualisation of brainstem perfusion using a high spatial resolution SPECT system.

R. Dierckx, A. Dobbeleir, J. Vandevivere, H. Abts, P. DeDeyn.

22) Clin Nucl Med 1993,18:532-534

Tc-99m HMPAO tomography using a three headed SPECT system equipped with lead fanbeam

collimators.

R. Dierckx, A. Dobbeleir, J. Martin, P. De Deyn.

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23) Clin Nucl Med 1993, 18 : 83-84.

High spatial resolution Tc-99m HMPAO brain SPECT in cerebellar emboligenic infarct.

R. Dierckx, L. Fidlers, A. Dobbeleir, P. De Deyn, J. Vandevivere.

24) Epilepsy Res 1992, 12 : 131-139.

Single photon emission computed tomography (SPECT) in seizure disorders using perfusion

tracers.

R. Dierckx, J. Vandevivere, L. Dom, K. Melis, G. Janssens, A. Dobbeleir, P. De Deyn.

25) European Heart Journal 1992, 13 : 1189-1194

Improvement in the efficacy of exercise first-pass radionuclide angiocardiography in

detecting coronary artery disease and the effect of patient age.

P. Franken, A. Vervaet, R. Ranquin, S. Lieber, P. Van Den Heuvel, F. Van Den Branden,

A. Dobbeleir and J. Vandevivere.

26) Eur. J. Nucl. Med. 1993, 20 : 684-689.

Quantification of technetium-99m hexamethylpropylene amine oxime brain uptake in routine

clinical practice using calibrated point sources as an external standard: phantom and human studies.

A. Dobbeleir, R. Dierckx.

27) Nucl. Med. Com. 1993, 14 : 792-797.

Sensitivity and specificity of Tc-99m HMPAO single headed SPECT in dementia.

R. Dierckx, M. Vandewoude, J. Saerens, T. Hartoko, P. Mariën, I. Capiau, A. Vervaet,

A. Dobbeleir and P. De Deyn.

28) Eur. J. Nucl. Med. 1994, 21 :514-520.

Parameters influencing SPET regional brain uptake of technetium-99m hexamethylpropylene amine

oxime measured by calibrated point sources as an external standard.

R. Dierckx, A. Dobbeleir, M. Maes, B. Pickut, A. Vervaet, P. De Deyn.

29) Eur. J. Nucl. Med. 1994, 21 :621-633.

Sensitivity and specificity of thallium-201 single-photon emission tomography in the

functional detection and differential diagnosis of brain tumours.

R. Dierckx, J. Martin, A. Dobbeleir, R. Crols, I. Neetens, P. De Deyn

30) Eur. J. Nucl. Med. 1995, 22 :427-433.

Technetium-99m HMPAO SPET in acute supratentorial ischaemic infarction, expressing deficits

as millilitre of zero perfusion.

R. Dierckx, A. Dobbeleir, B. Pickut, L. Timmermans, I. Dierckx, A. Vervaet, J. Vandevivere, W.

Deberdt, P. De Deyn.

31) Yearbook of Nuclear Medicine 1995: 273-275.

Quantification of technetium-99m hexamethylpropylene amine oxime brain uptake

in routine clinical practice using calibrated point sources as an external standard:

phantom and human studies.

A. Dobbeleir, R. Dierckx.

32) Nucl. Med. Com. 1996, 17 : 583-590.

240 Degrees: Why not ?

A.S. Hambÿe, A. Dobbeleir, E. Stulens, A. Vervaet, J. Vandevivere, P.R. Franken.

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33) Nucl. Med. Com. 1997, 18 : 751-760.

Can we rely on Tc99m -sestamibi gated tomographic myocardial perfusion imaging to quantify left

ventricular function? A comparative study with classical isotopic techniques

for the measurement of ejection fraction.

A.S. Hambÿe, A. Dobbeleir, A. Vervaet, H. Chi-Chou.

34) Clin Nucl Med 1997, 22 : 172-175.

Determination of systolic thickening index with gated Tc99m Sestamibi SPECT:

A new parameter of myocardial viability ?

A.S. Hambÿe, A. Dobbeleir, M. Derveaux, J. Vandevivere, P. Van Den Heuvel.

35) Nucl. Med. Com. 1997, 18 : 1135-1147

SPET generated colour-coded polar maps to quantify the uptake of 99mTc-sestaMIBI and 123I-

BMIPP in chronically dysfunctional myocardium: comparison with coronary anatomy and wall

motion.

A.S. Hambÿe, A. Dobbeleir, P.R. Franken.

36) Nuklearmedizin 1998, 37: S1-S6

BMIPP imaging to identify residual myocardial viability in patients with acute and

chronic left ventricular dysfunction.

P.R. Franken, A.S. Hambÿe, A. Dobbeleir, F. De Geeter, P. Dendale.

37) J. Nuclear Medicine 1998. Volume 39: 1845-1850

Abnormal BMIPP uptake in chronically dysfunctional myocardial segments: correlation

with contractile response to low-dose dobutamine.

A.S. Hambÿe, M. Vaerenberg, A. Dobbeleir, P. Van den Heuvel, P.R. Franken.

38) Psychiatry Research: Neuroimaging Section 90, 1999 : 103-112.

Validation of the cerebellum as a reference region for SPECT quantification in patients suffering

from dementia of the Alzheimer type.

B. Pickut, R. Dierckx, A. Dobbeleir, K. Audemaert, K. Van Laere, A. Vervaet, P De Deyn.

39) Nucl. Med. Com. 1999, 20 : 737-745

Quantification of 99mTc-sestaMIBI and 123I-BMIPP uptake for predicting functional outcome in

chronically ischaemic dysfunctional myocardium.

A.S. Hambÿe, A.Vervaet, A. Dobbeleir.

40) Eur. J. Nucl. Med. 1999, 26 :655-658.

Influence of high-energy photons on the spectrum of iodine-123 with low- and medium-energy

collimators: consequences for imaging with 123I-labelled compounds in clinical practice.

A. Dobbeleir, A.S. Hambÿe, P.R. Franken.

41) J. Nuclear Medicine 1999. Volume 40: 707-714

Influence of methodology on the presence and extent of mismatching between 99mTc-MIBI and

123I-BMIPP in myocardial viability studies.

A. Dobbeleir , A.S. Hambÿe, P.R. Franken.

42) J. Nuclear Medicine 1999. Volume 40: 1468-1476

BMIPP imaging to improve the value of sestamibi scintigraphy for predicting functional outcome in

severe chronic ischemic left ventricular dysfunction.

A.S. Hambÿe, A. Dobbeleir, A. Vervaet, P. Van den Heuvel, P.R. Franken.

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43) Nucl. Med. Com. 1999, 20 : 1031-1040

Quantification of 99mTc-HMPAO brain SPET in two series of healthy volunteers using different

triple-headed SPET configurations: Normal databases and methodological considerations.

K Van Laere, C. De Sadeleer, A. Dobbeleir, A. Bossuyt, P. De Deyn, R. Dierckx.

44) J. Nuclear Medicine 2000. Volume 41: 213-214

Effect of methodology on mismatching between 99mTc-MIBI and 123I-BMIPP.

A. Dobbeleir , A.S. Hambÿe, P.R. Franken.

45) Yearbook of Nuclear Medicine 2000: 279-280.

Influence of high-energy photons on the spectrum of iodine-123 with low- and medium-energy

collimators: consequences for imaging with 123I-labelled compounds in clinical practice.

A. Dobbeleir, A.S. Hambÿe, P.R. Franken.

46) Eur. J. Nucl. Med. 2000, 27 :1494-1500.

Prediction of functional outcome by quantification of sestamibi and BMIPP after acute myocardial

infarction.

A.S. Hambÿe, A.Vervaet, A. Dobbeleir. P. Dendale, P.R. Franken.

47) World Journal of Nuclear Medicine, Volume 1, Number 1, 10-2002

Image quality with Rhenium-188 and Technetium-99m: Comparative Planar and Spect Evaluation

in a Phantom Study and implications for dosimetry.

A.S. Hambÿe, A. Dobbeleir, A. Vervaet, FF (Russ) Knapp.

48) Nucl. Med. Com. 2004, 25, 347-353

Quantitative gated sestamibi SPECT for diagnosing coronary artery disease: a comparative study of

non corrected and scatter-corrected summed and end-diastolic images.

A.S. Hambÿe, A.Vervaet, A. Dobbeleir

49) Eur. J. Nucl. Med and Molecular Imaging 2004; 31: 1606-1613

Variability of left ventricular ejection fraction and volumes by quantitative gated SPET : influence

of algorithm, pixel size and reconstruction parameters in normal and small-sized hearts. A.S. Hambÿe, A.Vervaet, A. Dobbeleir

50) Submitted.

Quantification of Iodine-123-FPCIT SPECT with a resolution independent technique.

A. Dobbeleir, A.S. Hambÿe, A.Vervaet, H. Ham.

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8. Dankwoord.

Dit proefschrift kan moeilijk als klassiek beschouwd worden daar het data bevat die verzameld

werden gespreid over meerdere decennia. De noodzakelijke methodologie gaat zelfs terug tot het

begin van mijn loopbaan en daarom ben ik ook dank verschuldigd aan personen die niet voorkomen

in dit werk maar die mij wetenschappelijk hebben gevormd. Mijn dankbetuigingen zijn dan ook min

of meer in chronologische volgorde weergegeven.

Aan Dr Philippe Decostre die mij meer dan 30 jaar geleden, ondanks nog af te leggen militaire

dienst, uitkoos om onder zijn leiding te werken in het St-Pieter ziekenhuis (Universiteit Brussel).

Hij heeft mij de basis van nucleaire geneeskunde bijgebracht.

Aan François Erbsmann, fysicus en wetenschapper in hart en nieren, die mij wetenschappelijk heeft

gevormd. Onder zijn inspirerende leiding werd de afdeling fysica uitgebouwd en de eerste

wetenschappelijke werken gepubliceerd.

Aan Prof Ami Piepsz, die mij het belang van nauwkeurig werk heeft bijgebracht en toonde wat

doorzettingsvermogen is. Onder zijn impuls heeft nucleaire een belangrijke impact gekregen op de

nierfunktie.

Aan Prof Hamphrey Ham, die elk probleem toch nog op een andere manier zag en met zijn inzicht,

vernieuwende ideeën te voorschijn toverde.

Nooit zal ik de rit in mijn auto vergeten naar het congres in Lausanne in 1976 samen met François,

Ami en Hamphrey waar wij met jong enthousiasme de gescheiden nierklaring en whole body scan

voorstelden.

Half de jaren tachtig overtuigde Dr Vandevivere mij om in Middelheim te Antwerpen te werken

waar een tweede periode in mijn loopbaan aanbrak. Aldaar heb ik samengewerkt met Dr Roland en

Rudi Vandermeiren die veel routine op zijn schouders nam zodat ik de tijd kreeg om nieuwe zaken

te ontwikkelen. Tevens werd er de basis gelegd voor de aangename post-Middelheim

samenwerking met Dr Koen Melis.

Aan Prof Philippe Franken, die mij met zijn grote kennis van nucleaire en klinische cardiologie

stimuleerde om de resultaten te kwantificiëren.

Aan Prof Rudi Dierckx, die van oordeel is dat nucleaire geneeskunde best kan functioneren onder

multi-disciplinaire samenwerking. Onder zijn impuls werden de hersenen uitgebreid bestudeerd.

Aan Ann Vervaet, statisticus, die vele resultaten controleerde en deze daarna ook in een

publiceerbare vorm voorstelde.

Aan Prof Anne-Sophie Hambÿe, tevens mijn echtgenote, die de voornaamste rol heeft in veel van

de voorgestelde werken. Niet alleen haar kennis maar ook haar litteraire kwaliteiten dragen veel bij

tot dit werk. Zonder haar zouden vele gegevens begraven zijn in een schuif van mijn bureau.

Aan Prof Anne Paans voor zijn hartelijk onthaal en begeleiding in Groningen.

Heel belangrijk is dat dit werk uitgevoerd is in een vriendschappelijke samenwerking en dat die

vriendschap gebleven is door de jaren heen.

Tot slot bedank ik de leden van de jury en tevens mijn kinderen, zus en schoonbroer.