Journal of Neurological Sciences 155 (1998) 60–67
Differentiation of idiopathic Parkinson’s disease from striatonigral
degeneration and progressive supranuclear palsy using iodine-123
meta-iodobenzylguanidine myocardial scintigraphy
Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, Fuchu, Tokyo 183, Japan
Received 3 April 1997; received in revised form 29 July 1997; accepted 18 August 1997
Iodine-123 meta-iodobenzylguanidine ([
To investigate cardiac sympathetic function in PD, SND, and PSP, [
PD, 15 patients with SND, 14 patients with PSP, and 20 control subjects. In planar imaging studies, the heart-to-mediastinum average
count ratio (H/M) was calculated for both early and delayed images. The mean value of H/M in patients with PD was significantly lower
than those with SND, PSP, or no disease. Regardless of disease severity or intensity of anti-Parkinsonian pharmacotherapy, mean values
for H/M were always low in patients with PD. The mean value of H/M in SND with orthostatic hypotension (OH) was lower than that in
SND without OH. Although the mean value of H/M in PSP with amitriptyline treatment was significantly lower than that in PSP patients
without amitriptyline treatment, there was no significant difference between the mean value of H/M in PSP patients without amitriptyline
treatment and that in control. Thus, PD may have a abnormality of cardiac sympathetic function which has not been detected by previous
cardiovascular autonomic studies. Moreover, particularly in early stages, [
diagnostic information in these akinetic-rigid syndromes.
1998 Elsevier Science B.V.
I]MIBG), an analogue of norepinephrine, is a tracer for functioning of sympathetic neurons.
I]MIBG myocardial scintigraphy was performed in 25 patients with
I]MIBG myocardial scintigraphy may provide helpful
Keywords: Autonomic function; Iodine-123 meta-iodobenzylguanidine; Myocardial scintigraphy; Norepinephrine transporter; Parkinson’s
disease; Progressive supranuclear palsy; Striatonigral degeneration
(Spokes et al., 1979; Gosset et al., 1983; Adams and
Victor, 1985). The pathology of PSP is characterized by
neuronal loss, gliosis, and the formation of neurofibrillary
tangles primarily affecting the pallidosubthalamic com-
plex, the zona compacta of the substantia nigra, the
superior colliculus, periaqueductal gray matter, and pretec-
tal areas (Steele et al., 1964; Jellinger et al., 1980).
Among patients with MSA, a disorder which may
include varying combinations and degrees of striatonigral
degeneration (SND), olivopontocerebellar atrophy, and
autonomic involvement, it is difficult to distinguish be-
tween those with early SND lacking cerebellar or pyrami-
dal signs, and those with idiopathic PD. More generally,
PD, MSA, and PSP are all likely to cause diagnostic
difficulties in early clinical stages (Perkin et al., 1978;
Maher et al., 1986; Quinn, 1989). This problem is high-
Idiopathic Parkinson’s disease (PD), multiple system
atrophy (MSA) and progressive supranuclear palsy (PSP)
are pathologically distinct akinetic-rigid disorders. PD is
characterized by Lewy-body degeneration of dopaminergic
neurons of the substantia nigra pars compacta (Forno,
1982). MSA is characterized by marked neuronal loss in
the basal ganglia, pontine nuclei, inferior olives, cerebellar
Purkinje cells, and intermediolateral gray columns of the
spinal cord, with gliosis and glial cytoplasmic inclusions
*Corresponding author: Present address: Department of Neurology,
Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa
920, Japan. Tel.: 181 76 2652292; fax: 181 76 2344253; e-mail:
1998 Elsevier Science B.V. All rights reserved.
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–6761
lighted by pathologic series which indicate that the an-
temortem diagnosis of PD is correct only in about 80% of
cases (Rajput et al., 1991; Hughes et al., 1992), with PSP
and MSA being the mistaken diagnoses most commonly
applied (Hughes et al., 1992; Quinn, 1994).
Accurate differential diagnosis of PD from SND and
PSP is important for prognosis and therapy; both SND and
PSP respond poorly to levodopa and progress more rapidly
Iodine-123 meta-iodobenzylguanidine ([
radioiodinated analogue of norepinephrine used as a tracer
for functioning of sympathetic neurons. [
cumulates in storage vesicles of sympathetic nerve pre-
synaptic terminals (Wieland et al., 1981). MIBG competes
with norepinephrine for neuronal uptake (uptake one)
(Nakajo et al., 1983) and is also taken up by a non-
neuronal mechanism (uptake two) (Dae et al., 1989).
[ I]MIBG has been reported to be a useful source of
unique information regarding cardiac sympathetic function
in heart disease (Merlet et al., 1992; Gill et al., 1993a),
diabetes mellitus (Mantysaari et al., 1992), hyperthyroid-
ism, and Shy-Drager syndrome (Sisson et al., 1987).
However, cardiac sympathetic function has not yet been
quantitatively evaluated with [
akinetic-rigid disorders in which autonomic dysfunction
often occurs (Bannister and Oppenheimer, 1972; Ludin et
al., 1987; Gutrecht, 1992).
In this study, [ I]MIBG was used to investigate
cardiac sympathetic function in patients with clinically
defined PD, SND, and PSP. The aim of this study was to
determine whether the intensity of cardiac [
accumulation could be used to discriminate between these
different akinetic-rigid disorders.
form of MSA (as defined by Quinn, 1994) are shown in
Table 3. All had sporadic, adult-onset, parkisonian
syndrome poorly or non-responsive to levodopa. All had
documented autonomic failure, such as urinary inconti-
nence or retention, orthostatic hypotension, or impotence
in male. Pyramidal signs were present in 11, and cerebellar
signs in further 13 patients. None had supuranuclear palsy
or dementia. The mean age of the SND group was 63 years
(range, 51–79), and clinical disease duration ranged from
3–16 years (mean, 7).
Fourteen patients with PSP were studied; their clinical
features are shown in Table 4. All patients had a poorly or
non-levodopa responsive akinetic-rigid syndrome with
severe axial and proximal rigidity, poor balance, dysarthria
with slurring, and a supranuclear vertical gaze palsy
affecting both upward and downward gaze. All had no
autonomic failure. The mean age of the PSP group was 68
years (range, 62–74), with disease duration ranging from
1–11 years (mean, 5).
All patients were subjected to a test of orthostatic blood
pressure tolerance. Blood pressure was initially recorded
after a rest for 20 min in a supine position, and subsequent-
ly it was recorded for 10 min after standing. A diagnosis of
orthostatic hypotension (OH) was made when the systolic
blood pressure fell by 20 mmHg or below or the diastolic
blood pressure fell by at least 10 mmHg within 10 min of
standing (The Consensus Committee of the American
Autonomic Society and the American Academy of Neurol-
[ I]MIBG uptakes for the patient groups were com-
pared with uptakes for 20 healthy controls aged from
41–85 years (mean, 65) (Table 1).
None of the subjects had any history of cardiovascular
or thyroid disease, hyperlipidemia and, with the exception
of seven PSP patients, none had ever used any drugs
known to affect [ I]MIBG accumulation (Sollanki et al.,
1992). All were normotensive; diabetes mellitus was
excluded by testing urine and blood sugar. No abnor-
malities which indicate ischemic heart disease, arrhythmia,
or hypertrophy were seen on electrocardiograms or wall-
motion studies. As a precaution, eight patients (nos. 5, 8,
24, 25, 26, 33, 38, 49) had thallium-201 scintigraphy for
vague complaints and showed good perfusion. All patients
were not withdrawn from medication for this study.
These procedures were approved by the Ethics Commit-
te of the Tokyo Metropolitan Neurological Hospital.
Informed consent was obtained from all subjects prior to
the study, and no side effects were noted in any of them.
I]MIBG) is a
I]MIBG scintigraphy in
2. Materials and method
Fifty three patients treated at our hospital from Date to
Date had clinically definite idiopathic PD, as defined by
the UK Parkinson’s Disease Society Brain Bank criteria
(Gibb and Lees, 1988). All had levodopa-responsive
akinetic-rigid disorders, with no evidence of gaze palsy,
cerebellar deficit, or pyramidal signs. None had a history
of neuroleptic exposure or other identifiable cause of
secondary parkisonism. From among these patients, we
selected 25 PD patients with mild locomoter disability
(from I to III assessed by Hoehn and Yahr scale (Hoehn et
al., 1976)) and no autonomic failure (urinary incontinence
or retention, impotence in male, and orthostatic hypoten-
sion). The mean age was 69 years (range, 56–82). The
mean disease duration was 5 years (range, 1–16). Six
patients had never been treated, subsequently shown to be
highly levodopa responsive, while 19 others had been
treated with levodopa, bromocriptine, trihexyphenidyl or
other drugs, alone or in combination (Table 2).
Details of the 15 patients studied with probable SND
Clinical data and H/M of control subjects
Number Male FemaleAge
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–67
Details of patients with Parkinson’s disease
No. Age SexDisease durationHoehn and Yahr scoreTreatment H/M
(years) (M/F) (years)Early Delayed
Ld, A, P
Ld, A, P
Ld, T, P
Ld, B, A
Ld, B, T
Ld, D, A, P
Ld, L-dopa1dopa decarboxylase inhibitor; T, tryhexyphenidyl; B, bromocriptine; P, pergolide; D, droxidopa; A, amantadine.
using a triple-headed dedicated gamma camera system
(MULTISPECT 3, Siemens, IL) equipped with a high-
resolution parallel-hole collimator. Photopeak energy was
centered at 159 keV with a 20% window. Early and
delayed images were obtained 15 min and 3–4 h after
All subjects were injected intravenously with 111MBq
of [I]MIBG (Daiichi Radioisotope Laboratories, Tokyo,
Japan). Scintigraphic images of the chest were obtained
Details of patients with striatonigral degeneration
No. AgeSexDisease durationAFPSCSTreatmentH/M
Ld, D, A
Ld, T, B
B, T, D
Ld, L-dopa1dopa decarboxylase inhibitor; T, tryhexyphenidyl; B, bromocriptine; D, droxidopa; A, amantadine; AF, autonomic failure; PS, pyramidal sign;
CS, cerebellar sign.
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–6763
Details of patients with progressive supranuclear palsy
No. AgeSex Disease durationTreatmentH/M
Ld, T, Am
Ld, B, Am
Ld, A, T, D, Am
Ld, A, Am
D, droxidopa; B, bromocriptine; A, amantadine; T, tryhexyphenidyl; LD, L-dopa1dopa decarboxylase inhibitor; Am, amitriptyline.
injection, respectively. For the anterior planar image, the
data-acquisition matrix was 2563256, and a preset time of
5 min was used for image acquisition.
mediastinum. On the delayed images, the same ROI was
copied from the early image to obtain better reproducibil-
ity. Background subtraction was not performed from any
ROI count. H/M has been used previously as a simple
quantitative method (Merlet et al., 1992; Nakajima et al.,
2.2. Relative [
I]MIBG uptake ratio
Relative organ uptake was determined by setting the
region of interest (ROI) on the anterior view. The left
ventricular ROI, including the left ventricular cavity was
drawn, and a rectangular 939 pixel ROI was set on the
upper mediastinum area (Fig. 1). Size and positioning were
checked using the anterior view of the chest radiograph.
The ratio of heart-to-mediastinum (H/M) was calculated
using the average count per pixel in the heart and
Results are expressed as mean values6standard devia-
tion. Differences of the variances and averages were tested
by Student’s t-test and one-way analysis of variance
(ANOVA). Correlations were evaluated by Spearman’s
rank correlation test. A P value ,0.05 was considered
statistically significant. All statistical analysis were per-
formed using Stat View 4.1J software on a Macintosh
Both early and delayed H/M in the PD group was
significantly lower than those of control, SND, and PSP
groups (early H/M: PD 1.3660.15, SND 1.7760.24, PSP
1.8460.17, control 2.0360.16, P,0.0001; delayed H/M:
PD 1.1960.15, SND 1.8760.39, PSP 1.8960.28, control
2.2160.23, P,0.0001). There were also significant differ-
ences (P,0.01) between SND and control, as well as
between PSP and control, in both early and delayed H/M
(Fig. 2). H/M in the SND and PSP groups were lower than
those of control.
In the group of PD patients, delayed H/M tended to be
lower than early H/M (P,0.001). No significant differ-
ences in the early and delayed H/Ms were found between
treated and untreated patients. (early H/M: treated
1.3760.15, untreated 1.3360.14, P.0.5; delayed H/M:
Fig. 1. Definition of regions of interest (ROI) on the anterior planar image
of a control subject. The left ventricular ROI was drawn including the
ventricular cavity (H), and a rectangular ROI was set on the middle
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–67
Fig. 4. Effect of amitriptyline on H/M in PSP patients. Open columns
indicate mean H/M in PSP patients without amitriptyline treatment, and
black columns indicate mean H/M in patients with amitriptyline treat-
ment. Statistical comparison employed Student’s t-test. There was
significant difference between patients treated with amitriptyline and
others. *P,0.005, **P,0.001.
according to the Hoehn and Yahr scale (early H/M: I
1.4160.10, II 1.2860.13, III 1.4060.17, P.0.1; delayed
H/M: I 1.2560.15, II 1.1360.16, III 1.2260.13, P.0.2).
Among the SND patients, there were significant differ-
ences in the early and delayed H/Ms between those with
OH and without OH (early H/M: with OH 1.5860.33,
without OH 1.8760.09, P,0.05; delayed H/M: with OH
1.5660.49, without OH 2.0260.22, P,0.05; Fig. 3). H/M
tended to be lower in SND patients with OH than in those
without OH, and significantly lower in SND without OH
than in control (P,0.05).
Among the PSP patients, H/M was significantly higher
in patients untreated with amitriptyline than in those who
were treated. (early H/M: treated 1.7260.09, untreated
1.9760.15, P,0.005; delayed H/M: treated 1.6760.11,
untreated 2.1160.22, P,0.001; Fig. 4). There was no
significant difference in both early and delayed H/M
between control and PSP patients without amitriptyline
There was no correlation between H/M and disease
duration in the three akinetic-rigid syndromes (early H/M:
PD P.0.9, SND P.0.4, PSP P.0.05; delayed H/M: PD
P.0.8, SND P.0.9, PSP P.0.06).
Fig. 2. Comparison of mean values of the early (A) and delayed (B) H/M
for PD patients, SND patients, PSP patients and control subjects. Large
open circles represent mean H/M in each groups, and small ones indicate
individual subjects. Black arrows indicate patients with orthostatic
hypotension, and open arrows indicate patients with amitriptyline treat-
ment. Error bars represent standard deviation. Statistical comparisons
were with Student’s t-test. Mean values of H/M were significantly lower
in PD patients than in SND, PSP and control subjects. *P,0.0001,
treated 1.1960.15, untreated 1.2160.15, P.0.7). Further,
there were no significant differences in the early and
delayed H/Ms among patients with different severity
Two major findings arise from the present study. First,
despite absence of autonomic failure, H/M was signifi-
cantly lower in PD than in SND and PSP, being markedly
low even in early PD. Secondly, neither early nor late
scans demonstrated definite MIBG uptake in PD. Several
mechanisms might account for the markedly and globally
reduced MIBG uptake in PD.
Myocardial ischemia or coronary artery disease was
Fig. 3. H/M in SND patients with or without orthostatic hypotension
(OH). Open columns indicate mean H/M in SND patients without OH,
and black columns indicate mean H/M in patients with OH. Error bars
represent standard deviation. Statistical comparisons were with Student’s
t-test. There was a significant difference in the early and delayed H/M
between the patients with OH and those without OH (*P,0.05).
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–67 65
unlikely because there was no evidence of chest pain,
electrocardiogram abnormality, asynergic wall motion, or
coronary risk factors such as hyperlipidemia and diabetes
mellitus. There was no evidence of reduced thallium
perfusion. Thus, it is hard to accept that all PD patients
have silent ischemic heart disease.
The lack of MIBG positivity, even in early image,
suggests loss or destruction of cardiac sympathetic nerve
endings (Ganguly et al., 1987). In the sympathetic nervous
system, the Lewy-body has been found in the hypo-
thalamus (Langston and Forno, 1978), in the intermediola-
teral cell columns of the spinal cord, and in the sympa-
thetic ganglia (Jager and Bethlem, 1960; Rajput and
Rozdilsky, 1976) in patients with PD. In MSA, variable
degrees of SND and/or olivopontocerebellar atrophy, as
well as frequent cell loss from intermediolateral cell
columns of the spinal cord, have been found (Spokes et al.,
1979; Gosset et al., 1983; Adams and Victor, 1985).
Pathology in other regulatory centers of the sympathetic
nervous system, including hypothalamus (Shy and Drager,
1960), may also contribute to autonomic failure. Matthews
(1992) has found differences in the ganglionic pathology
between patients with PD and those with MSA. Although
it has been reported that PSP-associated pathologic find-
ings noted in autonomic sympathetic central nervous
system cause mild abnormalities in cardiovascular reflexes
(Gutrecht, 1992), sympathetic ganglionic change has not
been previously encountered in PSP and H/M in PSP
patients without amitriptyline treatment did not differ from
that in control. Denervated myocardium with stellate
ganglionectomy showed a decrease in tissue norepineph-
rine and MIBG in the myocardium as well (Dae et al.,
1989). It was suspected that pathologic sympathetic gang-
lionic change was responsible for the more severe reduc-
tion of [I]MIBG myocardial accumulation in PD com-
pared to that in SND or PSP.
MIBG cannot be metabolized by catechol-O-methyl
transferase or monoamine oxidase (Wieland et al., 1981).
Two types of uptake systems for norepinephrine and
MIBG have been identified in adrenergic tissues. The first
of these, the uptake one system (neuronal uptake), domi-
nates at low concentrations of the substrates, is sodium-
and ATP-dependent, and is inhibited by tricyclic antide-
pressants. The second, the uptake two system (non-neuro-
nal uptake) is a diffusion system that dominates at high
concentrations of norepinephrine or MIBG and is slightly
inhibited by tricyclic agents (Wieland et al., 1981; Tobes
et al., 1985; Sisson et al., 1987). Scanning during the first
15 min post-injection mainly reflects the greater influx of
MIBG into extraneural spaces in myocardial tissue rather
than into the neuronal component. The neuronal accumula-
tion of MIBG reaches its maximum 3–4 h after injection
(Gill et al., 1993b). Therefore, myocardial MIBG uptake
was assessed 15 min and 3–4 h post-injection in our
patient. The latter scan displays neural uptake of MIBG
Glowniak et al. (1993) reported that the characteristics
of specific MIBG uptake (neuronal uptake) could be
explained by the known properties of the norepinephrine
transporter (NET), and NET was responsible for specific
uptake of MIBG, as compared with the dopamine transpor-
ter (DAT) or the serotonin transporter. In this study,
delayed H/M tended to be lower than early H/M in all the
PD patients (P,0.001). It was suspected that dysfunction
of the NET may be responsible for the myocardial
[ I]MIBG defect in patients with PD. Though impairment
of the NET has not been verified, Uhl et al. (1994) have
reported a decrease in amounts of DAT mRNA in nigral
neurons in PD. The DAT could play a role in mechanisms
underlying parkisonism (Kitayama et al., 1992). Rat DAT
has an amino-acid sequence shared by the human NET for
64% of its length (Giros et al., 1991). Accordingly, it is
conceivable that not only the DAT but also the NET may
be impaired by the process underlying idiopathic PD. Thus,
impairment of the NET in PD may explain the reduced
cardiac accumulation of [I]MIBG in PD regardless of
In the SND group, H/M was lower than in the control
group, and H/M in patients with OH was significantly
lower than in those without OH. Therefore, when the H/M
is markedly low in a patient with an akinetic-rigid
syndrome with OH, it could be difficult to decide whether
the individual has PD or not. Fortunately, however, this
presentation is not always conspicuous in SND in the early
stage, and H/M in SND with OH is not always low
(patient no. 31). When the parkisonian patient has au-
tonomic failure, pyramidal signs, or cerebellar signs in
early stage, it is easy to decide clinically the individual has
not PD. According to Sisson et al. (1987), total cardiac
denervation which derives from injury to preganglionic
fibers of the sympathetic nervous system, reduced cardiac
uptake of [I]MIBG in Shy-Drager syndrome. Cohen et
al. (1987) hypothesized that in multiple system atrophy,
dysfunction of the postganglionic sympathetic fibers may
be caused by transsynaptic effects of preganglionic lesions.
Our findings suggest that SND with OH may reflect this
In the PSP group, H/M was significantly lower than in
controls. H/M in untreated patients tended to be sig-
nificantly higher than in those treated with amitriptyline.
This tricyclic antidepressant drug is known to inhibit
MIBG uptake to a particularly marked degree for neural
uptake (Sollanki et al., 1992). When amitriptyline is not
used in early stage PSP, [
easily distinguishes PD from PSP.
The relationship between autonomic disturbance and
severity of disease or disease duration has been reported
(Meco et al., 1991). In this study, [
PD was so markedly and globally reduced from early stage
that it is difficult to assess the relationship between H/M
and severity of disease or disease duration.
Though various drugs have been reported to cause
I]MIBG scintigraphy more
I]MIBG uptake in
M. Yoshita / Journal of Neurological Sciences 155 (1998) 60–67
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son drugs used for the patients tested in this study have not
been included in any of these reports. The relationships
between autonomic disturbance and dopaminergic medica-
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variable (Ludin et al., 1987; Durrieu et al., 1991; Meco et
al., 1991). Since there were no significant differences in
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PD, anti-Parkinson drugs are not believed to influence the
accumulation of [I]MIBG.
In conclusion, decreased H/M in PD, accompanying
reduced cardiac sympathetic accumulation of [
may reflect visible pathologic changes in the sympathetic
ganglion or impairment of the NET, or both. Especially in
the early stage of akinetic-rigid disorders, [
cardiac scintigraphy is a potential diagnostic tool in the
differential diagnosis and in the selection of patients
eligible for dopaminergic therapy.
I]MIBG defects (Sollanki et al., 1992), the anti-Parkin-
I wish to thanks Drs Michiyuki Hayashi and Eiji Isozaki
for their helpful comments and encouragements, and Dr
Shunsaku Hirai and colleagues in Tokyo Metropolitan
Neurological Hospital. I am also grateful to Mrs Mikiko
Yoshita for secretarial assistance.
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