Source:    JAMA. 2002;287:1653-1661
Date:        04/03/2002

The following article appeared in the Journal of the American Medical
Association 3 April 2002. The report was modified by Dr Abe Lieberman
for educational purposes to make it more readable for lay people with PD.

SPECT Imaging to Assess the Effects of Mirapex compared to Levodopa
on Parkinson Disease Progression

Parkinson Study Group

Abstract
Dopamine Transporter Imaging to Assess the Effects of Pramipexole
versus Levodopa on the Progression of Parkins Disease (original title)

Context  Pramipexole (mirapex) 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 2-carboxymethoxy-3(4-iodophenyl)tropane (-CIT) labeled with
iodine 123.

Design  Substudy of a parallel-group, double-blind randomized clinical
trial.

Setting and Patients  82 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]-CIT uptake after 46 months. The
percentage changes and absolute changes in striatal, putamen, and caudate
[123I]-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]-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 monthsapproximately 5.2% per year.

 (Comment: it's estimated the 'normal' age related loss of of striatal
uptake is 0.6% per year.  This is a measure of the loss of dopamine nerve
cells in the substantia nigra.  In PD  the 5.2% loss per year in this
study is 8.6 times higher than the 'normal' age related loss.  In other
words, PD represents about an 8 fold increase in the loss of dopamine
neurons per year).

The mean percentage loss in striatal [123I]-CIT uptake from baseline
was significantly reduced in the pramipexole group compared with the
levodopa group:

7.1% for pramipexole versus vs 13.5% for levodopa at 22 months.  This
change was NOT significant

10.9%  for pramipexole versus vs 19.6%  for levodopa at 34 months.  This
change was significant.

16.0%  for pramipexole versus 25.5%  for levodopa at 46 months.  This
change was significant.

The percentage loss from baseline in striatal [123I]-CIT uptake was
correlated with the change from baseline in UPDRS at the 46-month
evaluation.

Conclusions  Patients initially treated with pramipexole demonstrated a
reduction in loss of striatal [123I]-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.

JAMA. 2002;287:1653-1661

Introduction: 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 nigral dopamine degeneration.Dopamine replacement
therapy with 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 Studies have demonstrated that dopamine receptor
agonists protect cultured dopaminergic neurons from potential levodopa
toxicity and may exert direct antioxidant and receptor-mediated
ant-iapoptotic effects (slow down cell suicide).

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 dopamine markers in the striatum. In longitudinal studies of PD
progression, imaging ligands targeting both dopamine metabolism fluorine
18 fluorodopa ([18F]DOPA) and dopamine transporter density iodine 123
(2-carboxymethoxy-3[4-iodophenyl]tropane [123I]-CIT) and fluorine 18
(2-carboxymethoxy-3tropane [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]-CIT uptake of approximately 6% to 13% in patients with
PD compared with 0% to 2.5% change in healthy controls.

     The above 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.

     We have used in vivo imaging of the dopamine transporter with
[123I]-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
dopamine motor complications and changes associated with function and
quality of life.

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. In this report, we
present the 4-year follow-up of the subset of study patients who have
undergone sequential [123I]-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.


 METHODS: The methods and outcomes of the imaging substudy, called
CALM-PD-CIT, are described herein. The CALM-PD clinical outcomes at 4
years are 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.

CALM-PD:  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.  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 -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.

CALM-PD-CIT[123I]-CIT and SPECT Substudy
All patients in CALM-PD-CIT were evaluated sequentially with imaging
studies at baseline and 22, 34, and 46 months after baseline  Four
contiguous brain slices with the highest uptakes in striatum were
identified for anaylysis.

     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. The clinical
investigator was blinded to treatment assignment.

    The primary outcome variable in this study was the percentage change
from baseline to month 46 in the specific striatal [123I]-CIT uptake
ratio, a tissue equilibrium distribution volume that is linearly related
to the density of dopamine transporter binding sites in brain.

RESULTS

    During the 46-month evaluation period, 9 patients (21.4%) initially
treated with pramipexole and 8 patients (20%) initially treated with
levodopa withdrew  For patients who completed 46 months of follow-up, the
mean baseline striatal -CIT uptake was 3.0  in the pramipexole group (n =
33) vs 2.9 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.

    The mean percentage loss from baseline of striatal -CIT uptake was
10.3% at 22 months, 15.3% at 34 months, and 20.7% t 46 months, declining
approximately 5.2% per year during the 46-month evaluation period. The
mean percentage loss from baseline of [123I]-CIT uptake at 46 months was
greater in the putamen (22.5%) than in the caudate (19.6%). Although there
was a greater baseline reduction in the side contralateral to initial
symptoms  the progressive loss of [123I]-CIT uptake in each hemistriatum
did not differ.

    Analysis of the treatment groups demonstrated that the rate of decline
in striatal [123I]-CIT uptake from baseline was significantly reduced in
the group treated initially with pramipexole compared with the group
treated initially with levodopa (see abstact above)..

Correlation of [123I]-CIT Uptake and UPDRS Score

    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. There was a
correlation of the percentage loss of striatal [123I]-CIT uptake from
baseline with the change in total UPDRS score from baseline in all
patients. The percentage loss of putamen and caudate [123I]-CIT uptake
from baseline showed increasing correlation with the change in UPDRS score
from baseline as the duration of assessment increased).

COMMENT

     In vivo dopamine transporter imaging with [123I]-CIT SPECT
demonstrated reduced loss of striatal [123I]-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]-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 In vivo imaging offers the potential of an
objective method to monitor neuronal degeneration unaffected by a
short-term symptomatic drug effect.

    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. . We now present
data demonstrating a significant and persistent reduction in the rate of
loss of [123I]-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]-CIT uptake is a biomarker for striatal dopamine
transporter density and also dopamine neuronal terminal integrity.
Progressive nigrostriatal dopamine neuron loss is the predominant
pathologic finding of PD. Therefore, the relative reduction in the rate of
loss of [123I]-CIT uptake in those patients treated with pramipexole
compared with levodopa most likely reflects a reduction (by pramipexole)
in the progressive loss of striatal dopamine neuronal function.

    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. 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]-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]-CIT
uptake due to exposure to pramipexole rather than an increase due to
exposure to levodopa is more likely.

    In prior imaging studies, the annual percentage loss of [123I]-CIT
striatal uptake of untreated patients with PD was 6.8%, similar to the
levodopa group in this study. These imaging data suggest that treatment
with pramipexole may have decreased the rate of loss of [123I]-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]-CIT uptake in patients with early PD that will further elucidate
the relative effects of pramipexole and levodopa on [123I]-CIT uptake.5

    A key issue is whether the effects of pramipexole and levodopa on the
rate of loss of [123I]-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. These end points reflect the complex clinical progression of
PD symptoms and disability. The changes in imaging outcome measures such
as [123I]-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]-CIT correlates with the increasing severity measured
by the UPDRS.However, in prior longitudinal studies, there has been no
clear correlation between change in either [123I]-CIT or [18F]DOPA uptake
and the change in UPDRS score.

    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. 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]-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]-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.

    This study demonstrates that [123I]-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]-CIT uptake in patients initially treated with pramipexole
compared with levodopa.

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