Rev Esp Med Nucl Imagen Mol.

2015;34(2):8994

Original article

A novel, fully automated, observer-independent program for

semiquantifying striatal 123 I-FP-CIT uptake
P. Tamayo a,c,,1 , C. Montes b,c,1 , M.E. Perez b , E. Martin a , J.R. Garca-Talavera a
a
Nuclear Medicine Department, University Hospital of Salamanca, Spain
b
Medical Physics Department, University Hospital of Salamanca, Spain
c
Institute of Biomedical Research of Salamanca, Spain

a r t i c l e i n f o a b s t r a c t

Article history: Objective: To describe and validate a novel, fully automated program specically designed for the semi-
Received 11 April 2014 quantication of striatal 123 I-FP-CIT uptake using volumes of interest (VOI) analysis.
Accepted 20 August 2014 Material and methods: The proposed algorithm is based on a template that mimics the striatal 123 I-FP-CIT
Available online 8 October 2014
uptake in a healthy subjects, derived from dened anatomical VOIs available from WFU PickAtlas. Four
SPECT studies of the anthropomorphic Alderson phantom lled with variable radioactive concentrations
Keywords: were acquired for the experimental validation. Experimental SPECT images were spatially normalized
123
I-FP-CIT SPECT
with respect to the previously created template. The binary VOIs corresponding to left caudate and puta-
VOI analysis
SPM
men and right caudate and putamen, which were used to construct the template, were projected onto
Alderson RSD phantom the experimental images to obtain the counts for these regions. To minimize the partial volume effect, a
Striatal uptake semiquantication percentage of the voxels in these regions (threshold), rather than all of them, was used. A binary occipital
VOI was used to quantify the non-specic uptake. Experimental binding potentials (BPs) were calculated
from the counts in these regions. True BPs were calculated from aliquots taken from the solutions used
to ll the phantom.
Results: There were statistically signicant differences in the experimental BP values (p < 0.002) accord-
ing to the percentage of voxels used. A highly signicant correlation was achieved between true and
experimental BP values, regardless of the percentage of voxels included for quantication.
Conclusions: Our novel, observer-independent program automatically performs the semiquantication
of striatal 123 I-FP-CIT uptake in experimental studies.
2014 Elsevier Espaa, S.L.U. and SEMNIM. All rights reserved.

Un nuevo programa, totalmente automtico e independiente del observador

para semi-cuanticar la captacin estriatal de 123 I-FP-CIT

r e s u m e n

Palabras clave: Objetivos: Describir y validar un nuevo software, totalmente automtico, especcamente disenado para
123
I-FP-CIT SPECT semi-cuanticar la captacin estriatal de 123 I-FP-CIT usando volmenes de inters (VOIs).
Anlisis de VOIs Material y mtodos: El algoritmo propuesto se basa en una plantilla que remeda la captacin estriatal
SPM
de 123 I-FP-CIT en un sujeto sano, obtenida a partir de VOIs anatmicos denidos en WFU PickAtlas. Para
Maniqu RDS Alderson
la validacin experimental de este algoritmo se adquirieron 4 estudios SPECT del maniqu antropomr-
Semicuanticacin de la captacin estriatal
co Alderson llenado con concentraciones radioactivas variables. Las imgenes SPECT experimentales se
normalizaron espacialmente respecto a la plantilla creada. Los VOIs binarios correspondientes a ncleo
caudado y putmen derechos e izquierdos, utilizados para disenar la plantilla, se proyectaron sobre las
imgenes experimentales para obtener las cuentas en estas regiones. Para minimizar los efectos de vol-
umen parcial se utiliz un porcentaje de vxeles, en vez de utilizar todos los vxeles contenidos en estos
VOIs. Se ha utilizado un VOI binario situado en regin occipital para cuanticar la unin no especca.
Los potenciales de unin (BPs) experimentales se calcularon a partir de las cuentas obtenidas en estas
regiones. Los BPs reales se calcularon a partir de alcuotas tomadas de las soluciones utilizadas para llenar
el maniqu.
Resultados: Hubo diferencias estadsticamente signicativas en los BPs experimentales en funcin del
porcentaje de vxeles utilizados para la cuanticacin (p < 0.002). Se alcanz una alta correlacin entre
los BPs reales y los experimentales, independientemente del porcentaje de vxeles utilizados para la
cuanticacin.

Corresponding author.
E-mail address: ptamayo@usal.es (P. Tamayo).
1
Both authors contributed equally to this work.

http://dx.doi.org/10.1016/j.remn.2014.08.004
2253-8089/ 2014 Elsevier Espaa, S.L.U. and SEMNIM. All rights reserved.
2253-654X/
90 P. Tamayo et al. / Rev Esp Med Nucl Imagen Mol. 2015;34(2):8994
Conclusiones: Este nuevo programa automtico e independiente del observador realiza la semicuanti-
cacin de la captacin estriatal de 123 I-FP-CIT en estudios experimentales.
Introduction
Parkinsons disease (PD) is a progressive neurodegenerative
disorder characterized by the motor triad of tremor, rigidity and
bradykinesia. These symptoms are associated with the loss of
dopaminergic neurons in the substance nigra pars compacta, the
presence of ubiquinated protein deposits in the cytoplasm of neu-
rons, and a subsequent decline in dopamine levels in the striatum,
which is required to control movement.1
123 I-FP-CIT, a radioiodinated cocaine analog, is a radiophar-
maceutical that binds specically, though not selectively, to
presynaptic dopamine transporters (DATs) in vivo. This enables
the study of nigrostriatal dopaminergic system integrity, which is
altered in PD and preserved in essential tremor and drug-induced
parkinsonism, by means of the Single Photon Emission Com-
puted Tomography (SPECT) imaging technique.2 In routine clinical
practice, results of 123 I-FP-CIT SPECT are qualitatively evaluated,2,3
although this involves a degree of subjectivity and some uncer-
tainty about incipient parkinsonism. The results are categorical,
and so cannot fully reect the continuous characteristics of clinical
variability and disease progression. However, accurate semiquan-
tication of DAT binding could be helpful in the early stages of PD
to detect subtle changes in DAT binding,4 and in sequential stud-
ies to monitor disease progression57 and the benecial effects of
putative neuroprotective drugs.8
DAT binding is usually quantied as the ratio of specic bind-
ing in striatal regions to nonspecic binding in a reference region
devoid of DAT. There are several methods for quantifying DAT den-
sity using regions of interest (ROI) in which striatal regions are
usually manually delineated in the reconstructed SPECT images.
The results obtained are expressed as a continuous rather than
a categorical variable, thereby reecting the great clinical vari-
ability more fully. However, such techniques based on manual or
semiautomatic ROIs are operator-dependent and so are prone to a
considerable inter- and intraobserver variability that is no longer
considered acceptable in clinical practice or research studies.9
Therefore, automated observer-independent systems are required
for several reasons: to overcome observer dependency and min-
imize variability, to provide 3D information that reects the
structure of the entire striatum, and to standardize the semiquan-
tication process, so enabling the comparison of data from different
centers.
Here we propose a novel fully automated observer-independent
program specically designed for processing and quantifying 123 I-
FP-CIT SPECT images using volumes of interest (VOI) analysis. The
method is based on a specic low-resolution template that rep-
resents a realistic simulation of the activity distribution from the
basal ganglia of a healthy subject. Experimental validation of this
method with an anthropomorphic striatal phantom (Alderson RSD
phantom) is presented.
Material and methods
The proposed algorithm is based on a template that mimics stri-
atal 123 I-FP-CIT uptake in a healthy subject. The aim of creating this
template was to have a common stereotactic space to t 123 I-FP-CIT
SPECT images of patients so that comparisons can be made. Patient
studies have not been used in this work. Instead, experimental
studies were made with the anthropomorphic Alderson phantom
2014 Elsevier Espaa, S.L.U. y SEMNIM. Todos los derechos reservados.
(available from Radiology Support Devices Inc. and provided by
GE-Healthcare), which reproduces the striatal morphology. VOIs
corresponding to left and right caudate and putamen and to a
reference area (occipital area) were then applied to spatially nor-
malized phantom images to obtain the count statistics for these
regions and thereby to calculate the binding potentials (BP). These
procedures were performed with Statistical Parametrical Mapping
software (SPM8).10 The details of the process are described in the
following sections.
Construction of the template
As SPM does not have a specic template for the striatal
uptake of 123 I-FP-CIT, it is necessary to create one that resem-
bles this uptake.13 SPM contains the WFU PickAtlas toolbox,11,12
which enables anatomical VOIs as binary masks to be dened. The
Anatomical Automatical Labelling atlas14 was selected in the soft-
ware WFU PickAtlas and four binary VOIs, left and right caudate
and putamen, representing striatal structures, were used. The vol-
ume of these VOIs was 4.95, 4.96, 9.35 and 9.24 ml for left and right
caudate and putamen, respectively. These regions are dened in
the standard space of the Montreal Neurological Institute (MNI). To
reproduce the background uptake in 123 I-FP-CIT patient studies, the
a priori maps of gray and white matter included in SPM were added.
These maps were also dened in the MNI space. The template
was built adding the following binary VOIs: left and right caudate
nucleus, with a weighting factor of 4; left and right putamen, with
a weighting factor of 2; and a background region with a weight-
ing factor of 1. These weighting factors were selected to mimic the
123 I-FP-CIT uptake of a subject who had involvement of striatal
uptake in a moderate degree. This template is used to spatially
normalize all the studies in the same space, both healthy and patho-
logical subjects. If similar weighting factors would had been applied
for putamen as for caudate a good normalization would be achieved
in healthy subjects but not in pathological ones. On the contrary, if
the weighting factors applied were much higher for caudate than
for putamen, a good normalization would be achieved in patholog-
ical subjects but not in healthy ones. The template obtained in this
way is of high resolution.
The 123 I-FP-CIT SPECT images of patient studies are affected by
the characteristic low resolution of images obtained with gam-
macameras and thus differ from the high-resolution template
built here. To transform the high-resolution template to a low-
resolution one an 8 mm 8 mm 8 mm full width at half maximum
(FWHM) 3D Gaussian lter was applied. The low-resolution tem-
plate obtained is shown in Fig. 1.
Experimental studies
Four SPECT studies of the anthropomorphic Alderson phantom
were acquired to validate the proposed quantication method.
With the rst acquisition, referred to as the reference acquisi-
tion, both caudate and putamen contained the same radioactive
concentration of approximately 150 kBq/ml of 123 I-NaI. The back-
ground chamber, mimicking the cerebral cortex, was lled with a
radioactive concentration of 19.0 kBq/ml solution. After this ref-
erence SPECT acquisition, three acquisitions were performed by
reducing sequentially the radioactive concentration of striatum.
The rst was acquired by reducing the concentration of the right
 P. Tamayo et al. / Rev Esp Med Nucl Imagen Mol. 2015;34(2):8994
Figure 1. Low-resolution template designed with 3D binary regions that mimics 123 I-FP-CIT striatal uptake in a healthy subject.
putamen (lled with a solution of 110 kBq/ml), the second by reduc-
ing of the left putamen (lled with a solution of 54.8 kBq/ml) and
the third by reducing the concentration of left caudate (lled with
a solution of 87.7 kBq/ml).
The four experimental SPECT studies were acquired with a
dual-head rotating gamma camera (Axis, Picker) tted with an
ultra-high-resolution fan-beam collimator. SPECT data were col-
lected in a 128 128 matrix, for 35 min, in step-and-shoot mode
(120 steps, 3 , 35 s per step) with a symmetrical window of 20%
centered on a 159 keV 123 I photopeak. Images were reconstructed
using an OSEM algorithm (4 iterative steps). The postltering used
in this study was a low-frequency lter (Low-Pass, order 5 and
cut-off 0.40/cm). The images were corrected for attenuation by the
Chang method using an attenuation coefcient of 0.04/cm, obtained
experimentally for this equipment with a uniform phantom lled
with 123 I. The isotropic voxel size of the reconstructed studies was
2.6 mm. The spatial resolution (FWHM) of the camera tted with
ultra-high-resolution fan-beam collimators, at 15 cm from the col-
limator surface, is 8.6 mm.
Aliquots of 0.1 ml of each solution used to ll the four striatal
regions and the background chamber were taken to obtain accurate
radioactive counts in each region. These aliquots were measured in
a NaI well counter 20 h after SPECT images were acquired to mini-
mize count loss due to dead time. The dead time of the system was
always less than 1%. In any case the system automatically corrects
for dead time providing both the real time and the live time. True BP
values were calculated as BPtrues = (aliquot counts background
counts)/background counts.
Spatial normalization
Once SPECT studies had been acquired and reconstructed, they
were transferred via DICOM to a PC and converted to Nifti format by
means of the free MRICro software.15 Then, by SPM8, experimental
images were spatially normalized to the previously created tem-
plate. This spatial normalization consisted of 12-parameter afne
transformations composed of 3 translations, 3 rotations (rigid-
body), 3 shears and 3 zooms. Nonlinear warps were then performed
Figure 2. 3D binary regions projected onto the reference phantom acquisition used to calculate experimental BP values.
91
to account for global shape differences (which is not done by the
afne registration) between the studies and the template. This
spatial normalization allowed us to have all the experimental
images and the template in the same anatomical space, enabling us
to assume voxel-to-voxel correspondence. These co-registrations
were visually validated.
VOI analyses and experimental BP calculations
VOIs that t the 3D shape of striatal structures are needed to
semiquantify the striatal uptake of 123 I-FP-CIT. To do this, pre-
viously used high-resolution binary VOIs corresponding to left
caudate and putamen and right caudate and putamen were used to
construct the template. As these regions were in the same space as
in normalized studies, they were projected onto the experimental
images to obtain the counts in these regions (Fig. 2).
The log roi batch function16 allows mean counts to be made in
a VOI. However, in small volumes, such as striatal structures, there
is a count loss due to the partial volume effect (PVE) and the mean
count of all the voxels contained in a VOI is not a good estimator
of the activity concentration in that VOI. To minimize the effect,
it is necessary to establish a threshold as a percentage of voxels
with the higher counts. For this purpose the log roi batch function
was modied in such way that the counts in the VOI were ranked in
decreasing order and then a range of percentages of voxels with the
higher counts (550%) were selected. The mean count of selected
voxels was calculated for each threshold.
A binary occipital VOI was dened in the reference phantom
image using MRICro software. The original log roi batch func-
tion was used to obtain the mean counts in this background
region in order to quantify the non-specic radiotracer uptake.
Experimental BP were calculated as BPexperimentals = (striatal
activity occipital activity)/occipital activity.
Statistics
Pearson correlation coefcients (r) between true and exper-
imental BP values were calculated and considered statistically
92 P. Tamayo et al. / Rev Esp Med Nucl Imagen Mol. 2015;34(2):8994

Table 1 0.976
True and experimental BP values in striatal structures obtained with different voxel
thresholds for the four acquisition performed with phantom.

Pearson correlation coefficient (r)

True BP Experimental BP
0.974
Threshold

5% 15% 25% 35% 50%

Reference acquisition 0.972

Right C 6.57 3.42 3.12 2.91 2.73 2.48
Left C 6.57 3.25 3.00 2.80 2.62 2.37
Right P 6.57 3.32 3.00 2.75 2.54 2.28
Left P 6.57 3.47 3.09 2.83 2.63 2.36 0.97
2nd acquisition
Right C 6.57 3.34 3.01 2.78 2.59 2.33
Left C 6.57 3.34 3.02 2.80 2.60 2.35
Right P 5.03 2.76 2.47 2.26 2.09 1.86 0.968
0 10 20 30 40 50
Left P 6.57 3.56 3.22 2.95 2.73 2.45
Threshold (%)
3rd acquisition
Right C 6.57 3.26 2.96 2.75 2.55 2.28
Figure 3. Pearson correlation coefcients between true and experimental BP values
Left C 6.57 3.25 2.87 2.59 2.38 2.11
for different percentages of voxels (thresholds).
Right P 5.03 2.68 2.40 2.18 2.01 1.78
Left P 2.28 1.58 1.41 1.28 1.18 1.03
3
4th acquisition
Right C 6.57 2.95 2.68 2.45 2.20 1.83
Left C 3.92 1.91 1.72 1.55 1.37 1.10
Right P 5.03 2.51 2.27 2.09 1.92 1.68
Left P 2.28 1.45 1.23 1.05 0.91 0.74

C = Caudate nucleus, P = Putamen. 2

Experimental BP

signicant at an -level of <0.05. One-way ANOVA was used to

test whether the range of percentages of used voxels resulted in
statistically signicant differences in experimental BP values. 1

Results

The experimental BP values of right caudate and putamen and

left caudate and putamen regions, obtained by the quantication
method presented here and using different percentages of voxels,
are shown in Table 1. True BPs are also displayed in this table. It
can be seen that the lower the percentage of voxels included in
the quantication the higher the experimental BP values obtained,
probably due to the weaker inuence of the partial volume effect.
There were statistically signicant differences between the
experimental BP values for all the thresholds analyzed (p < 0.002).
Specically, signicant differences were observed between the 5
and 50% (p < 0.005) thresholds but not between the others (15%,
25% and 35%). This means that either of the later thresholds might
be used to quantify striatal 123 I-FP-CIT uptake.
A highly signicant correlation was noted between true and
experimental BP values, regardless of the percentage of voxels
included for the quantication, with the highest Pearson correla-
tion coefcient recorded for the 25% threshold (r = 0.975, p < 0.0001;
Fig. 3). The scatter plot of the true and measured BP values for the
25% threshold in the right and left caudate and putamen regions
(R2 = 0.950, p < 0.0001) is displayed in Fig. 4. We therefore used
the 25% threshold to calculate the experimental BP values, which
proved to be approximately 43% of the true values.
Discussion
Our results show that a novel, fully automated, observer-
independent program, specically designed for processing and
quantifying 123 I-FP-CIT SPECT images using VOI analysis, works
under experimental conditions and may be of great value for quan-
tifying striatal uptake in clinical practice. This program is based on
a specic low-resolution template that realistically simulates the
distribution of activity from the basal ganglia of a healthy subject,
and on the use of VOIs representing left caudate and putamen, right
0
1 2 3 4 5 6 7
Trues BP
Figure 4. Scatter plot of the true and measured BP values for the 25% threshold in
the right and left caudate and putamen regions.
caudate and putamen and occipital regions to measure radiotracer
uptake in these regions and thereby to calculate the BP values.
The availability of an automated image-analysis program would
be desirable for diagnosing PD in its early stages, so that subtle
changes in DAT binding can be detected, and for monitoring disease
progression and the benecial effects of putative neuroprotective
drugs. This novel program is fully automated once transverse slices,
which have already been reconstructed and attenuation-corrected
on the departments workstation, have been transferred to the PC
via the DICOM protocol. All subsequent processing is accomplished
rapidly (within 15 min) and without any manual intervention. Thus,
the process is not too time-consuming for the operator and is
observer-independent.
Several automated quantication programs have been pro-
posed, but none have been universally accepted as a standard
method of quantication.17 In 2007, Calvini and coworkers
designed an algorithm named BasGan (the acronym derived from
basal ganglia),18 based on a high-denition (3D) striatal tem-
plate derived from the Talairach atlas, which is converted to a
low-resolution template by applying a 3D Gaussian lter. This low-
resolution template is meant to represent the striatal radiotracer
uptake of a healthy subject. The algorithm automatically makes
the transformation necessary to achieve optimal positioning of the
3D striatal template on the 123 I-FP-CIT SPECT images of the patient.
However, these SPECT images of patient previously need to be man-
ually oriented so that they lie parallel to the bicommissural line
 P. Tamayo et al. / Rev Esp Med Nucl Imagen Mol. 2015;34(2):8994
(AC-PC position), which requires operator intervention, whereas
our method is fully automatic and independent of operator. With
the BasGan program, which includes PVE correction, the authors
found a highly signicant correlation between true and experi-
mental BP values (r = 0.97) in the phantom images (as we found in
ours), and more accurate semiquantitative results following PVE
correction. Despite the very close correlation between true and
experimental BP values in the phantom studies, the BP obtained
in the regions with the lowest radiotracer concentrations led to an
overestimation of the counts, which might have been due to an
overcorrection of PVE. We did not perform PVE correction, which
may explain why our experimental BP values were lower (43%) than
the true BP values.
Tossici-Bolt et al.19 proposed the Southampton method as
another automated DAT quantication method. It uses geometri-
cal VOIs for the striatum, which are large enough to ensure the
inclusion of all the counts detected outside the physical volume
of the structures due to the PVE, and a reference VOI for measur-
ing the specic to non-specic ratio. Thus, this technique accounts
for the PVE by measuring total striatal uptake. However, measure-
ment of total striatal uptake is a limitation of this method because
it obviates subdivision into striatal subregions such as the head
of the caudate and the putamen tail. Intra-striatal quantication
might improve discrimination between normality and disease as
well as providing futher information about disease severity and
progression.2022 The VOIs are manually positioned, which results
in intra- and inter-observer variability of 3% and 4%, respectively,
for experienced operators. The method we propose resolves these
constraints since it is completely automatic and uses subregions
within the striatum, which yields more information about disease
severity and progression.
BRASS23 is a commercial program running on the Hermes work-
station (Nuclear Diagnostics, Stockholm, Sweden). It uses a map of
anatomical VOIs obtained from the MRI of a control patient. Clinical
studies are registered on the 123 I-FP-CIT template, obtained from
healthy subjects. A VOI map is used to adjust the patient striatal
VOIs to compensate for individual anatomic variations in order to
obtain counts in such VOIs. The BP in right caudate and putamen
and left caudate and putamen were obtained from these counts.
The BRASS software includes both a VOI map and a tracer-specic
template of healthy control subjects, although the latter should be
specic to the equipment and gamma camera collimators used in
each center.18 In contrast, our template is built using validated
and universally available software that is not dependent on the
equipment used, so it can easily be created at each center.
Accurate measurement of 123 I-FP-CIT striatal uptake is limited
by scatter, attenuation and the nite resolution of the gamma cam-
era. Without any correction, the striatal activity is underestimated
by 90%. With attenuation correction, striatal uptake remained
underestimated by 67%. Combining scatter and attenuation cor-
rection striatal uptake remained underestimated by about 50%.
When PVE correction is added to scatter and attenuation correc-
tion reduces the underestimation in BP values to 10%.24 We only
performed attenuation correction before the transverse slices were
transferred to the PC via DICOM. We did not perform scatter correc-
tion because it is not used in most nuclear medicine departments.25
Our algorithm does not perform PVE correction. The BP values
obtained by our program were underestimated by 57%, which is
consistent with other published results of studies in which PVE
correction was not performed.24,26
Another limitation of this study is the different geometry of
the striatal structures of phantom with respect to the striatal VOIs
used to create the template, which makes it more difcult to spa-
tially coregister both phantom images and the template. However,
good coregistration is observed in the visual analysis of the overlap
between the phantom images and the template. In addition, the
93
semiquantication of striatal uptake of 123 I-FP-CIT reveals a close
correlation between true and experimental BP values.
In general, the BPs values obtained depend on the equipment
and the methodology used to acquire the images as well as the
method used for the semiquantication. The algorithm proposed
by us aims to control the variability due to the semiquantica-
tion since it is a fully automated observer-independent program. To
control the variability due to both the equipment and the method-
ology used it would require to acquire experimental studies with
phantoms for correction factors then applied to clinical studies with
patients.27
The software proposed by us is neither freely downloadable
from the web nor offered commercially, but rather is designed to
be developed in individual centers, where the VOIs and thereby
the template for standardizing clinical studies must be created and
the 123 I-FP-CIT uptake in the VOIs quantied. These steps may seem
somewhat complex, but detailed information about how to perform
each of the steps is provided in the materials and methods sec-
tion of this paper. Furthermore, todays Nuclear Medicine Services
include other professionals such as engineers or medical physicist,
who are familiarized with Matlab and SPM platforms for processing
and quantication of medical images, and therefore are capable to
implement this method without much difculty.
Conclusion
The algorithm described here is novel, fully automated, and
observer-independent. The program has been specically designed
for processing and quantifying 123 I-FP-CIT SPECT images using VOI
analysis. It has been shown to work effectively in phantom studies.
Conicts of interest
The authors have no conicts of interest to declare.
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