Context Pramipexole and levodopa are effective medications to treat motor symptoms
of early Parkinson disease (PD). In vitro and animal studies suggest that
pramipexole may protect and that levodopa may either protect or damage dopamine
neurons. Neuroimaging offers the potential of an objective biomarker of dopamine
neuron degeneration in PD patients.
Objective To compare rates of dopamine neuron degeneration after initial treatment
with pramipexole or levodopa in early PD by means of dopamine transporter
imaging using single-photon emission computed tomography (SPECT) with 2β-carboxymethoxy-3β(4-iodophenyl)tropane
(β-CIT) labeled with iodine 123.
Design Substudy of a parallel-group, double-blind randomized clinical trial.
Setting and Patients Eighty-two patients with early PD who were recruited at 17 clinical
sites in the United States and Canada and required dopaminergic therapy to
treat emerging disability, enrolled between November 1996 and August 1997.
Interventions Patients were randomly assigned to receive pramipexole, 0.5 mg 3 times
per day with levodopa placebo (n = 42), or carbidopa/levodopa, 25/100 mg 3
times per day with pramipexole placebo (n = 40). For patients with residual
disability, the dosage was escalated during the first 10 weeks, and subsequently,
open-label levodopa could be added. After 24 months of follow-up, the dosage
of study drug could be further modified.
Main Outcome Measures The primary outcome variable was the percentage change from baseline
in striatal [123I]β-CIT uptake after 46 months. The percentage
changes and absolute changes in striatal, putamen, and caudate [123I]β-CIT
uptake after 22 and 34 months were also assessed. Clinical severity of PD
was assessed using the Unified Parkinson Disease Rating Scale (UPDRS) 12 hours
off anti-PD medications.
Results Sequential SPECT imaging showed a decline in mean (SD) [123I]β-CIT
striatal uptake from baseline of 10.3% (9.8%) at 22 months, 15.3% (12.8%)
at 34 months, and 20.7% (14.4%) at 46 months—approximately 5.2% per
year. The mean (SD) percentage loss in striatal [123I]β-CIT
uptake from baseline was significantly reduced in the pramipexole group compared
with the levodopa group: 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P = .004); 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P = .009); and 16.0% (13.3%) vs 25.5% (14.1%) at 46 months (P = .01). The percentage loss from baseline in striatal [123I]β-CIT
uptake was correlated with the change from baseline in UPDRS at the 46-month
evaluation (r = − 0.40; P = .001).
Conclusions Patients initially treated with pramipexole demonstrated a reduction
in loss of striatal [123I]β-CIT uptake, a marker of dopamine
neuron degeneration, compared with those initially treated with levodopa,
during a 46-month period. These imaging data highlight the need to further
compare imaging and clinical end points of PD progression in long-term studies.
Parkinson disease (PD) is a slow but relentlessly progressive neurodegenerative
disorder characterized clinically by bradykinesia, tremor, rigidity, and gait
dysfunction. The clinical decline reflects ongoing nigrostriatal dopaminergic
degeneration.1-3
Dopaminergic replacement therapy with the precursor levodopa or agonists that
stimulate the dopamine receptor is effective in ameliorating many signs and
symptoms of early PD. However, progressive neuronal degeneration ultimately
results in severe motor, mental, and functional disability.
Increasing evidence from laboratory and animal studies suggests that
in addition to their symptomatic effects, levodopa and dopamine receptor agonists
may either accelerate or slow the dopaminergic degeneration of PD. Recent
data regarding the effects of levodopa have been controversial with in vitro
data supporting both a potential toxic and protective effect on dopaminergic
neurons.4,5 Studies have demonstrated
that dopamine receptor agonists protect cultured dopaminergic neurons from
potential levodopa toxicity and may exert direct antioxidant and receptor-mediated
antiapoptotic effects.6-8
The putative neurotoxic or neuroprotective actions of levodopa or dopamine
receptor agonists have provided the rationale for assessing the progression
of dopamine neuronal degeneration in patients with PD after treatment with
these drugs.
During the past decade, in vivo imaging of the nigrostriatal dopaminergic
system has been developed as a research tool to monitor progressive dopaminergic
neuron loss in PD. Several reports have demonstrated that at the time of emergence
of PD symptoms there is a loss of approximately 40% to 60% of dopaminergic
markers in the striatum.9-14
In longitudinal studies of PD progression, imaging ligands targeting both
dopamine metabolism fluorine 18 fluorodopa ([18F]DOPA) and dopamine
transporter density iodine 123 (2β-carboxymethoxy-3β[4-iodophenyl]tropane
[123I]β-CIT) and fluorine 18 (2β-carboxymethoxy-3βtropane
[18F]CFT) using both positron emission tomography and single-photon
emission computed tomography (SPECT) have demonstrated an annualized rate
of reduction in striatal [18F]DOPA, [18F]CFT, or [123I]β-CIT uptake of approximately 6% to 13% in patients with PD
compared with 0% to 2.5% change in healthy controls.15-19
These imaging studies are consistent with pathological studies showing that
the rate of nigral degeneration in patients with PD was 8- to 10-fold that
of healthy, age-matched controls.2,20
We have used in vivo imaging of the dopamine transporter with [123I]β-CIT and SPECT to assess the progression of dopaminergic
degeneration in a subset of patients with early PD participating in a clinical
trial that compared the option of initial treatment with pramipexole with
the option of initial treatment with levodopa. The clinical study (called
CALM-PD) was a multicenter, parallel-group, double-blind, randomized clinical
trial comparing the option of initial treatment with pramipexole or levodopa
with regard to the development of dopaminergic motor complications and changes
associated with function and quality of life.21
After 2 years of prospective follow-up, initial treatment with pramipexole
delayed the onset of dopaminergic motor complications compared with levodopa
therapy but initial levodopa therapy was more effective than pramipexole in
ameliorating signs and symptoms of PD.22 In
this report, we present the 4-year follow-up of the subset of study patients
who have undergone sequential [123I]β-CIT SPECT imaging to
compare the rate of loss of the dopamine transporter, a marker for dopamine
nerve terminal loss, between the groups treated initially with pramipexole
or levodopa.
The methods and results of the CALM-PD trial after 2 years of follow-up
have been previously reported.21,22
With patient informed consent, the trial was extended to a 4-year follow-up
with maintenance of the parallel-group, double-blind, randomized design. The
methods and outcomes of the imaging substudy, called CALM-PD-CIT, are described
herein. The CALM-PD clinical outcomes at 4 years will be reported separately.
A total of 82 of the 301 patients in the CALM-PD trial, enrolled between November
1996 and August 1997, participated in the imaging substudy. Research participants
in the imaging substudy were recruited at 17 clinical sites (14 in the United
States and 3 in Canada) and traveled to the imaging center in New Haven, Conn,
for up to 4 imaging assessments. The imaging study was approved by the institutional
review board and radiation safety committee. All patients gave written informed
consent.
Complete eligibility requirements for the trial have been previously
detailed.21 Eligible patients were randomized
with equal allocation to each of the 2 treatment groups (pramipexole group
or carbidopa/levodopa group) using a computer-generated randomization plan.
Participation in the imaging substudy was not considered in the randomization
plan. All patients enrolled at sites that chose to participate in the imaging
substudy were offered the option, but were not required to participate in
the β-CIT SPECT substudy. Baseline imaging was completed prior to randomization.
Patients took study drugs orally 3 times daily, approximately 6 (SD,
2) hours apart, throughout the study. Initially patients entered a 10-week
dosage escalation period to reach one of the predetermined dosage levels:
1.5 mg of pramipexole or 75 or 300 mg of carbidopa/levodopa (level 1 dosage);
3.0 mg of pramipexole or 112.5 or 450 mg of carbidopa/levodopa (level 2 dosage);
or 4.5 mg of pramipexole or 150 or 600 mg of carbidopa/levodopa (level 3 dosage).
Study drug was then maintained at that level until 24 months after baseline,
and subsequently the dosage level could be modified during an additional 22-
to 36-month evaluation period. Patients with emerging disability posing a
threat to ambulation, activities of independent living, or gainful employment
were prescribed open-label carbidopa/levodopa as needed.
All patients in CALM-PD-CIT were evaluated sequentially with imaging
studies at baseline and 22, 34, and 46 months after baseline as indicated
in Figure 1. Thirteen patients also
underwent imaging studies at 10 weeks after baseline to assess short-term
effects of study drugs on the imaging outcome.
Imaging Data Acquisition and Image Analysis
High specific-activity [123I]β-CIT was prepared from
the corresponding trimethylstannyl precursor as previously described.23 Patients were injected with a 6-mCi (222-MBq) dosage
of [123I]β-CIT after pretreatment with Lugol solution to prevent
thyroid uptake of any free 123I. One hundred twenty raw projection
images were acquired in a 128 × 128 matrix into a 20% energy window
centered on 159 keV at a mean of 24 (SD, 2) hours following injection on a
3-headed detector SPECT system (Picker Prism 3000XP; Marconi Medical, Cleveland,
Ohio) fitted with low-energy, high-resolution fan beam collimators.
Projection data were filtered with a standardized 2-dimensional Butterworth
filter and reconstructed using a ramp filter. Spatial resolution for this
reconstruction method is a full width at half maximum of 12.2 mm measured
with a 123I line source in a 20-cm cylindric phantom filled with
water. Attenuation correction ellipses were fit using a Chang zero order (homogeneous)
correction applied to the reconstructed data.24
Four contiguous transaxial slices with the highest uptakes in striatum were
identified and digitally summed to yield a transaxial slice 14.2 mm thick.
This plane of slice is a noted distance superior to and parallel with the
canthomeatal line. Standard uniform, circular regions of interest for left
and right caudate and putamen, and a larger region of interest for the background
cortical region (occipital cortex) were drawn using previously described operationalized
criteria.15,25 All analyses were
completed by a single technologist (M.E.) blinded to any patient information.
While the study was ongoing, an improvement in the reconstruction algorithm
was introduced by the camera manufacturer, which modified the equilibrium
brain tissue distribution volume by improving the reconstruction for regions
with low counts. Preliminary findings from the baseline to 22-month scan were
reported22 using the old reconstruction algorithm.
All raw projection data from the baseline and 22-month scan were subsequently
reanalyzed with the improved algorithm and reported herein in conjunction
with month 34 and 46 scan data. The decision to use the reanalyzed raw projection
data in the statistical analysis of this study was made before data analysis
and while investigators were blinded to treatment assignment.
All study participants were evaluated after 12 hours without study drug
and anti-PD medications, the "defined off" state, with Unified Parkinson Disease
Rating Scale (UPDRS) and Hoehn and Yahr scores determined at the imaging center
before each imaging study.26-28
The clinical investigator was blinded to treatment assignment.
The prespecified primary outcome variable in this study was the percentage
change from baseline to month 46 in the specific-nondisplaceable striatal
[123I]β-CIT uptake ratio, a tissue equilibrium distribution
volume sampled in regions of caudate and putamen that is linearly related
to the density of dopamine transporter binding sites in brain.29,30
Specific uptake was determined by subtracting occipital densities (nondisplaceable
uptake) from total caudate and/or putamen count densities and dividing by
the occipital background region. Striatal uptake was the mean of the caudate
and putamen uptake.
Secondary outcome variables included percentage changes from baseline
to month 46 in caudate and putamen [123I]β-CIT uptake ratios
and percentage changes from baseline to months 22 and 34 for [123I]β-CIT
uptake ratio (striatum, putamen, and caudate). Secondary outcomes also included
these variables expressed as absolute change in [123I]β-CIT
uptake ratio from baseline and changes from baseline in UPDRS scores (total
and motor) after 22, 34, and 46 months.
Analysis of covariance was used to compare the treatment groups with
regard to mean percentage changes (and mean changes) in [123I]β-CIT
uptake and mean changes in UPDRS scores, with the baseline value included
as a covariate. Two-tailed t tests were used to compare
the adjusted treatment group means.
The association between change from baseline in UPDRS score (dependent
variable) and percentage change from baseline in [123I]β-CIT
uptake (independent variable) was examined using a multiple regression model
that adjusted for initial treatment (pramipexole, levodopa) and baseline UPDRS
score. This analysis was performed separately for each time point (months
22, 34, and 46).
For all analyses, patients were grouped by the intention-to-treat principle
according to their original randomized treatment assignment (pramipexole,
levodopa) even if they received supplemental levodopa therapy or withdrew
from CALM-PD, but continued to be followed up in CALM-PD-CIT. Two separate
analyses were performed, one using only available data and another that incorported
imputation of missing follow-up data. Imputation was performed as follows:
(1) for patients with complete data at month 22, a regression model was fit
with the month 22 value as the dependent variable and the baseline value and
treatment group as the independent variables; (2) using this regression model,
a missing value at month 22 was imputed given the treatment group and baseline
value for a patient with missing data; (3) for patients with complete data
at month 34, a regression model was fit with the month 34 value as the dependent
variable and the baseline value, month 22 value, and treatment group as the
independent variables; and (4) using this regression model, a missing value
at month 34 was imputed given the treatment group, baseline value, and month
22 value for a patient with missing data. Steps 3 and 4 were repeated to impute
a missing value at month 46 given the treatment group and baseline, month
22, and month 34 values for a patient with missing data. Unless otherwise
specified, the analyses reported are those that were performed using only
available data. The results obtained using these 2 analysis strategies were
similar. All statistical tests were 2-tailed. Statistical analyses were performed
using SAS version 8.0 (SAS Institute Inc, Cary, NC) and tested at the .05
level of significance.
The demographic characteristics of the study cohort at baseline are
shown in Table 1. The 82 patients
participating in the imaging substudy did not differ from the 301 patients
in the CALM-PD study.22 The age, sex, and ethnic
distributions of patients enrolled in the 2 treatment groups were similar.
The patients initially treated with levodopa were slightly less impaired as
measured by the baseline UPDRS. There was a similar reduction in striatal β-CIT
uptake consistent with early PD in both treatment groups.
During the 46-month evaluation period, 9 patients (21.4%) initially
treated with pramipexole and 8 patients (20%) initially treated with levodopa
withdrew from the study (Figure 1).
For patients who did not complete 46 months of follow-up, the mean (SD) baseline
striatal β-CIT uptake was 2.8 (0.9) in the pramipexole group (n = 9)
and 3.1 (1.1) in the levodopa group (n = 8). For patients who completed 46
months of follow-up, the mean (SD) baseline striatal β-CIT uptake was
3.0 (0.7) in the pramipexole group (n = 33) vs 2.9 (0.5) in the levodopa group
(n = 32). One patient in the pramipexole group withdrew because of worsening
PD with hallucinations; 1 patient in the pramipexole group and 3 patients
in the levodopa group withdrew because of worsening medical illness not related
to PD. There were 4 deaths in the pramipexole group and 2 deaths in the levodopa
group that were judged to be unrelated to study drug.
Sequential Imaging Analysis
Sequential imaging of the entire study cohort showed a mean (SD) decline
from baseline in [123I]β-CIT striatal uptake of 0.28 (0.31)
at 22 months, 0.42 (0.36) at 34 months, and 0.58 (0.40) at 46 months. The
corresponding mean (SD) percentage loss from baseline of striatal β-CIT
uptake was 10.3% (9.8%) at 22 months, 15.3% (12.8%) at 34 months, and 20.7%
(14.4%) at 46 months, declining approximately 5.2% per year during the 46-month
evaluation period (Figure 2). The
mean (SD) percentage loss from baseline of [123I]β-CIT uptake
at 46 months was greater in the putamen (22.5% [19.5%]) than in the caudate
(19.6% [13.6%]). Although there was a greater baseline reduction in the side
contralateral to initial symptoms (Table
1), the progressive loss of [123I]β-CIT uptake in
each hemistriatum did not differ.
Analysis of the treatment groups demonstrated that the rate of decline
in striatal [123I]β-CIT uptake from baseline was significantly
reduced in the group treated initially with pramipexole compared with the
group treated initially with levodopa (Figure
3A and Table 2). The
mean (SD) percentage loss from baseline of [123I]β-CIT striatal
uptake in the pramipexole vs levodopa groups was 16.0% (13.3%) vs 25.5% (14.1%)
at 46 months (P = .01). Similarly, comparison of
the percentage loss from baseline in the pramipexole group with the levodopa
group was 7.1% (9.0%) vs 13.5% (9.6%) at 22 months (P
= .004) and 10.9% (11.8%) vs 19.6% (12.4%) at 34 months (P = .009). Putamen and caudate [123I]β-CIT uptake showed
a similar reduction in the rate of decline in the pramipexole group (Figure 3B and C and Table 2). Analyses that incorporated imputation of missing follow-up
data revealed similar results (pramipexole vs levodopa at 46 months): striatal
[123I]β-CIT uptake, 16.6% (12.7%) vs 24.9% (14.0%) (P = .005); caudate [123I]β-CIT uptake,
15.6% (11.6%) vs 23.7% (12.5%) (P = .003); and putamen
[123I]β-CIT uptake, 18.6% (18.8%) vs 27.2% (19.3%) (P = .05).
During the initial 22 months of the study, 19 of 39 patients in the
pramipexole group and 22 of 39 patients in the levodopa group were treated
with study drug alone without requiring supplemental levodopa. The percentage
loss of [123I]β-CIT striatal uptake from baseline after 22
months in these study participants was 6.9% (9.0%) in the pramipexole group
compared with 12.0% (11.1%) in the levodopa group (P
= .08), a relative decrease in the pramipexole group of 43%. Among study participants
who did require supplemental levodopa by 22 months after baseline, the percentage
loss of [123I]β-CIT striatal uptake from baseline after 22
months was 7.3% (9.2%) in the pramipexole group compared with 15.5% (7.0%)
in the levodopa group (P = .009), and after 46 months
from baseline was 17.2% (15.5%) in the pramipexole group vs 28.9% (16.4%)
in the levodopa group (P = .03).
The short-term effect of pramipexole (n = 7) and levodopa (n = 6) on
[123I]β-CIT uptake was further assessed in the subset of study
participants who underwent imaging 10 weeks after initiating treatment. Comparison
of [123I]β-CIT striatal uptake at 10 weeks with baseline showed
a decrease of 5.4% (12.2%) in the pramipexole group and 4.6% (4.4%) in the
levodopa group.
The mean total and motor UPDRS scores obtained in the "defined off"
state were reduced in the levodopa group at 22 months compared with baseline
and the pramipexole group, but were not significantly different from baseline
or the pramipexole group by 34 or 46 months (Table 3). There was a correlation of the percentage loss of striatal
[123I]β-CIT uptake from baseline with the change in total
UPDRS score from baseline in all patients (r = −
0.01, P = .94 at 22 months; r
= − 0.30, P = .01 at 34 months; and r = − 0.40, P = .001 at 46 months from
baseline). The percentage loss of putamen and caudate [123I]β-CIT
uptake from baseline showed increasing correlation with the change in UPDRS
score from baseline as the duration of assessment increased (putamen: r = − 0.03, P = .78 at 22
months; r = − 0.39, P
= .001 at 34 months; and r = − 0.39, P = .001 at 46 months from baseline; caudate: r = 0.02, P = .89 at 22 months; r = − 0.20, P = .11 at 34 months; and r = − 0.35, P = .005 at
46 months from baseline).
In vivo dopamine transporter imaging with [123I]β-CIT
SPECT demonstrated reduced loss of striatal [123I]β-CIT uptake
in patients with PD treated initially with pramipexole compared with those
treated initially with levodopa during a 46-month evaluation period. As [123I]β-CIT SPECT is a quantitative biomarker for striatal dopamine
neuron terminals, these data indicate that treatment with pramipexole, levodopa,
or both may modify the dopaminergic neuronal degeneration of PD.
The identification of disease-modifying therapies for PD is a major
unmet need. Studies that evaluate neuroprotective effects of medications have
been limited by the lack of a clear end point defining neuroprotection and
confounded by potential simultaneous symptomatic and neuroprotective benefit.31,32 In vivo imaging offers the potential
of an objective method to monitor neuronal degeneration unaffected by a short-term
symptomatic drug effect.33
Several recent studies have used neuroimaging to investigate the possible
neuroprotective effects of dopamine agonists. A preliminary study that assessed
the effects of ropinirole hydrochloride did not demonstrate a change in neuronal
loss as measured by [18F]DOPA positron emission tomography, but
showed a trend toward reduction in the change of [18F]DOPA uptake
in the patients treated with the dopamine agonist.34
Initial analysis of our data in the CALM-PD-CIT study after 22 months
showed a similar trend toward reduction in the rate of loss of [123I]β-CIT
uptake in patients initially treated with pramipexole compared with those
treated with levodopa.22 The 22-month data
presented in this study differ from the previous study because these data
were analyzed using improved reconstruction analysis technology developed
during the study and designed to more accurately measure count density in
regions with low counts. During the past 2 years, we have both improved our
reconstruction analysis technology and extended the duration of the double-blind,
parallel-group design, while retaining 79% of enrolled patients at 46 months.
We now present data demonstrating a significant and persistent reduction in
the rate of loss of [123I]β-CIT uptake in patients with PD
initially treated with pramipexole compared with levodopa during the 46-month
evaluation period.
Evidence from animal studies, healthy humans, and patients with PD has
demonstrated that [123I]β-CIT uptake is a biomarker for striatal
dopamine transporter density and also dopamine neuronal terminal integrity.9,25,35,36 Progressive
nigrostriatal dopamine neuron loss is the predominant pathologic finding of
PD. Therefore, the relative reduction in the rate of loss of [123I]β-CIT
uptake in those patients treated with pramipexole compared with levodopa most
likely reflects a reduction (by pramipexole) or acceleration (by levodopa)
in the progressive loss of striatal dopamine neuronal function. Although it
remains possible that the difference in the pramipexole vs levodopa groups
is because of an interaction between pramipexole, levodopa, or both and the
dopamine transporter, it is likely that such an interaction would be present
shortly after initiating therapy. In this study, short-term sequential imaging
at 10 weeks did not demonstrate any significant effect of either pramipexole
or levodopa on [123I]β-CIT uptake. These data were also consistent
with prior studies showing no short-term effects of levodopa, selegiline,
or pergolide on [123I]β-CIT uptake.37,38
Approximately 20% of the study cohort withdrew from CALM-PD-CIT before
the month 46 visit. However, in both treatment groups, the baseline transporter
density measurements in patients who withdrew from the trial were similar
to those in patients who completed the trial. The frequency and reasons for
withdrawal were also similar in the 2 groups and the treatment effects were
reasonably consistent over time, including month 22 in which 95% of the cohort
remained. The analyses that incorporated imputation of missing follow-up data
yielded results that were similar to those based on only available follow-up
data. The regression-based imputation strategy that we used seems reasonable
in our setting and more appropriate than an ad-hoc approach such as carrying
forward the last available observation.39 For
all of these reasons, we do not believe that participant withdrawal had a
major impact on the overall results.
Since this study compared 2 active medications without a placebo group,
these data cannot directly distinguish whether the difference in the rate
of loss of [123I]β-CIT uptake in the treatment groups results
from a decrease due to pramipexole, an increase due to levodopa, or both.
However, indirect evidence from preclinical studies and prior imaging studies
suggests that a decrease in the percentage loss of [123I]β-CIT
uptake due to exposure to pramipexole rather than an increase due to exposure
to levodopa is more likely. Preclinical data regarding the effects of levodopa
suggest both possible toxic and protective action,4,5
whereas emerging data regarding dopamine agonists have supported a neuroprotective
action via antioxidant or antiapoptotic mechanisms.7,8,40
In prior imaging studies, the annual percentage loss of [123I]β-CIT
striatal uptake of untreated patients with PD was 6.8%, similar to the levodopa
group in this study.41 Furthermore, the percentage
loss from baseline of [123I]β-CIT striatal uptake after 46-month
follow-up in this study in those patients initially treated with pramipexole
who did require supplemental levodopa by 22 months remained reduced compared
with those patients initially treated with levodopa also requiring supplemental
levodopa by 22 months. These imaging data suggest that treatment with pramipexole
may have decreased the rate of loss of [123I]β-CIT uptake
despite treatment with levodopa. However, the duration and dose of exposure
to supplemental levodopa and the effect of pretreatment with a dopamine agonist
on a possible levodopa disease-modifying effect have not been fully evaluated.
Studies are under way to directly assess the effect of treatment with levodopa
compared with placebo on the rate of loss of [123I]β-CIT uptake
in patients with early PD that will further elucidate the relative effects
of pramipexole and levodopa on [123I]β-CIT uptake.5
A key therapeutic issue is whether the effects of pramipexole and levodopa
on the rate of loss of [123I]β-CIT uptake are associated with
a persistent change in clinical function in patients with PD. Several clinical
end points for progressive functional decline in PD have been used, including
UPDRS in the "defined off" state or after drug washout up to 2 weeks, time
to need for dopaminergic therapy, or time to the development of motor fluctuations.5,32,42 These end points reflect
the complex clinical progression of PD symptoms and disability. The changes
in imaging outcome measures such as [123I]β-CIT provide a
method to assess the striatal dopamine pathologic features of PD. In several
cross-sectional studies of PD cohorts, the reduction in [123I]β-CIT
correlates with the increasing severity measured by the UPDRS.9,25
However, in prior longitudinal studies, there has been no clear correlation
between change in either [123I]β-CIT or [18F]DOPA
uptake and the change in UPDRS score.15,16
Several explanations for this poor correlation have been suggested.
First, the UPDRS score is likely confounded by the effects of anti-PD medications,
despite patient evaluation in the "defined off" state because of long-duration
effects of these treatments.43 Second, in early
PD the temporal patterns for rate of loss of dopamine transporter and the
change in UPDRS score may not be congruent. This is best illustrated by data
demonstrating a loss of approximately 40% to 50% of striatal [123I]β-CIT
uptake at the time of diagnosis when clinical symptoms measured by the UPDRS
may be minimal. These data suggest that in patients with early PD clinical
and imaging outcomes provide complementary data and that long-term follow-up
will be required to correlate changes in clinical and imaging outcomes. In
this study, the loss of striatal [123I]β-CIT uptake from baseline
was significantly correlated with the change in UPDRS score from baseline
at the 46-month evaluation, suggesting that the correlation between clinical
and imaging outcomes will emerge with longer monitoring. We plan to extend
the follow-up of this imaging cohort and examine the associations between
changes in the loss of striatal [123I]β-CIT uptake and the
complete clinical data in the CALM-PD study.
This study demonstrates that [123I]β-CIT SPECT imaging
can detect treatment-related changes in the progressive rate of loss of striatal
dopamine transporters in patients with early PD. During a 46-month evaluation
period, these data show a decrease in the rate of loss of striatal [123I]β-CIT uptake in patients initially treated with pramipexole
compared with levodopa. These data highlight the need to compare this imaging
marker of dopamine neuronal loss with multiple meaningful clinical end points
of disease progression in larger, long-term studies to fully assess its clinical
relevance.
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