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[ 123 I]P-CIT/SPECT imaging demonstrates
bilateral loss of dopamine transporters
in hemi-Parkinson’s disease
K.L. Marek, MD; J.P. Seibyl, MD; S.S. Zoghbi, PhD; Y. Zea-Ponce, PhD; R.M. Baldwin, PhD; B. Fussell, RN;
D.S. Charney, MD; C. van Dyck, MD; P.B. Hoffer, MD; and R.B. Innis, MD, PhD
porter with 2~-carboxymethoxy-3~-(4-iodophenyl)tropane
patients with early Parkinson’s disease (PD). Striatal uptake of [‘2311p-CIT was compared in eight early-PD patients with
exclusively hemiparkinsonism and eight age- and sex-matched healthy subjects. p-CIT striatal uptake was reduced
by approximately 53% contralateral and by 38% ipsilateral to the clinically symptomatic side in the hemi-PD patients,
compared with the mean striatal uptake in age- and sex-matched healthy subjects. The relative reduction in p-CIT
uptake in the hemi-PD patients was greater in the putamen than in the caudate. These data demonstrate that SPECT
imaging of the dopamine transporter with [12311p-CIT can identify patients with PD at the onset of motor symptoms and
suggest that this technique also may be useful in identifylng individuals with developing dopaminergic pathology before
onset of motor symptoms.
have used in vivo single-photon emission computed tomography (SPECT) of the dopamine trans-
([12311p-CIT) to investigate striatal dopamine transporter loss in
Parkinson’s disease (PD) develops insidiously with a
prolonged presymptomatic phase during which mes-
encephalic dopaminergic neuronal loss occurs.14 The
clinical presentation of PD characteristically begins
with unilateral symptoms that gradually, but relent-
lessly, progress to involve both
identified very early in the course of their disease
with only hemiparkinsonism help to establish the
threshold of early clinical detection of PD. Further-
more, by contrasting the symptomatic with the
presymptomatic side, these patients provide a natu-
ral model in which to evaluate methods for presymp-
From the Departments of Neurology (Dr. Marek and B. Fussell), Psychiatry (Drs. Zoghbi, Zea-Ponce, Baldwin, Charney, van Dyck, and Innis), and Diagnostic
Radiology (Drs. Seibyl and Hoffer), Yale University School of Medicine and VA Medical Center, West Haven, CT.
Supported by funds from the National Parkinson Foundation (award to K.L.M.); Department of Veterans Afhirs (award to R.B.I.); and Guilford Pharmaceu-
ticals Inc, Baltimore, MD; and by a .gift from Philip and Rose Hoffer.
Received February 2, 1995. Accepted in final form April 26, 1995.
Address correspondence and reprint requests to Dr. K.L. Marek, Department of Neurology, Yale University School of Medicine, 333 Cedar St, New Haven, CT
Copyright 0 1996 by the American Academy of Neurology 231
Table Characteristics of patients
Patient Age (yr) Sex PD duration (yr)
Amantadine 200 mg, pergolide 1.5 mg
Selegiline 2.5 mg, cogentin 1 mg
Selegiline 10 mg
Demographic characteristics of patients include duration of Parkinson's disease (PD) in years, evaluation with Hoehn and Yahr (H&Y)
scale, and Unified Parkinson's Disease Rating Scales (LPDRS-total and motor), and side of body with symptoms (Side). The neurologi-
cal evaluation was done within 48 hours of single-photon emission computed tomography.
tomatic detection of PD. For example, studies exam-
ining motor function in hemi-PD patients, by using
electrophysiologic assessments, have demonstrated
motor abnormalities in the presymptomatic and the
symptomatic side.8 PET studies have shown a reduc-
tion in ["Flfluorodopa (["F]FDopa) uptake in early
hemi-PD patients in the striatum ipsilateral and
contralateral to symptoms.g-" In addition, PET stud-
ies have identified a dopaminergic deficit before
symptoms in subsets of individuals at risk for PD or
other parkinsonian syndromes. 12-15
In vivo single-photon emission computed tomogra-
phy (SPECT) and PET imaging of the dopamine
transporter provides an alternative approach to ex-
amine the mesencephalic dopamine neuronal projec-
tions in early PD. The dopamine transporter is a
protein located in the presynaptic membrane on the
terminals of dopaminergic projections from the sub-
stantia nigra to the striatum and provides a marker
of dopamine terminal innervation.I6 Prior studies
have demonstrated that striatal uptake of
["Clnomifensine, a monoamine transporter inhibi-
tor, was reduced comparably with ["FIFDopa up-
take in patients with PD.17 Several phenyltropane
analogues of cocaine, including 2P-carboxymethoxy-
3P-(&iodophenyl)tropane (['2311p-CIT) and ["CICFT,
have been developed as PET and SPECT probes of
the dopamine transporter with high affinity and low
nonspecific binding. 18-20 Initial clinical studies using
these probes have demonstrated significant striatal
dopamine transporter loss in patients with PD.21-23
More detailed SPECT imaging studies have shown
that the reduction in [12311p-CIT striatal uptake in
PD patients correlates with severity of disease and
that the reduction in ['231]P-CIT striatal uptake is
greater in putamen than in c a ~ d a t e . ~ ~ , ~ ~
study, we compared SPECT imaging with [ '2311P-CIT
in eight early-PD patients with hemiparkinsonism
exclusively and eight age- and sex-matched healthy
subjects. Our goals were to examine the extent of
transporter loss in patients with minimal symptoms
and to determine whether SPECT imaging with
232 NEUROLOGY 46 January 1996
['2311P-CIT can identify striatal dopamine trans-
porter loss in hemiparkinsonism in the striatum con-
tralateral to symptoms (the symptomatic side) and
the striatum ipsilateral to symptoms (the presymp-
Methods. Subjects. Eight patients with hemi-PD un-
treated with L-dopa were studied (table). The criteria for
inclusion were age >35 years; at least two of the following:
resting tremor, bradykinesia, rigidity, postural instability,
and freezing phenomenon (one of which is rest tremor or
bradykinesia); and response to a single-dose L-dopa chal-
lenge. Patients with bilateral signs of PD (Hoehn and Yahr
Stage 22) were excluded. All patients were recruited from
the Yale Movement Disorders Center and were evaluated
in the Yale-New Haven Hospital General Clinical Re-
search Center by using the following examination protocol,
a modification of the core assessment protocol for intrace-
rebral transplantation (CAPIT). Patients were examined
using the Hoehn and Yahr Scale, the Unified Parkinson's
Disease Rating Scales (UPDRS), and four timed tasks
(CAPIT protocol) in the morning after 12 hours off all
anti-Parkinson drugs and subsequently 1 hour after a sin-
gle dose of carbidopah-dopa (25/100 mg).6,25.26
to L-dopa was defined as a 33% improvement in the total
UPDRS scores or in one of the timed tests. Patients who
failed to respond to the initial L-dopa dose and who toler-
ated the test were retested with a single dose of carbidopal
L-dopa (25/250 mg).
The eight patients were paired with eight healthy sub-
jects similar in age (56 years) and the same sex. The
healthy subjects were taking no medications and were free
of serious medical illnesses, by physical examination and
laboratory testing, and had no family history of PD. All
subjects gave written informed consent after the nature
and consequences of the study had been explained.
Radiopharmaceutical preparation. High specific activ-
ity ['2311P-CIT was prepared from the corresponding tri-
methylstannyl precursor, supplied by Research Biochemi-
cals International, Natick, MA, and high radionuclidic
purity NaI (Nordion International, Ltd, Vancouver,
British Columbia, Canada) as previously des~ribed.~~
diochemical purity was 98 k 1% as measured by high-
performance liquid chromatography. Specific activity was
Data acquisition and analysis. Subjects received
Lugol's solution before [ 12311p-CIT injection to minimize
radioactive uptake by the thyroid. Four fiducial markers
filled with 8 to 10 pCi [99mTc]NaTc0, were attached to
both sides of the subject's head at the level of the can-
thomeatal line before imaging to facilitate post hoc com-
puter reorientation of transaxial images. At 18'21, and 24
hours after the intravenous bolus injection of 398.3 2 84.8
MBq (10.8 ? 2.3 mCi) p-CIT, SPECT brain scans
were acquired in a 64 x 64 X 32 matrix on the Ceraspect
device (Digital Scintigraphics, Waltham, MA), a head-
dedicated SPECT tomograph with spatial resolution of 7.5
to 8 mm full width at half maximumB in all three axes.
Three 12 to 15-minute acquisitions were obtained at 18,
21, and 24 hours after injection.
Raw data were reconstructed from photopeak counts
within a 20% symmetric energy window centered around
159 keV by using a two-dimensional Butterworth filter
(power factor, 10; cutoff, 1 cm). Transaxial images were
reoriented parallel to the canthomeatal plane and attenu-
ation corrected using Chang zero order correctionz9 based
on an ellipse fit to brain using a linear attenuation factor
(p = 0.15 cm-') determined empirically from 1231-contain-
ing distributed source phantom.
Two outcome measures were evaluated: the ratio of spe-
cific striatal uptake to nondisplaceable striatal uptake (ie,
activity not associated with binding to receptors) and the
total striatal uptake expressed as a percentage of injected
radioactivity. Both outcome measures showed robust test
or retest reproducibility in healthy subjects and PD pa-
tient~?~ The first measure, also designated the striatal
binding ratio or V3", is linearly related to the density of
receptors within the region of interest (ROI) if one as-
sumes ['231]P-CIT brain uptake is unchanging during the
time of imaging.3o This assumption is appropriate based on
the extremely slow elimination rates of plasma parent
compound, occipital, and striatal activity in previous stud-
ies of human subjects receiving bolus injections of ['2311p-
C I T . ~ ~
The ratio of specific to nondisplaceable striatal uptake
was calculated by summing the four contiguous transaxial
slices representing the most intense striatal uptake. A
standard ROI template was constructed based on coregis-
tered MRI scans obtained from previous ['231]P-CIT stud-
ies in four healthy human controls. This template included
regions for left and right striatum, frontal cortex, occipital
cortex, midbrain, and cerebellum. Striata were further an-
alyzed with an additional ROI placed in caudate and puta-
men bilaterally. Small variations in individual brains re-
quired movement of the ROIs within the template without
changing the individual ROI shape or size. Data were ex-
pressed as counts per pixel per minute (counts/pixelfmin)
for each brain region. Estimates of striatal specific uptake
were made by subtracting occipital counts/pixel/min from
total striatal counts/pixeYmin based on the low density of
monoamine transporters in the occipital brain. This
method assumes equivalence of nonspecific uptakes in stri-
atum and occipital cortex.
Specific to nondisplaceable striatal uptake was derived
by dividing the striatal specific uptake by occipital uptake.
The final ratio was calculated as the mean of all measure-
ments at 18, 21, and 24 hours (nine scans total).
The second outcome measure, percent uptake in the
striatal and occipital regions, used a larger number of
transaxial slices (14) than the ratio of specific to nondis-
placeable striatal uptake (four) to recover all specific activ-
ity associated with the striatum. In all subjects, the
summed slices included one or two slices extending beyond
visually identified striatum. A striatal ROI slightly larger
than that used in the other ROI analysis above was placed
over the summed slices over regions corresponding to left
and right striatum and occipital cortices bilaterally. This
ROI thus produced an identical volume of counts for all
brain regions. As in the previous analysis, nondisplaceable
striatal uptake was estimated from occipital counts. Total
counts within the occipital volume of interest were sub-
tracted from the total counts within the striatal volumes to
generate a measure of counts associated with specific stri-
atal uptake. In this instance the measure is related to the
total transporter number rather than transporter concen-
tration estimated in the previous analysis. Counts were
corrected for physical decay and converted to microcuries
(pCi) of activity based on an 1231-distributed 11-cm-diame-
ter phantom source containing 500 pCi of activity and
acquired on the day of each examination. The mean of
three measurements made at 24 hours is reported.
In the analysis of both outcome measures, a striatal
asymmetry index (AI) for P-CIT activity was defined
as the absolute value of (left - right)/(mean [left + right]).
The Wilcoxon signed rank test
was used to compare regional brain data in the hemi-PD
patients and healthy subjects. The relationship between
tracer uptake and age was examined by linear regression
analysis. Significance was reported at the p < 0.05 level.
Results. The patients in this study had mild, exclusively
hemi-PD with total UPDRS of 21.6 t 3.4 (all data ex-
pressed as mean ? SEMI and a mean disease duration of
1.4 years. Five of the eight patients were newly diagnosed
and three had been followed for up to 4 years. One patient
was treated with pergolide and two patients with selegi-
line. In vitro studies have demonstrated weak inhibitory
effects of L-selegiline on the selective dopamine transporter
inhibitor [3H]GBR-12935 binding in rat striatal slices.31 All
patients were L-dopa naive to minimize drug effect on im-
[ 1231]/3-CIT brain activity was highly concentrated in
the striatal region (figure 1). In the hemi-PD patients,
striatal [ 1231]p-CIT activity was reduced bilaterally, al-
though the reduction in activity was greater contralateral
to the symptomatic side. Both measures of ['231]p-CIT up-
take, total striatal uptake expressed as percent injected
dose (AI = 25.3 ? 3.5) and the ratio of specific to nondis-
placeable striatal uptake (AI = 30.0 * 3.9), demonstrated
an asymmetric loss of transporter activity, which in each
patient was greater contralateral to the symptomatic side
(figure 2). In contrast, the healthy subjects showed no sig-
nificant asymmetry, ie, total striatal uptake (AI = 4.3 5
1.2) and specific to nondisplaceable ratio (AI = 3.4 ? 1.2).
Comparison of the AI in the PD patients and healthy
subjects was significant at p < 0.01 for both outcome
The specific to nondisplaceable striatal uptake of the
hemi-PD patients was reduced by 53 5 4% contralateral
January 19% NEUROLOGY 46 233
Figure 1. Single-photon emission computed tomography (SPECT) /3-CIT images from a healthy subject and from a
patient with hemi-Parkinson's disease acquired 24 hours after injection. Note the asymmetric reduction in activity more
marked in the putamen than caudate in the patient. Leuels of SPECT actiuity are color encoded from low (black) to high
(yellow 1 white).
and by 37 2 5% ipsilateral to the symptomatic side com-
pared with the mean uptake in age- and sex-matched
healthy subjects (p < 0.01) (figure 2). Similarly, the total
striatal uptake expressed as percent injected dose of the
hemi-PD patients was reduced by 52 f 5% contralateral
and by 39 ? 7% ipsilateral to the asymptomatic side com-
pared with the mean total striatal uptake in age- and
sex-matched healthy subjects (p < 0.01). In addition, in
the eight hemi-PD patients, the relative reduction in the
speeificlnondisplaceable striatal uptake and in the total
striatal uptake was significantly different in the side con-
tralateral compared with the side ipsilateral to symptoms
(p < 0.01).
Recent evidence has shown that striatal [12311f3-CIT ac-
tivity is reduced by about 3 to 7% per decade in healthy
~ubjects.~~.~~ In figure 2, specific to nondisplaceable striatal
54 57 61
234 NEUROLOGY 46 January 1996
Figure 2. 2/3-Carboxymethoxy-3/3-(4-
iodopheny1)tropane ['""IIP-CIT striatal
uptake in eight hemi-Parkinson's dis-
easelhealthy subject pairs (mean age of
pair indicated). For each pair, the ratio
of the specific to nondisplaceable stria-
tal uptake is compared in right and left
striatum in the healthy subjects with
striatum ipsilateral to symptoms (Ipsi)
and contralateral to symptoms (Contra)
in the hemi-Parkinson's disease pa-
= left; E 4 = ipsi;
44 54 57
uptake in healthy subjects and in hemi-PD patients was
reduced with increasing age, ie, healthy subjects, p < 0.05;
ipsilateral PD, p < 0.05; contralateral PD, p < 0.09 (exam-
ined with linear regression analysis). However, the rela-
tive reduction of tracer uptake in the hemi-PD patients
compared with their age-matched controls did not vary
with age, but rather was a fairly constant percentage of
the healthy subject value. This result suggests that symp-
tom threshold is not entirely dependent on an absolute
reduction in dopamine transporter density, but may de-
pend on age-related compensatory mechanisms of the do-
Anatomic and biochemical pathology as well as PET
imaging have demonstrated that the dopaminergic loss in
PD is greater in the putamen than the caudate.g,11.17.37,38
Data comparing the relative loss of [‘231]P-CIT putamenal
and caudate striatal uptake in the hemi-PD patients show
a reduction in the putamen and caudate both contralateral
(58 ? 4% and 41 ? 6%) and ipsilateral (44 2 6% and 22 ?
6%) to symptoms compared with the putamenal and cau-
date uptake in age- and sex-matched healthy subjects (p <
0.01 for each of the four values). The greater loss of [12311P-
CIT activity in the putamen is further reflected in figure 3.
The caudatelputamen uptake is increased in the hemi-PD
patients both ipsilateral (1.5 2 0.1) and contralateral (1.5
? 0.1) to symptoms compared with their matched control
subjects (1.1 +- O.l),p < 0.01.
Discussion. [12311p-CIT SPECT imaging of the do-
pamine transporter reliably distinguished patients
with mild, hemi-PD disease from healthy subjects.
Furthermore, these data showed that there is a sig-
nificant reduction in [12311p-CIT striatal uptake con-
tralateral (symptomatic side) and ipsilateral (pre-
symptomatic side) to the parkinsonian symptoms.
The interval between the onset of disease and the
onset of symptoms in PD is unknown, but evidence
suggests that the usual presymptomatic period may
be several years.220.127.116.11x40
hemi-PD are by definition not strictly presymptom-
Although patients with
Figure 3. The ratio of caudate to puta-
men specific to nondisplaceable ZP-car-
([12311P-CIT) uptake is compared in
right and left striatum of healthy sub-
jects with striatum ipsilateral to symp-
toms (Ipsi) and contralateral to symp-
toms (Contra) in the hemi-Parkinson’s
disease patients. (0 = right; 0 = left;
= ipsi; H = contra.)
atic, the interval between diagnosis and development
of bilateral symptoms may be as long as several
years.6 Therefore, our data show clearly that dopa-
mine transporter imaging can identify PD patients
at the onset of symptoms, and further suggest that
dopamine transporter imaging may be able to iden-
tify presymptomatic patients destined to develop PD.
We selected two different outcome measures (total
striatal uptake and the ratio of specific to nondis-
placeable striatal uptake) to compare [12311p-CIT ac-
tivity in parkinsonian patients and healthy subjects.
Both outcome measures demonstrated a significant
reduction in [12311p-CIT activity in both the symp-
tomatic and presymptomatic striatum. Total striatal
uptake is both a straightforward concept and a ro-
bust signal, because biodistribution studies have
shown that approximately 1% of the injected dose is
taken up by the ~triatum.~~
uptake will be influenced by variations in peripheral
clearance between subjects. Importantly, the almost
identical reduction in p-CIT binding in PD pa-
tients, as measured by either total striatal uptake or
the specific to nondisplaceable ratio, indicates that
the peripheral clearance does not vary significantly
among subjects. The specific to nondisplaceable ratio
is a measure of specific [12311p-CIT in the target
brain region to a control region. This ratio may be
the most practical clinical measure, because it re-
quires neither calibration of the camera relative to
injected dose nor any plasma measurements. In ad-
dition, the kinetics of p-CIT indicate that aRer
a single injection of the ligand in healthy subjects a
rise in activity occurs on day 1, but very stable levels
of striatal activity are present from 18 to 30 hours
after injection, with an average decline of 0.3%/h1-.~~
PD patients achieve a plateau of activity on day 1, as
expected from a decreased number of target sites.22
Therefore, during this “equilibrium” period, the spe-
However, total striatal
January 1996 NEUROLOGY 46 235
cific to nondisplaceable ratio is linearly related to the
density of dopamine transporter sites in the striatum
(given the likely assumptions that affinity [l/KdI and
nonspecific distribution volume W21 is equivalent
among subjects). In clinical practice, this measure-
ment might be done at any convenient time the day
after an injection of [12311p-CIT, taking full advan-
tage of the relative ease and the longer half-life ra-
dioligands available with SPECT imaging.
PET imaging, using both general measures of me-
tabolism (glucose) and more-specific measures of do-
pamine function, [l8F1Fdopa, have been used by sev-
eral investigators to examine the in vivo
neurochemistry of early PD.9.11.17,40,41
aging shows an approximate 50 to 60% decrease in
putamenal activity and a 20 to 25% decrease in cau-
date activity in patients with PD.1°J1J7 Our data in
hemi-PD patients show a similar reduction in puta-
menal [12311p-CIT activity of 58% and 41%, and in
caudate p-CIT activity of 44% and 22%,, con-
tralateral and ipsilateral to symptoms, respectively.
[l8F1Fdopa imaging is dependent on dopamine turn-
over and therefore may be influenced by neuronal
metabolism, whereas the dopamine transporter bind-
ing site imaged by ['2311p-CIT is a more direct mea-
sure of presynaptic mesencephalic dopaminergic
neuron pathology. Although both [l8F1Fdopa and
[12311p-CIT are sensitive markers of PD, they may
measure different aspects of the developing dopa-
minergic deficit in these patients. In particular, the
increase in dopamine turnover that occurs in early
PD may confound the ["FIFdopa studies, suggesting
that transporter imaging may more accurately re-
flect early dopaminergic loss.
Although the reduction in dopamine transporter
density in the entire striatum clearly distinguishes
hemi-PD patients from healthy subjects, more de-
tailed examination of the striatum demonstrating
the greater loss of ['2311P-CIT uptake in the putamen
than caudate may increase the sensitivity of p-
CIT imaging for early PD detection. This anatomy of
dopamine transporter SPECT imaging is consistent
with the relatively selective loss of dopamine in the
posterior putamen in idiopathic PD in pathological
and PET ~ t u d i e s . ~ J ~ , ~ ~ Similarly, the characteristic
unilateral presentation of PD is reflected in the dra-
matic asymmetry in the loss of dopamine transporter
uptake. Elevation of the caudate/putamen ratio and
marked asymmetry of [12311p-CIT activity may be
useful in distinguishing idiopathic PD from atypical
parkinsonian syndromes that show a more uniform
and usually symmetric striatal loss of dopaminergic
activity both involving the caudate and p ~ t a m e n . ~ ~
Thus, SPECT imaging with ['2311P-CIT is a potential
diagnostic tool to identify patients with PD with
early or presymptomatic disease and to distinguish
patients with PD from those patients with other par-
kinsonian syndromes. Given the wide availability of
SPECT technology, dopamine transporter imaging
may also be used to monitor progression of disease
236 NEUROLOGY 46 January 1996
and to assess the efficacy of putative neuroprotective
agents for PD.
We gratefully acknowledge the nuclear medicine technologist sup-
port of E.O. Smith and G. Wisniewski, data analysis by L.
Poutages-Torak and Q. Ramsby, radiochemistry technical help of
M. Stratton, and provision of CIT precursor from John Neumeyer
of Research Biochemicals International.
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