Individual time course of pre- and postsynaptic PET imaging may improve differential diagnosis of Parkinson’s disease and multiple system atrophy: a case report
Ishibashi et al. BMC Res Notes
Individual time course of pre- and postsynaptic PET imaging may improve differential diagnosis of Parkinson's disease and multiple system atrophy: a case report
Kenji Ishibashi 0
Hirofumi Nishina 1
Kiichi Ishiwata 0
Kenji Ishii 0
0 Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology , 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015 , Japan
1 Department of Neurology, Tokyo Metropolitan Geriatric Hospital , Tokyo 173-0015 , Japan
Background: Many in vivo studies have shown a difference in pre- and/or postsynaptic imaging between Parkinson's disease and multiple system atrophy; however, time course differences in pre- and postsynaptic imaging between Parkinson's disease and multiple system atrophy have not been rigorously investigated. Case presentation: We report serial positron emission tomography images of both dopamine transporters and dopamine D2 receptors, obtained from a Japanese patient with Parkinson's disease who underwent positron emission tomography scanning at ages 71, 72, 74, and 75 years, and another Japanese patient with multiple system atrophy who underwent positron emission tomography scanning at ages 65, 66, and 67 years. Volumes-of-interest were placed on the striatal subregions. The percentage decreases between the first and last images showed that dopamine transporter availability decreased with disease progression in both patients, but that dopamine D2 receptor availability decreased only in the patient with multiple system atrophy. A partial correlation analysis between dopamine transporter and dopamine D2 receptor availability, controlling for the effects of striatal subregional differences, revealed a positive correlation in the patient with multiple system atrophy (r = 0.893, P = 0.0002), but no significant correlation in the patient with Parkinson's disease (r = −0.036, P = 0.89). Conclusions: The time course of pre- and postsynaptic imaging can be considerably different between Parkinson's disease and multiple system atrophy, and may be useful in improving the accuracy of discrimination between Parkinson's disease and multiple system atrophy.
Parkinson's disease; Multiple system atrophy; Dopamine transporter; Dopamine D2 receptor; Positron emission tomography
Parkinson’s disease (PD) and multiple system atrophy
(MSA) are neurodegenerative disorders affecting the
nigrostriatal dopaminergic system. Imaging of
presynaptic neurons using positron emission tomography
(PET) or single photon emission computed tomography
(SPECT) with a radioligand for dopamine
transporters (DATs) cannot distinguish between PD and MSA,
especially on the individual level, because both diseases
cause neuronal degeneration in the substantia nigra (SN)
]. However, PET or SPECT imaging of
postsynaptic neurons with a radioligand for dopamine D2
receptors (D2Rs) can improve the accuracy of discrimination
between PD and MSA, as D2R-expressing striatal
neurons tend to degenerate in MSA but not in PD [
Many in vivo studies have shown a difference in
preand/or postsynaptic imaging between PD and MSA
]; however, differences in the time course of these
measures between PD and MSA have not been rigorously
investigated. In order to address this deficit, we examined
pre- and postsynaptic imaging time courses in a patient
with PD and another with MSA, focusing on the
differential diagnosis between PD and MSA. To quantify
availability of DATs and D2Rs, we used carbon-11-labeled
(11CCFT) and carbon-11-labeled raclopride (11C-raclopride),
Participants comprised two Japanese female patients, one
each with PD and MSA, who were recruited from
crosssectional studies of PD and PD-related disorders at the
Tokyo Metropolitan Institute of Gerontology [
PET data used in this study were collected for research
purposes. All procedures were approved by the Ethics
Committee of the Tokyo Metropolitan Institute of
Gerontology. The two patients provided written informed
consent for publication.
Patient with Parkinson’s disease
Six months after developing a right leg tremor, she was
diagnosed with PD at the age of 71, and underwent
11CCFT and 11C-raclopride PET scanning at ages 71, 72, 74,
and 75 years. On initial examination at age 71, she had
resting tremor and mild rigidity of her right arm and leg.
Levodopa was administered and effective, but without
levodopa a mild postural instability developed at age 74.
Her Hoehn and Yahr stage at ages 71 and 75 were 1 and
Patient with multiple system atrophy
A 65-year-old woman was referred to the neurology
department of our hospital after she had developed a
progressive gait disturbance over the previous 2 years.
On initial examination, she had parkinsonian symptoms
(postural instability, bradykinesia, and mild cogwheel
rigidity on the left side), cerebellar ataxia, pyramidal
sign in both legs, and orthostatic hypotension which
was confirmed by a head-up tilt test. She was diagnosed
with MSA, and underwent 11C-CFT and 11C-raclopride
PET scanning at ages 65, 66, and 67 years. Levodopa
was ineffective. Ages for aid-requiring walking,
wheelchair dependence, and a bedridden state were 65, 66, and
67 years, respectively.
Positron emission tomography scanning and data analysis
PET scanning was performed on a SET-2400 W
scanner (Shimadzu, Kyoto, Japan) in three-dimensional mode
at the Institute. Static emission data were acquired for
75–90 min and 40–55 min after an intravenous bolus
infusion of 11C-CFT and 11C-raclopride, respectively. The
injection doses for both radioligands were 300 MBq.
Volumes-of-interest (VOIs) were placed on the striatal
subregions: the ventral striatum (VST), pre-commissural
dorsal caudate (pre-DCA), post-commissural caudate
(post-CA), pre-commissural dorsal putamen (pre-DPU)
and post-commissural putamen (post-PU) [
visual cortex VOI was also created and used as a reference
]. To estimate DAT and D2R availability in
each VOI, the uptake ratio index (URI) of 11C-CFT and
11C-raclopride was calculated by the following formula:
URI = [(activity in the target region) − (activity in the
visual cortex)]/[(activity in the visual cortex)] . The
normal range for URI is different among striatal
subregions. In order to compare the magnitude of changes in
DAT and D2R availability from the first to last PET images
across striatal subregions, the Z score for each was
calculated in contrast with the mean and standard deviation
(SD) values of controls (with data belonging to the Tokyo
Metropolitan Institute of Gerontology), as in the
following formula: Z score = [(URI in the patient) − (mean URI
in controls)]/[(SD URI in controls)].
In order to compare the time course of pre- and
postsynaptic imaging between the patients with PD and MSA,
we tested the relationship between DAT and D2R
availability with a partial correlation approach, controlling for
the effects of striatal subregional differences, using SPSS
Statistics version 22 (IBM, Armonk, NY). Statistical
significance was set at P < 0.05.
The Z score and percentage decreases of DAT and D R
availability from the first to last PET images in each
striatal subregion and whole striatum are shown in Fig. 1 and
Table 1, respectively. Table 1 shows that DAT availability
decreased with disease progression in both patients, and
that D2R availability also decreased in the patient with
MSA, but not the patient with PD. The partial correlation
analysis showed a positive correlation between DAT and
D2R availability for the patient with MSA (partial
correlation coefficient: r = 0.893, P = 0.0002), but there was
no any significant correlation for the patient with PD
(r = −0.036, P = 0.89).
The first and last DAT and D R PET images are
played in Fig. 2. Consistent with Table 1, DAT availability
tended to decrease in both patients. However, D2R
availability tended to decrease in the patient with MSA, but
not the patient with PD.
Discussion and conclusions
Longitudinal changes in DAT and D2R imaging have
been established in PD patents. The dorsal posterior part
of the putamen, which is anatomically equivalent to the
post-PU in this study, is the initial region of DAT loss and
is most severely affected throughout the illness [
2, 9, 10
Percentage decreases were calculated by the following formula: 100 × [(uptake ratio index in the first image) − (uptake ratio index in the last image)]/(uptake ratio
index in the first image)
The number of DATs in each subregion of the striatum
decreases along with neuronal loss in the SN and the
disease progression, presumably following an exponential
2, 10, 13
]. On the other hand, according to in vitro
studies showing that the number of striatal D2Rs is
constant even in the advanced stage of PD [
], striatal D2R
availability in an imaging study is also expected to be
constant throughout the illness. D2R images, however, may
be complicated. In early PD, the expression of D2R may
be upregulated as a compensatory response to a decrease
in endogenous dopamine levels [
]. In longstanding
PD, chronic dopaminergic therapy or structural
adaptation of the postsynaptic neurons to the progressive
degeneration of the presynaptic dopaminergic system
may downregulate D2R expression [
]. Additionally, the
loss of endogenous dopamine can cause increased
binding of 11C-raclopride (i.e., increased D2R availability)
throughout the illness [
]. Our findings from an early
PD patient were explainable based on those findings.
To our knowledge, this is the first study to investigate
the time course of pre- and postsynaptic imaging in a
patient with MSA, and that showed a positive
correlation between the two (Fig. 1). A pathological study with
35 MSA patients has reported that neurons in both the
SN and striatum, especially the putamen, were severely
depleted in most cases, and that the degree of nigral
and putaminal damage tended to be associated with
disease duration [
]. The latter finding was supported by
two neuroimaging studies (not longitudinal) showing a
positive correlation between DAT and D2R availability
in MSA groups [
]. Together, previous and our
findings show that the functional impairment of both
preand postsynaptic dopaminergic systems in MSA should
develop with disease progression due to neuronal
degeneration in the SN and striatum.
Differentiating MSA from PD is often difficult in their
early stages, and this sometimes remains difficult even in
the late stages of these diseases. About 20 % of patients
still carrying a diagnosis of PD were pathologically
diagnosed with another neurodegenerative disorder at the
time of death, and MSA was the most frequently
misidentified pathology [
]. Pre- and postsynaptic
striatal imaging can help in differential diagnosis; however,
not all MSA patients exhibit a significant reduction of
D2R availability , especially when neuronal loss in the
striatum is mild. DAT imaging can demonstrate
differences between PD and MSA on the group level but not
on an individual level [
]. On the other hand, the present
study showed that along with decreasing DAT availability
(i.e., disease progression), D2R availability also decreased
in the patient with MSA, but not in the patient with PD,
and suggests that the time course of pre- and
postsynaptic imaging can be considerably different between these
conditions. Thus, in cases where initial pre- and
postsynaptic imaging cannot discriminate between PD and
MSA, observation of the individual time courses of
preand postsynaptic imaging, at an interval of at least a few
years, may improve the differential diagnosis of PD and
MSA. However, when pre- and postsynaptic imaging is
used for clinical purposes, the subsequent PET or SPECT
scans should be reserved for unclear cases and their
indication should be scrutinized to avoid cumulative
exposure to radiation.
One of the limitations of the present study is that PD
and MSA are heterogeneous disorders with multiple
factors contributing to symptoms and disease
]. Thus, one cannot necessarily expect other
patients with PD or MSA to follow the cases presented
here. However, as typical cases of PD and MSA, our cases
may provide essential information for differentiating
between PD and MSA.
PD: Parkinson’s disease; MSA: multiple system atrophy; DAT: dopamine
transporter; D2R: dopamine D2 receptor; PET: positron emission tomography;
SPECT: single photon emission computed tomography; SN: substantia nigra;
11C-CFT: carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl)-tropane;
11C-raclopride: carbon-11-labeled raclopride; VOI: volume-of-interest; VST:
ventral striatum; pre-DCA: pre-commissural dorsal caudate; post-CA:
postcommissural caudate; pre-DPU: pre-commissural dorsal putamen; post-PU:
post-commissural putamen; URI: uptake ratio index; SD: standard deviation.
KIshibashi participated in the design and conceptualization of the study,
performed the analysis and interpretation of the data, and drafted the
manuscript. HN and KIshii managed the patients, and participated in the design and
conceptualization of the study. KIshiwata drafted the manuscript. All authors
read and approved the final manuscript.
The authors thank Mr. Kunpei Hayashi and Ms. Hiroko Tsukinari for their
Compliance with ethical guidelines
The authors declare that they have no competing interests.
Written informed consent was obtained from the two patients for
publication of this Case Report and any accompanying images. A copy of the written
consent from each patient is available for review by the Editor-in-Chief of this
1. Wenning GK , Ben-Shlomo Y , Magalhaes M , Daniel SE , Quinn NP . Clinicopathological study of 35 cases of multiple system atrophy . J Neurol Neurosurg Psychiatry . 1995 ; 58 ( 2 ): 160 - 6 .
2. Fearnley JM , Lees AJ . Ageing and Parkinson's disease: substantia nigra regional selectivity . Brain J Neurol . 1991 ; 114 (Pt 5): 2283 - 301 .
3. Guttman M , Seeman P , Reynolds GP , Riederer P , Jellinger K , Tourtellotte WW . Dopamine D2 receptor density remains constant in treated Parkinson's disease . Ann Neurol . 1986 ; 19 ( 5 ): 487 - 92 . doi: 10 .1002/ana.410190510.
4. Bokobza B , Ruberg M , Scatton B , Javoy-Agid F , Agid Y. [3H] spiperone binding, dopamine and HVA concentrations in Parkinson's disease and supranuclear palsy . Eur J Pharmacol . 1984 ; 99 ( 2-3 ): 167 - 75 .
5. Antonini A , Leenders KL , Vontobel P , Maguire RP , Missimer J , Psylla M , et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson's disease . Brain J Neurol . 1997 ; 120 (Pt 12): 2187 - 95 .
6. Knudsen GM , Karlsborg M , Thomsen G , Krabbe K , Regeur L , Nygaard T , et al. Imaging of dopamine transporters and D2 receptors in patients with Parkinson's disease and multiple system atrophy . Eur J Nucl Med Mol Imaging . 2004 ; 31 ( 12 ): 1631 - 8 . doi: 10 .1007/s00259-004-1578-x.
7. Nocker M , Seppi K , Donnemiller E , Virgolini I , Wenning GK , Poewe W , et al. Progression of dopamine transporter decline in patients with the Parkinson variant of multiple system atrophy: a voxel-based analysis of [123I]beta-CIT SPECT . Eur J Nucl Med Mol Imaging . 2012 ; 39 ( 6 ): 1012 - 20 . doi: 10 .1007/s00259-012-2100-5.
8. Pirker W , Djamshidian S , Asenbaum S , Gerschlager W , Tribl G , Hoffmann M , et al. Progression of dopaminergic degeneration in Parkinson's disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study . Mov Disord Off J Mov Disord Soc . 2002 ; 17 ( 1 ): 45 - 53 .
9. Ishibashi K , Saito Y , Murayama S , Kanemaru K , Oda K , Ishiwata K , et al. Validation of cardiac (123)I-MIBG scintigraphy in patients with Parkinson's disease who were diagnosed with dopamine PET . Eur J Nucl Med Mol Imaging . 2010 ; 37 ( 1 ): 3 - 11 . doi: 10 .1007/s00259-009-1202-1.
10. Ishibashi K , Oda K , Ishiwata K , Ishii K. Comparison of dopamine transporter decline in a patient with Parkinson's disease and normal aging effect . J Neurol Sci . 2014 ; 339 ( 1-2 ): 207 - 9 . doi: 10 .1016/j.jns. 2014 . 01 .015.
11. Ishibashi K , Robertson CL , Mandelkern MA , Morgan AT , London ED. The simplified reference tissue model with 18F-fallypride positron emission tomography: choice of reference region . Mol Imaging . 2013 ; 12 ( 8 ).
12. Hashimoto M , Kawasaki K , Suzuki M , Mitani K , Murayama S , Mishina M , et al. Presynaptic and postsynaptic nigrostriatal dopaminergic functions in multiple system atrophy . NeuroReport . 2008 ; 19 ( 2 ): 145 - 50 . doi: 10 .1097/ WNR.0b013e3282f3e3d8.
13. Nandhagopal R , Kuramoto L , Schulzer M , Mak E , Cragg J , Lee CS , et al. Longitudinal progression of sporadic Parkinson's disease: a multi-tracer positron emission tomography study . Brain J Neurol . 2009 ; 132 (Pt 11): 2970 - 9 . doi: 10 .1093/brain/awp209awp.
14. Kaasinen V , Ruottinen HM , Nagren K , Lehikoinen P , Oikonen V , Rinne JO . Upregulation of putaminal dopamine D2 receptors in early Parkinson's disease: a comparative PET study with [11C] raclopride and [11C] N-methylspiperone . J Nucl Med . 2000 ; 41 ( 1 ): 65 - 70 .
15. Rinne JO , Laihinen A , Rinne UK , Nagren K , Bergman J , Ruotsalainen U . PET study on striatal dopamine D2 receptor changes during the progression of early Parkinson's disease . Mov Disord Off J Mov Disord Soc . 1993 ; 8 ( 2 ): 134 - 8 . doi: 10 .1002/mds.870080203.
16. Antonini A , Schwarz J , Oertel WH , Pogarell O , Leenders KL . Long-term changes of striatal dopamine D2 receptors in patients with Parkinson's disease: a study with positron emission tomography and [11C]raclopride . Mov Disord Off J Mov Disord Soc . 1997 ; 12 ( 1 ): 33 - 8 . doi: 10 .1002/ mds.870120107.
17. Ishibashi K , Ishii K , Oda K , Mizusawa H , Ishiwata K. Competition between 11C-raclopride and endogenous dopamine in Parkinson's disease . Nucl Med Commun . 2010 ; 31 ( 2 ): 159 - 66 . doi: 10 .1097/MNM.0b013e328333e3cb.
18. Hughes AJ , Daniel SE , Kilford L , Lees AJ . Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases . J Neurol Neurosurg Psychiatry . 1992 ; 55 ( 3 ): 181 - 4 .
19. Rajput AH , Rozdilsky B , Rajput A . Accuracy of clinical diagnosis in parkinsonism-a prospective study . Can J Neurol Sci . 1991 ; 18 ( 3 ): 275 - 8 .
20. Schulz JB , Klockgether T , Petersen D , Jauch M , Muller-Schauenburg W , Spieker S , et al. Multiple system atrophy: natural history, MRI morphology, and dopamine receptor imaging with 123IBZM-SPECT . J Neurol Neurosurg Psychiatry . 1994 ; 57 ( 9 ): 1047 - 56 .
21. Lewis SJ , Foltynie T , Blackwell AD , Robbins TW , Owen AM , Barker RA . Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach . J Neurol Neurosurg Psychiatry . 2005 ; 76 ( 3 ): 343 - 8 . doi: 10 .1136/jnnp. 2003 . 033530 .
22. Ozawa T , Paviour D , Quinn NP , Josephs KA , Sangha H , Kilford L , et al. The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations . Brain J Neurol . 2004 ; 127 (Pt 12): 2657 - 71 . doi: 10 .1093/brain/ awh303.