Brain TRODAT-SPECT Versus MRI Morphometry in

Distinguishing Early Mild Parkinson’s Disease from Other

Extrapyramidal Syndromes
Mohammad Reza Hossein-Tehrani, Tahereh Ghaedian , Etrat Hooshmandi, Leila Kalhor,
Amin Abolhasani Foroughi, Vahid Reza Ostovan
From the Clinical Neurology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran (MRHT, EH, VRO); Nuclear Medicine and Molecular Imaging Research
Center, Namazi Teaching Hospital, Shiraz University of Medical Sciences, Shiraz, Iran (TG, LK); Medical Imaging Research Center, Shiraz University of Medical Sciences,
Shiraz, Iran (AAF); and Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran (AAF).

ABSTRACT
BACKGROUND AND PURPOSE: The clinical differentiation of Parkinson’s disease (PD) from other extrapyramidal syndromes
has made a challenge in neurology. This study aimed to compare the specificity and sensitivity of brain MRI volumetry and
dopamine transporter scans in differentiating PD from other extrapyramidal syndromes in the early stages of the disease.
METHODS: This study included 34 patients younger than 70 years old with less than 3 years of extrapyramidal symptoms.
Demographic and clinical history of the patients, including age, sex, and disease duration, was gathered. Disease severity was
assessed using Unified Parkinson’s Disease Rating Scale III (UPDRS III). For all patients, 99m Tc-TRODAT single-photon emission
computed tomography (SPECT) and MRI volumetry were performed. Patients were followed up for 1 year and examined for final
diagnosis.
RESULTS: According to the quantitative 99m Tc-TRODAT analysis, all of the specific binding ratio (SBR) parameters, including
right, left, and bilateral SBRs, were significantly higher in the non-Parkinsonian patients. Also, the results indicated a high
diagnostic accuracy for both quantitative 99m Tc-TRODAT analysis (about 88% for SBR parameters) and MRI volumetry (71% for
bilateral olfactory bulbs volume) in diagnosing PD. Regarding the diagnosis of PD, there were no significant differences between
quantitative scan results and olfactory bulb volumetry according to the area under the receiver operating characteristic curves.
CONCLUSION: 99m Tc-TRODAT has a higher accuracy in differentiation of early PD from non-Parkinsonian conditions, particularly
essential tremor. Olfactory bulbs volumetry by using MRI can also serve as a potential alternative method in this regard.

Keywords: Parkinson’s disease, brain MRI volumetry, 99m TC-TRODAT, SPECT, extrapyramidal syndromes.

Acceptance: Received February 4, 2020, and in revised form May 18, 2020. Accepted for publication May 21, 2020.
Correspondence: Address correspondence to Vahid Reza Ostovan, MD, Clinical Neurology Research Center, Shiraz University of Medical Sciences,
Shiraz 7193635899, Iran. E-mail: ostovanv@gmail.com.

Acknowledgments and Disclosure: This article is in partial fulfillment of thesis project for specialty of neurology degree by Dr. “Mohammad Reza
Hussein Tehrani” in the School of Medicine and financially supported by the Office of Vice Chancellor for Research in Shiraz University of Medical
Sciences (grant no#15270).The authors would like to thank Center for Development of Clinical Research of Namazee Hospital for statistical assistance.
We appreciate Dr. Nasrin Shokrpour at the Research Consultation Center of Shiraz University of Medical Sciences for improving the use of English
language/grammar in this manuscript. The authors declare that they have no conflict of interests related to this manuscript.

J Neuroimaging 2020;0:1-7.
DOI: 10.1111/jon.12740

Introduction be occasionally challenging. The reported error rate in the clin-

Parkinson’s disease (PD) is a progressive multisystem neurode-
generative disorder affecting the elderly. It is considered as
the second most common neurodegenerative disease in the
world.1,2 The main characteristics include deficits in motor
functions, such as bradykinesia, akinesia, rigidity, postural in-
stability, and resting tremor.3 It has been demonstrated that
approximately 25% of PD patients have been diagnosed with
other conditions, such as essential tremors (ETs) and atypical
Parkinsonian syndromes.4-7 ET is one of the most frequent neu-
rological disorders, the prevalence of which rises with age.8,9
The knowledge of tremor, particularly ET, has developed no-
ticeably over the past decades.10 Although PD and ET are two
distinct common movement disorders, growing evidence has
suggested an association and coexistence of these two disor-
ders in some individual patients.11-15 As a result of overlapping
symptoms and signs, differentiation between PD and ET might
ical diagnosis of these disorders is about 24%.15,16 In the early
stages of PD, conventional brain magnetic resonance imaging
(MRI) does not manifest any abnormalities and is only use-
ful for excluding other diagnoses; however, volumetric MRI
can quantify the volume loss in different parts of the brain of
parkinsonian patients.17 Previous investigations have reported
changes in various parts of the brain in PD patients, includ-
ing putamen, caudate, and hippocampus.18,19 Regularly, brain
MRI is used as an assistant tool in differentiating PD from other
neurodegenerative Parkinson-like disorders. Recent investiga-
tions have focused on basal ganglia, whereas the degenerative
process is not limited to the dopaminergic system.20 It has been
suggested that there are significant changes in nigrostriatal, ol-
factory bulb, hippocampus, piriform, and orbitofrontal cortices
volumes via MRI volumetric evaluations in early stages of the
brain disease.21

◦ 2020 by the American Society of Neuroimaging

C 1
 A noninvasive embodiment of the striatal dysfunction in the
patients with PD has been provided by positron emission to-
mography (PET) and single photon emission computed tomog-
raphy (SPECT). Additionally, they have been recently used as
in vivo biomarkers to distinguish PD from ET. Brain imaging
via dopamine transporter (DAT) ligand, in the early phases
of PD, demonstrates a high sensitivity for detecting degenera-
tion of the dopaminergic neurons.22 There are various synthe-
sized radioligands for PET and SPECT imaging with high bind-
ing affinity and significant imaging characteristics for DAT.23-26
TRODAT-1 radionuclide, a cocaine analog, has been recently
developed as a DAT-SPECT imaging tracer.23,27,28 This agent
has been suggested as an imaging tool for the assessment of the
presynaptic neuronal function. In general population, striatal
TRODAT uptake is normal, while there is a significant decline
in patients with PD.29 In the last decades, different studies have
claimed that this modality could be useful for screening PD
and differentiating it from ET.30-32 Although most of the I-123-
containing radiotracers are more widely available with higher
image quality, technetium-99m (99m Tc) is also suitable for bind-
ing with DAT in routine clinical studies. In addition, 99m Tc-
based radiopharmaceuticals are used in most nuclear medicine
protocols and are less expensive.27 Kung et al27,33 demonstrated
that 99m Tc-TRODAT-1 SPECT is an appropriate ligand with a
high affinity and specificity for DAT in human imaging stud-
ies. Furthermore, numerous studies have revealed that 99m Tc-
TRODAT-1 SPECT has a high sensitivity and specificity in
distinguishing movement disorders, such as PD and ET, from
each other.30,34
Given that PD and ET are common neurological disorders
in the elderly, and that some of their features may overlap,
treatment approaches for patients with PD and ET require an
early and precise diagnosis of these diseases. Hence, the current
study aimed to compare the diagnostic values of brain volumet-
ric MRI and 99m Tc-TRODAT in differentiating PD from other
extrapyramidal syndromes in the early stages of the disease.
Methods
Patients
This prospective, double-blind study was conducted on 38 con-
secutive patients in the movement disorder clinic of Shiraz Uni-
versity of Medical Sciences, Shiraz, Iran. We recruited patients
with equivocal signs and symptoms who had been visited by
an expert neurologist and their diagnoses were not established
clinically from May to November 2017. Patients younger than
70 years old with less than 3 years of extrapyramidal symp-
toms (particularly tremor) were included. Exclusion criteria
were history of repeated strokes or head injury with stepwise
progression of parkinsonian features, encephalitis, oculogyric
crises, neuroleptic treatment at onset of symptoms, supranu-
clear gaze palsy, cerebellar signs, early severe autonomic in-
volvement, unexplained Babinski sign, and exposure to toxic
agents. Moreover, to avoid involving demented individuals, the
patients who scored <24 (for educated individuals) and <21 (for
noneducated individuals) on the Mini Mental State Examina-
tion (MMSE) were excluded. Ultimately, 38 patients who had
fulfilled the inclusion and exclusion criteria provided written
informed consent and were included in the analysis. Clinical
severity was determined by a staff neurologist according to the
Unified Parkinson’s Disease Rating Scale III (UPDRSIII).
2 Journal of Neuroimaging Vol 0 No 0 XXXX 2020
The enrolled patients were referred to nuclear medicine
and radiology departments for obtaining DAT imaging and
brain MRI volumetry, respectively. The diagnosis of PD is still
based on clinical criteria, such as the United Kingdom Parkin-
son’s Disease Society Brain Bank task force clinical diagnostic
criteria.35 Therefore, patients were followed up for 1 year and
visited by an expert neurologist at regular intervals for final
diagnosis. In this follow-up period, diagnosis of 34 out of 38
patients became clinically definite. The clinical diagnosis of the
remainder four patients was still uncertain; therefore, we ex-
cluded these patients from our study. At the end, results of DAT
scan and MRI volumetry of 34 patients were evaluated and cor-
related with clinical diagnosis for determinations of specificity
and sensitivity of these modalities. The protocol of this study
was approved by the ethics committee of Shiraz University of
Medical Sciences (Approval No# 15270).
SPECT Acquisition and Processing
For all patients referred for DAT imaging, 20 mCi (740 MBq)
99m
Tc-TRODAT was injected followed by SPECT acquisition
after 4 hours. Data were obtained using a dual-head SPECT
system (Infinia Hawkeye, GE Healthcare) equipped with a low-
energy high-resolution collimator, using a 180° noncircular or-
bit, with 60 projection angles for each detector and a 64 ×
64 matrix size. A symmetrical 10% wide energy window for
the acquisition was centered at 140 keV. SPECT data recon-
struction was performed using ordered subsets expectation-
maximization (order: 4; subset: 10; Butterworth post-filter)
and Chang’s attenuation correction. After reconstruction, the
trans-axial slice with maximum striatal count was selected and
summed with a slice before and a slice after it to make a new
trans-axial image, which was a composite of three slices. For
quantitative analysis, a rectangular region of interest (ROI) with
fixed volume of 176 mm2 , which was derived from normal CT
images, was manually drawn and copied for the left and right
striatum in composite images of all the patients. For evaluation
of nonspecific binding ratio (SBR) of TRODAT in the brain,
a circular ROI with 103 mm2 area was also placed on the oc-
cipital region of the brain images as background. To compare
quantitative results, the SBRs, defined as [mean count of the stri-
atal region (Cs) – mean count of background (Cb)]/Cb, were
calculated for each patient. Striatal asymmetry index (SAI) was
calculated as ‫(׀‬right SBR – left SBR)/((right SBR+left SBR)/2)‫׀‬.
Magnetic Resonance Imaging
For obtaining brain ROI volumes, the patients were examined
using a 1.5 T MRI (Siemens Magnetomavanto B15 Signo ma-
chine) with a standard quadrature head coil. All participants
underwent the same MRI protocol (characterized by MPRAGE
sequence with 1 mm slice thickness; voxel size 1 × 1 × 1 mm3 ;
field-of-view 250 × 250 mm2 ; matrix size 256 × 256). Cushions
and adhesive medical tape were used to center the patients in
the head coil and limit their movements. Volumetric analysis of
the ROIs (including one ROI for bilateral olfactory bulbs, and
separate ROIs for the right and left putamen nucleus, caudate
nucleus, and hippocampus) was performed using the Medical
Imaging Interaction Toolkit (MITK) (ITK 4.7.1 VTK 6.2.0 Qt
5.4.2 MITK 2016.3.0) software. All ROIs were selected and
cropped according to the standard anatomical brain atlases by
one investigator who was blinded to the patient’s clinical diag-
nosis. A second investigator estimated the ROIs for reliability of
Table 1. Demographic Characteristics of Patients in the PD and Non-Parkinsonian Groups

PD Non-Parkinsonian
Variables N (%) or Mean ± SD N (%) or Mean ± SD Pvalue

Bradykinesia in examination 9 (52.9) 3 (17.6) .03

Gait problems in examination 6 (35.3) 1 (5.8) .04
Tremor in examination 15 (88.2) 17 (100) .145
Sex
Male 8 (47.1) 6 (35.3) .36
Female 9 (52.9) 11 (64.7)
Age (years) 62.82 ± 14.66 53.06 ± 13.90 .06
Disease duration (months) 18.35 ± 9.95 16.41 ± 9.27 .56
Symptoms laterality at the onset of disease
RT 11 (64.7) 3 (17.6) .000
LT 6 (35.3) 1 (5.8)
Symmetric 0 13 (76.4)
UPDRS III score at base 7.53 ± 5.53 4.71 ± 6.16 .17
UPDRS III score on the follow-up 8.00 ± 5.59 4.88 ± 5.68 .12
UPDRS III tremor subscore at base 4.71 ± 4.1 4.05 ± 5.20 .69
UPDRS III tremor subscore on the follow-up 5.24 ± 4.37 4.24 ± 5.29 .55
MMSE 26.73 ± 2.28 27.18 ± 2.31 .59

LT, left; MMSE, mini mental state examination; N, number; PD, Parkinson’s disease; RT, right; SD, standard deviation; UPDRS, unified Parkinson’s disease rating
scale.

measurements. The nuclei borders or boundaries were defined Table 2. TRODAT Scans Parameters in the Two PD and Non-
according to the previous studies.36,37 Parkinsonian Groups

PD Non-Parkinsonian
Statistical Analysis Variables Mean (SD) in mm3 Mean (SD) in mm3 Pvalue
Data analysis was done using statistical software SPSS version
SAI .35 (.67) .10 (.06) .14
16 and the P values less than .05 were considered as statis- Right SBR .33 (.16) .53 (.11) .000
tically significant. Descriptive statistical analysis was used to Left SBR .30 (.18) .53 (.12) .000
compare demographic characteristics. Independent Student’s Bilateral SBR .32 (.16) .53 (.11) .000
t-test and Bonferroni correction were performed for comparing
PD, Parkinson’s disease; SAI, striatal asymmetry index; SBR, specific binding
the differences of quantitative data and multiple comparisons ratio; SD, standard deviation.
correction, respectively. Bivariate correlations (Pearson’s r)
were calculated to determine the correlation of disease duration
and severity with scan parameters and severity of volume loss
in all measured ROIs. In addition, we used Medcalc software
(Version 14.8.1) to generate and compare receiver operating and bilateral SBRs, were significantly higher among the non-
characteristic (ROC) curves and to determine the sensitivity Parkinsonian than the PD patients (P < .0001 with 95%
and specificity of each test, and also cutoff point for each value. confidence interval: .11-.29, .12-.33, and .11-.31, respectively)
(Table 2).
As shown in Table 3, the volume of the left caudate nucleus
Results was significantly less in PD than the non-Parkinsonian group
Among all 34 patients included in the study, 17 patients were (P = .02), and the bilateral olfactory bulbs volume loss showed
finally diagnosed clinically as PD (11 were right-sided onset and borderline significance (P = .05); however, after Bonferroni cor-
6 were left-sided onset) and 17 patients as non-Parkinsonian rection, Pvalue < .005 was considered as statistically significant
syndromes. and neither left caudate nucleus nor bilateral olfactory bulbs
The qualitative demographic and clinical parameters of pa- volume changes remained significant after correction. Other
tients in the PD and non-Parkinsonian groups are shown in ROIs (including the right and bilateral caudate nucleus, right,
Table 1. No significant differences were found in age and sex left, and bilateral putamen and hippocampus) did not indicate
distributions between the two groups. However, the results re- significant volumetric differences between the two groups. To
vealed that bradykinesia (P = .03) and gait problems (P = .04) find the best scans and volumetric accuracy in predicting and
were significantly more prevalent in the PD group than the diagnosing the kind of the disease, we analyzed the area under
non-Parkinsonian group. The mean UPDRS motor score (III) ROC curves (AUC), sensitivity, specificity, and Youden’s cutoff
at the base of the study was 4.71 in the non-Parkinsonian and value for all of the scans and volumetric parameters obtained
7.53 in the PD group. After 1-year follow-up, the mean UPDRS from 99m TC-TRODAT SPECT and brain MRI (Table 4).These
III scores were 4.88 and 8.0 in the non-Parkinsonian and PD results revealed a significant accuracy of the bilateral olfactory
groups, respectively. Moreover, the mean MMSE score was bulbs volume (P = .03, 95% confidence interval: .52-.85), right,
27.18 in the non-Parkinsonian patients and 26.73 in the PD left, and bilateral SBRs (P < .0001, 95% confidence interval:
patients. .717-.963, .719-.964, and .730-.969, respectively). However, the
Based on the quantitative analysis of 99m TC-TRODAT us- ROC curves for other brain ROIs volume and SAI showed no
ing t-test, all of the SBR parameters, including right, left, statistically significant accuracy.

Hossein-Tehrani et al: MRI and TRODAT-SPECT 3

Table 3. MRI-Based Volumes of ROIs in the Two PD and Non-Parkinsonian Groups

PD Non-Parkinsonian
Variables Mean (SD) in mm3 Mean (SD) in mm3 Pvalue *

Right caudate nucleus volume (mm3 ) 3,001.88 (608.08) 3,143.00 (664.63) .52
Left caudate nucleus volume (mm3 ) 2,757.94 (691.27) 3,293.88 (638.46) .02
Bilateral caudate nucleus volume (mm3 ) 2,879.90 (614.90) 3,218.40 (625.78) .12
Right putamen nucleus 3,482.76 (657.40) 3,635.18 (507.70) .45
Left putamen nucleus volume (mm3 ) 3,475.59 (627.56) 3,755.00 (485.48) .15
Bilateral putamen nucleus volume (mm3 ) 3,479.18 (600.11) 3,695.10 (459.77) .25
Right hippocampus volume (mm3 ) 4,328.12 (985.31) 4,694.82 (984.81) .29
Left hippocampus volume (mm3 ) 4,001.71 (759.34) 4,479.24 (995.47) .13
Bilateral hippocampus volume (mm3 ) 4,164.90 (842.19) 4,587 (983.46) .19
Bilateral olfactory bulbs volume (mm3 ) 275.65 (115.83) 367.00 (137.07) .05
∗
Pvalue <. 005 is considered as statistically significant after Bonferroni correction.
PD, Parkinson’s disease; ROI, region of interest; SD, standard deviation.

Table 4. Accuracy of TRODAT Scan and MRI Volumetry Parameters in Diagnosing PD

Variables AUC Sensitivity Specificity

(%) (%) (%) value Cutoff * Pvalue

TRODAT SPECT SAI 66 58 82 >.16 .09

Right SBR 87 76 100 ࣘ.4 .000
Left SBR 88 82 94 ࣘ.36 .000
Bilateral SBR 89 78 100 ࣘ.36 .000
MRI volumetry Right caudate nucleus 56 47 76 ࣘ2807 .58
Left caudate nucleus 67 53 88 ࣘ2593 .08
Bilateral caudate nucleus 62 47 82 ࣘ2643 .23
Right putamen nucleus 59 65 71 ࣘ3509 .38
Left putamen nucleus 64 71 59 ࣘ3702 .15
Bilateral putamen nucleus 64 71 65 ࣘ3602 .15
Right hippocampus 61 65 65 ࣘ4402 .25
Left hippocampus 65 82 53 ࣘ4377 .12
Bilateral hippocampus 63 65 65 ࣘ4311 .19
Bilateral olfactory bulbs 71 83 60 ࣘ309 .03

∗
Cutoff value consistent with the maximum Youden’ s index value.
AUC, area under the curve; PD, Parkinson’s disease; SAI, striatal asymmetry index; SBR, specific binding ratio.

To find out whether 99m Tc-TRODAT or MRI quantitative

analysis is more accurate in distinguishing PD from other ex-
trapyramidal syndromes, we made a comparison between AUC
of 99m Tc-TRODAT and MRI quantitative parameters (Fig 1).
Comparison between ROC curves of the scan (left, right, and
bilateral SBRs) and MRI (bilateral olfactory bulbs) did not show
significant differences between the two methods (left SBR vs.
olfactory bulbs, P = .19; right SBR vs. olfactory bulbs, P = .16;
and bilateral SBR vs. olfactory bulbs, P = .15). Also, there were
no significant differences between any parameters of SBR.
Pearson’s correlation coefficients showed significant nega-
tive relationships between SBR parameters and left putamen
volume and severity and duration of disease in the PD group,
but other scan and MRI-based values did not indicate statisti-
cally significant correlations (Table 5).

Discussion
Because of the high error rates in the clinical diagnosis of PD
at the onset of symptoms,38,39 the differential diagnosis in early
stage of the disease is considered as one of the most challenging
subjects in neurology. Accordingly, this study aimed to compare Fig 1. Comparison of the AUC of the best quantitative parameters
the sensitivity and specificity of the brain MRI volumetry with within each analysis including bilateral, left, and right SBR and bilat-
99m eral olfactory bulbs for distinguishing between Parkinson’s disease
Tc-TRODAT SPECT in order to discover which method and non-Parkinsonian groups.
favors the diagnosis of PD in early phases. The findings revealed

4 Journal of Neuroimaging Vol 0 No 0 XXXX 2020

Table 5. Correlations of Scan and MRI Parameters with Clinical Characteristics in the PD Group
Baseline UPDRS II
Variables r Pvalue
Right SBR –.67 .003
Left SBR –.65 .005
Bilateral SBR –.68 .003
Left putamen volume –.48 .05
Only significant correlations between striatal dopamine transporter uptake and MRI volumetry parameters and disease severity and duration are shown.
PD, Parkinson’s disease; r, Pearson’s correlation coefficient; SBR, specific binding ratio; UPDRS, unified Parkinson’s disease rating scale.
that although some demographic parameters, such as age and
sex, did not show significant differences between the two groups
of PD and non-Parkinsonian, bradykinesia and gait problems
were significantly more frequent in the PD group. This was
predictable due to characteristics of PD.40,41 Due to overlapping
patterns of tremor in some cases and the resultant complexities
in clinical diagnosis, the patients in this study undertook 99m Tc-
TRODAT scan and volumetric brain MRI. Both groups had
almost the same disease duration. UPDRS III score was higher
in the PD group (due to more prominent symptoms), but this
difference was not statistically significant; this could be due to
the short disease duration at the time of evaluations.
Our findings revealed that 99m TC-TRODAT SPECT in com-
parison to MRI-base parameters had higher accuracy in differ-
entiating PD from other extrapyramidal syndromes such as ET.
Therefore, 99m Tc-TRODAT SPECT is a valuable method for di-
agnosis of patients with early PD. In this regard, previous studies
also demonstrated a high diagnostic value for 99m Tc-TRODAT
SPECT in PD.30,31,42 Although there are various methods for
calculation of SBR with different shapes and sizes of ROIs, simi-
lar results have been reported with high accuracy for this param-
eter in different studies. Our results suggested that the analysis
using the mean of the contralateral and ipsilateral striatal DAT
uptake improved the accuracy of SPECT for detection of PD in
early phases, which is consistent with the previous findings.43,44
In our study, the SBR parameters of 99m Tc-TRODAT SPECT
showed significant negative correlations with the severity and
duration of disease in the PD group, as in the previous report for
123
I-β-CIT.45 Therefore, SBR measurement is useful for regular
checking of disease progression in PD. Furthermore, SAI (as an
indicator of striatal asymmetry) is another quantitative param-
eter in 99m Tc-TRODAT SPECT, which is considered to be an
additional diagnostic criterion for PD. According to the results
of previous studies, the diagnostic value of SAI in differentiating
PD from other extrapyramidal syndromes is still questionable.
Some prior studies showed that SAI could be effective in differ-
entiating idiopathic PD from ET and vascular parkinsonism46
and also PD from other parkinsonian syndromes.47 However,
our results revealed lower accuracy of SAI in differentiating
early PD from other extrapyramidal syndromes (specificity:
82%, sensitivity: 58%, and AUC: .66), similar to Hwang et al’s31
reports. The difference between radiotracers pharmacokinet-
ics may explain these differences. There are few studies that
directly compare 123 I-FP CIT with 99m Tc-TRODAT. Both of
these radiotracers have the same awaiting time about 4 hours
from injection to taking an image.42 Van Laere et al48 reported
that 123 I-FP CIT had higher striatum-occipital cortex binding
ratio in comparison with 99m Tc-TRODAT, which led to the
increased accuracy in detecting PD in early stages. However,
Follow-up UPDRS III Disease Duration
r Pvalue r Pvalue
–.73 .001 –.75 .001
–.70 .002 –.75 ࣘ.001
–.74 .001 –.78 ࣘ.001
–.50 .04 –.49 .048
123
I-FP CIT showed 9.6%/decade reduction in binding ratio
with aging in healthy controls.49 Therefore, 99m Tc-TRODAT
may be a preferable radiotracer for SPECT imaging in elderly.
Both ipsilateral and contralateral striatum to the more affected
limbs exhibit reduced DAT uptake in SPECT imaging in early
phases of PD, although PD is clinically unilateral at the onset of
symptoms.50 This may be an explanation for our findings that
SAI was less conclusive than SBRs in diagnosing PD in early
stages.
PD is a neurodegenerative disease with ongoing neuronal
loss in different regions of brain as the disease progressed. In
the prodromal or early motor stages of PD, loss of neurons and
the resulting volume loss are not visually apparent using con-
ventional MRI. Therefore, for quantifying the degree of volume
loss in the various parts of the brain in the PD, it is necessary
to utilize advanced MRI techniques such as volumetry. Conse-
quently, MRI volumetry can be a useful diagnostic tool for the
detection of PD in the early phases and differentiating it from
other extrapyramidal syndromes.17,19
In the present study, all the participants were in early stages
of the disease (less than 3 years since the initial symptoms) and
none of them was demented (regarding to MMSE score). As a
result, our findings did not indicate significant changes in the
hippocampus volume in either of the two groups of PD and
non-Parkinsonian. In contrast, Gee et al examined PD patients
with cognitive decline and detected atrophy in the uncus at
the baseline in all patients. Also, they disclosed significant atro-
phy in the left hippocampus and parahippocampal region after
developing dementia.51
ROIs were selected and cropped manually via MITK soft-
ware (as mentioned earlier) based on anatomical atlases in our
study. Some previous studies also demonstrated that manual
brain volumetry had a higher accuracy compared with auto-
mated methods (eg, Freesurfer software).52 On the other hand,
Heim et al claimed that automated approaches could be more
accurate by reducing individual errors in segmentation.19
It was reported that the most significant volume loss in PD
patients’ brain occurred in substantia nigra (SN), which could
be captured by 3.0 Tesla MRI. This criterion can be useful for
early diagnosis of PD.19 However, lack of access to 3.0 T MRI
was one of the limitations in our study. Therefore, we were
not able to evaluate the SN volume. In addition, it has been
indicated that SN morphological changes can be detected by
1.5 T MRI in advanced stages of the disease.31 In that way,
SN volume can be measured more accurately in further studies
through extending the follow-up duration for testing more ad-
vanced stages of PD. On the other hand, some studies showed
decreased volume of different regions in the brain of PD pa-
tients. For instance, Heim et al reported significant changes in
Hossein-Tehrani et al: MRI and TRODAT-SPECT 5
the putamen nucleus volume19 and Tanner et al53 suggested
partial negative correlation between disease duration and puta-
men volume in patients with PD. Similarly, we demonstrated
partial negative correlations between left putamen volume and
disease duration and severity. Our explanation in regard to the
left side predominance is that most of the recruited patients with
PD in our study had right-sided disease onset. In the present
study, bilateral olfactory bulbs volume was identified as the
most sensitive marker of MRI volumetry (83%) in diagnosing
early PD. This sensitivity was close to scan results though we
measured that with lower resolution imaging sequences (1.5 T
MRI). Through enhancing the imaging quality to 3.0 T, the
sensitivity can be evaluated with higher accuracy. However,
the specificity was about 60%, which implies the presence of
false-positive results. Hummel et al also performed 1.5T MRI
for evaluating the volume changes in the olfactory bulb. They
showed that there was no difference in the olfactory bulb vol-
ume between the PD patients and normal group. They claimed
that alterations in olfactory tests in PD patients could be a result
of central nervous system (CNS) changes in these patients.54
On the contrary, Brodoehl et al, by using 3.0 Tesla MRI, re-
ported that a significant loss in the olfactory bulbs volume and
specifically in its height on the left side was seen in patients with
PD.55
In our study, none of the MRI morphometry parame-
ters showed significant differences between PD and the non-
Parkinsonian group in the early stages of the disease. There-
fore, on the basis of our findings, practical usefulness of MRI
volumetry is limited in distinguishing early and mild PD from
other extrapyramidal syndromes; as a result, further studies
with higher resolution MRI are necessary to elucidate the effi-
cacy of MRI mophometry in diagnosing PD in the early phases.
There are only a few studies that have directly compared
DAT SPECT with other modalities for diagnosis of early PD.
For instance, Georgiopoulos et al evaluated the efficacy of DAT
SPECT and olfactory testing in diagnosing PD and atypical
parkinsonian syndromes; they concluded that DAT imaging
had higher accuracy than olfactory testing in differentiating
PD. Furthermore, they proved that the combination of these
two diagnostic methods could be more effective for accurate
diagnosis than either of the two independently.56 In this re-
gard, our study revealed a higher accuracy of 99m Tc-TRODAT
SPECT as compared to MRI volumetry for different structures
of the brain.
Among the volumes measured through MITK software, only
bilateral olfactory bulb volume had relatively enough accuracy
to differentiate PD from other extrapyramidal syndromes. This
could be due to the fact that we used manual MRI volumetry,
which is an operator-dependent procedure. In contrast to our
findings, Scherfler et al, by using automated and not manual
methods, proved that putaminal volume (with 97% accuracy)
could differentiate PD from other parkinsonian syndromes.
This difference might be due to the longer disease duration
and follow-up in their study in comparison to ours.57
This study showed higher accuracy for 99m Tc-TRODAT in
comparison to MRI, in the early stages of PD. On the other
hand, brain MRI is less expensive and is more available than
TRODAT scan; also, considering the acceptable results of ol-
factory bulb volumetry, it can be a useful alternative marker in
differentiating PD from other extrapyramidal syndromes when
TRODAT SPECT is not available. Nonetheless, studies with
6 Journal of Neuroimaging Vol 0 No 0 XXXX 2020
higher brain MRI resolution and longer follow-up duration are
recommended to further investigate the accuracy of MRI vol-
umetry in comparison to other modalities.
References
1. DeMaagd G, Philip A. Parkinson’s disease and its management:
part 1: disease entity, risk factors, pathophysiology, clinical presen-
tation, and diagnosis. P T 2015;40:504-32.
2. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease:
why is advancing age the biggest risk factor? Ageing Res Rev
2014;14:19-30.
3. Juh R, Kim J, Moon D, et al. Different metabolic patterns analysis of
Parkinsonism on the 18F-FDG PET. Eur J Radiol 2004;51:223-33.
4. Kägi G, Bhatia KP, Tolosa E. The role of DAT-SPECT in move-
ment disorders. J Neurol Neurosurg Psychiatry 2010;81:5-12.
5. Park E. A new era of clinical dopamine transporter imaging using
123I-FP-CIT. J Nucl Med Technol 2012;40:222-8.
6. Wang L, Zhang Q, Li H, et al. SPECT molecular imaging in Parkin-
son’s disease. J Biomed Biotechnol 2012;2012:412486.
7. Patel A, Simon S, Elangoven IM, et al. Dopamine transporter imag-
ing with Tc-99m TRODAT-1 SPECT in Parkinson’s disease and its
correlation with clinical disease severity. Asia Ocean J Nucl Med
Biol 2019;7:22-8.
8. Louis ED. Essential tremors: a family of neurodegenerative disor-
ders? Arch Neurol 2009;66:1202-8.
9. Choi SM, Kim BC, Chang J, et al. Comparison of the brain vol-
ume in essential tremor and Parkinson’s disease tremor using an
automated segmentation method. Eur Neurol 2015;73:303-9.
10. Benito-León J. Essential tremor: from a monosymptomatic disorder
to a more complex entity. Neuroepidemiology 2008;31:191-2.
11. Rocca WA, Bower JH, Ahlskog JE, et al. Increased risk of essential
tremor in first-degree relatives of patients with Parkinson’s disease.
Mov Disord 2007;22:1607-14.
12. Tan EK, Lee SS, Lum SY. Evidence of increased odds of essential
tremor in Parkinson’s disease. Mov Disord 2008;23:993-7.
13. Benito-Leon J, Louis E, Bermejo-Pareja F. Risk of incident Parkin-
son’s disease and parkinsonism in essential tremor: a population
based study. J Neurol Neurosurg Psychiatry 2009;80:423-5.
14. Baumann CR. Epidemiology, diagnosis and differential diagno-
sis in Parkinson’s disease tremor. Parkinsonism Relat Disord
2012;18:S90-2.
15. Thenganatt MA, Louis ED. Distinguishing essential tremor from
Parkinson’s disease: bedside tests and laboratory evaluations. Ex-
pert Rev Neurother 2012;12:687-96.
16. Tarakad A, Jankovic J. Essential tremor and Parkinson’s disease:
exploring the relationship. Tremor Other Hyperkinet Mov (N Y)
2019;8:589.
17. Mahlknecht P, Hotter A, Hussl A, et al. Significance of MRI in
diagnosis and differential diagnosis of Parkinson’s disease. Neu-
rodegener Dis 2010;7:300-18.
18. Elshafey RA, Eltomey MA, Faed H, et al. Volumetric brain MRI
changes in Parkinson’s disease. Presented at the 27th European
Congress of Radiology, Vienna; 2015.
19. Heim B, Krismer F, De Marzi R, et al. Magnetic resonance imaging
for the diagnosis of Parkinson’s disease. J Neural Transm (Vienna)
2017;124:915-64.
20. Lin WC, Chou KH, Lee PL, et al. Parkinson’s disease: diagnostic
utility of volumetric imaging. Neuroradiology 2017;59:367-77.
21. Tanik N, Serin HI, Celikbilek A, et al. Associations of olfactory bulb
and depth of olfactory sulcus with basal ganglia and hippocampus
in patients with Parkinson’s disease. Neurosci Lett 2016;620:111-4.
22. Huang WS, Chiang YH, Lin JC, et al. Crossover study of (99m)Tc-
TRODAT-1 SPECT and (18)F-FDOPA PET in Parkinson’s disease
patients. J Nucl Med 2003;44:999-1005.
23. Booij J, Habraken JB, Bergmans P, et al. Imaging of dopamine
transporters with iodine-123-FP-CIT SPECT in healthy controls
and patients with Parkinson’s disease. J Nucl Med 1998;39:
1879-84.
24. Booij J, Sokole EB, Stabin MG, et al. Human biodistribution and
dosimetry of [123 I] FP-CIT: a potent radioligand for imaging of
dopamine transporters. Eur J Nucl Med 1998;25:24-30.
25. Kazumata K, Dhawan V, Chaly T, et al. Dopamine trans-
porter imaging with fluorine-18-FPCIT and PET. J Nucl Med
1998;39:1521-30.
26. Rinne JO, Ruottinen H, Bergman J, et al. Usefulness of a dopamine
transporter PET ligand [(18)F]beta-CFT in assessing disability
in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:
737-41.
27. Kung HF, Kim H-J, Kung M-P, et al. Imaging of dopamine trans-
porters in humans with technetium-99m TRODAT-1. Eur J Nucl
Med 1996;23:1527-30.
28. Asenbaum S, Pirker W, Angelberger P, et al. [123 I]beta-CIT
and SPECT in essential tremor and Parkinson’s disease. J Neural
Transm (Vienna) 1998;105:1213-28.
29. Kung HF, Kung MP, Wey SP, et al. Clinical acceptance of a molec-
ular imaging agent: a long march with [99mTc] TRODAT. Nucl
Med Biol 2007;34:787-9.
30. Huang WS, Lee MS, Lin JC, et al. Usefulness of brain 99m Tc-
TRODAT-1 SPET for the evaluation of Parkinson’s disease. Eur J
Nucl Med Mol Imaging 2004;31:155-61.
31. Hwang WJ, Yao WJ, Wey SP, et al. Reproducibility of 99mTc-
TRODAT-1 SPECT measurement of dopamine transporters in
Parkinson’s disease. J Nucl Med 2004;45:207-13.
32. Weng YH, Yen TC, Chen MC, et al. Sensitivity and specificity
of 99mTc-TRODAT-1 SPECT imaging in differentiating patients
with idiopathic Parkinson’s disease from healthy subjects. J Nucl
Med 2004;45:393-401.
33. Kung MP, Stevenson DA, Plössl K, et al. [99m Tc] TRODAT-1: a
novel technetium-99m complex as a dopamine transporter imaging
agent. Eur J Nucl Med 1997;24:372-80.
34. Mozley PD, Schneider JS, Acton PD, et al. Binding of [99mTc]
TRODAT-1 to dopamine transporters in patients with Parkin-
son’s disease and in healthy volunteers. J Nucl Med 2000;41:
584-9.
35. Gibb WR, Lees AJ. The relevance of the Lewy body to the patho-
genesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psy-
chiatry 1988;51:745-52.
36. Abedelahi A, Hasanzadeh H, Hadizadeh H, et al. Morphometric
and volumetric study of caudate and putamen nuclei in normal in-
dividuals by MRI: effect of normal aging, gender and hemispheric
differences. Pol J Radiol 2013;78:7-14.
37. Mohandas AN, Bharath RD, Prathyusha PV, et al. Hippocampal
volumetry: normative data in the Indian population. Ann Indian
Acad Neurol 2014;17:267-71.
38. Bajaj N, Hauser RA, Grachev ID. Clinical utility of dopamine
transporter single photon emission CT (DaT-SPECT) with (123I)
ioflupane in diagnosis of parkinsonian syndromes. J Neurol Neu-
rosurg Psychiatry 2013;84:1288-95.
39. Pagan FL. Improving outcomes through early diagnosis of Parkin-
son’s disease. Am J Manag Care 2012;18:S176-82.
40. Magrinelli F, Picelli A, Tocco P, et al. Pathophysiology of
motor dysfunction in Parkinson’s disease as the rationale for
drug treatment and rehabilitation. Parkinsons Dis 2016;2016:
9832839.
41. Chen P-H, Wang R-L, Liou D-J, et al. Gait disorders in Parkin-
son’s disease: assessment and management. Int J Gerontol 2013;7:
189-93.
42. Wang J, Jiang YP, Liu XD, et al. 99mTc-TRODAT-1 SPECT study
in early Parkinson’s disease and essential tremor. Acta Neurol
Scand 2005;112:380-5.
43. Tissingh G, Bergmans P, Booij J, et al. Drug-naive patients with
Parkinson’s disease in Hoehn and Yahr stages I and II show a
bilateral decrease in striatal dopamine transporters as revealed by
[123I]beta-CIT SPECT. J Neurol 1998;245:14-20.
44. Chou KL, Hurtig HI, Stern MB, et al. Diagnostic accuracy of
[99mTc]TRODAT-1 SPECT imaging in early Parkinson’s disease.
Parkinsonism Relat Disord 2004; 10:375-9.
45. Seibyl JP, Marek KL, Quinlan D, et al. Decreased single-photon
emission computed tomographic [123I] β -CIT striatal uptake cor-
relates with symptom severity in Parkinson’s disease. Ann Neurol
1995;38:589-98.
46. Contrafatto D, Mostile G, Nicoletti A, et al. [123I] FP-CIT-SPECT
asymmetry index to differentiate Parkinson’s disease from vascular
parkinsonism. Acta Neurol Scand 2012;126:12-6.
47. Niimi Y, Ito S, Murate K, et al. Usefulness of combining
123I-FP-CIT-SPECT striatal asymmetry index and cardiac 123I-
metaiodobenzylguanidine scintigraphy examinations for diagnosis
of parkinsonisms. J Neurol Sci 2017;377:174-8.
48. Van Laere K, De Ceuninck L, Dom R, et al. Dopamine transporter
SPECT using fast kinetic ligands: 123 I-FP-β-CIT versus 99m Tc-
TRODAT-1. Eur J Nucl Med Mol Imaging 2004;31:1119-27.
49. Tissingh G, Booij J, Bergmans P, et al. Iodine-123-N-ω-
fluoropropyl-2/β-carbomethoxy3β-(4-iodophenyl)tropane SPECT
in healthy controls and early-stage, drug-naive Parkinson’s disease.
J Nucl Med 1998;39:1143-8.
50. Marek KL, Seibyl JP, Zoghbi SS, et al. [123I]β-CIT SPECT imag-
ing demonstrates bilateral loss of dopamine transporters in hemi-
Parkinson’s disease. Neurology 1996; 46:231-7.
51. Gee M, Dukart J, Draganski B, et al. Regional volumetric
change in Parkinson’s disease with cognitive decline. J Neurol Sci
2017;373:88-94.
52. Tae WS, Kim SS, Lee KU, et al. Validation of hippocampal vol-
umes measured using a manual method and two automated meth-
ods (FreeSurfer and IBASPM) in chronic major depressive disor-
der. Neuroradiology 2008;50:569-81.
53. Tanner JJ, McFarland NR, Price CC. Striatal and hippocampal at-
rophy in idiopathic Parkinson’s disease patients without dementia:
a morphometric analysis. Front Neurol 2017;8:139.
54. Hummel T, Witt M, Reichmann H, et al. Immunohistochemical,
volumetric, and functional neuroimaging studies in patients with
idiopathic Parkinson’s disease. J Neurol Sci 2010;289:119-22.
55. Brodoehl S, Klingner C, Volk GF, et al. Decreased olfactory bulb
volume in idiopathic Parkinson’s disease detected by 3.0-Tesla
magnetic resonance imaging. Mov Disord 2012;27:1019-25.
56. Georgiopoulos C, Davidsson A, Engström M, et al. The diagnostic
value of dopamine transporter imaging and olfactory testing in
patients with parkinsonian syndromes. J Neurol 2015;262:2154-63.
57. Scherfler C, Göbel G, Müller C, et al. Diagnostic potential of auto-
mated subcortical volume segmentation in atypical parkinsonism.
Neurology 2016;86:1242-9.
Hossein-Tehrani et al: MRI and TRODAT-SPECT 7