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Dopamine agonists and Parkinson's disease progression What can we learn from neuroimaging studies.

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Dopamine Agonists and Parkinson’s Disease
Progression: What Can We Learn from
Neuroimaging Studies
Kenneth Marek, MD, Danna Jennings, MD, and John Seibyl, MD
Parkinson’s disease is a relentlessly progressive disorder
causing disability in most individuals that cannot be
controlled with available medications. The identification of medications that might slow progression or restore neuronal function thus is a major unmet need for
Parkinson’s disease patients and a major goal of neurotherapeutics.1 Recent advances in neuroscience have
provided the rationale to test several candidate drugs as
putative neuroprotective agents. These include bioenergetic agents (eg, coenzyme Q10), trophic factors (eg,
GDNF and neuroimmunophilin A), antiglutamatergic
agents (eg, riluzole or N-methyl-D-aspartate receptor
antagonists), antiapoptotic drugs (eg, CEP 1347 and
CTCH 346), and dopamine agonists such as
pramipexole and ropinirole.2– 8 An extensive body of in
vitro and in vivo data indicate that dopamine agonists
have the potential to slow neuronal degeneration.
These studies are reviewed in this supplement and elsewhere9 and suggest that dopamine agonists have the
capacity to exert a neuroprotective effect via both dopamine receptor–mediated and non–dopamine receptor–mediated mechanisms.10 These basic science studies have led to clinical trials designed to assess the
capacity of dopamine agonists to modify the rate of
PD progression using neuroimaging biomarkers of nigrostriatal function as primary outcome measures. Imaging techniques have emerged as a bridge that enables
clinical studies to test basic science hypotheses in the
human brain, thereby translating advances in neuroscience into relevant clinical neurology. In this review,
we focus on the use of in vivo imaging to assess potentially neuroprotective drugs, in general, and dopamine agonists, in particular.
In Vivo Imaging Assessment of Parkinson’s
Disease Progression
In vivo imaging of the nigrostriatal dopaminergic system has been developed as a research tool to monitor
the rate of dopaminergic neuronal loss in PD. The two
From the Institute for Neurodegenerative Disorders, New Haven,
CT.
Published online Mar 24, 2003, in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.10486.
S160
© 2003 Wiley-Liss, Inc.
most widely used imaging biomarkers are striatal fluorodopa uptake on positron emission tomography
(PET/F-dopa), which measures dopamine function, and
striatal 2␤-carboxymethoxy-3␤(4-iodophenyl)tropane
uptake on single-photon emission tomography (SPECT/
␤-CIT), which targets the dopamine transporter. Several reports have demonstrated that at the time of
emergence of PD symptoms there is a loss of approximately 40 to 60% of these dopaminergic markers in
the striatum.11–16 In longitudinal studies of PD progression, the annualized rate of reduction of striatal uptake for both PET/F-dopa and SPECT/␤-CIT is approximately 6 to 13% in PD patients compared with 0
to 2.5% in healthy controls.17–21
Imaging studies assessing progression of PD also
have provided data that are necessary to estimate sample sizes required to detect slowing of disease progression due to a study intervention. The sample size required depends on the anticipated magnitude of
benefit (effect size) of the disease-modifying drug and
the duration of exposure to the drug (the length of the
study). The effect of the drug generally is expressed as
the percentage of reduction in rate of loss of the imaging marker in the group treated with the study drug
versus a comparison or control group. Imaging studies
performed to date have specifically sought a reduction
of between 25 and 50% in the rate of loss of F-dopa or
␤-CIT uptake that occurs in PD (ie, a reduction from
10%/yr to 5–7.5%/yr). The sample size needed to detect a reduction in the rate of loss of F-dopa or ␤-CIT
uptake of this magnitude during the course of a 24month interval ranges from approximately 30 to 120
research subjects in each study arm. Larger sample sizes
are required with greater variance and smaller sample
sizes are sufficient if the magnitude of change is similar
in all patients.
These data support the use of dopamine neuroreceptor imaging to assess the effects of potential neuropro-
Address correspondence to Dr Marek, Institute for Neurodegenerative Disorders, 60 Temple Street, Suite 8B, New Haven, CT 06510.
E-mail kmarek@indd.org
tective drugs in PD. There are, however, several caveats
in the design and interpretation of these studies.
Although the imaging measures used in these studies
are biomarkers of nigrostriatal function, it is not established that any benefits obtained are direct measures of
the number of nigral neurons or striatal terminals.22
Investigational drugs that are studied may have effects
on dopamine neurons unrelated to their potential to
slow neuronal degeneration and/or may have effects
outside the dopaminergic system.
The rate of change in imaging outcomes used to
measure disease progression is very slow, likely reflecting the slow rate of clinical progression in PD. Although some of this problem can be overcome by using large sample sizes, in most instances this requires
that the imaging study should be at least 18 to 24
months in duration to detect clear evidence of disease
progression. In a recent study evaluating the potential
disease-modifying effects of neuroimmunophilin A, a
study duration of 6 months resulted in an equivocal
outcome necessitating a second longer study to clarify
the drug’s effects.23
There is a progressive loss in brain dopaminergic imaging activity in aging healthy individuals, although at
a rate approximately one tenth that found in PD patients.17,24,25 Nonetheless, this requires the use of
larger sample sizes to detect a given neuroprotective effect.
Imaging outcomes of disease progression may be
confounded by pharmacological effects of the study
drug. Studies reviewing potential drug effects on the
imaging ligands are discussed further below.
Imaging technology is rapidly improving and longterm progression studies must be designed to take advantage of relevant changes in technology. For example, recent studies assessing potential neuroprotective
effects of dopamine agonists have used improved analysis methodology to reduce variance in imaging outcomes.26,27
Dopamine Agonist Studies of Parkinson’s
Disease Progression
During the past decade, several prospective doubleblind studies have examined the effect of dopamine
agonists on the natural history of PD and estimates of
its rate of progression. In these studies, initial treatment with a dopamine agonist versus L-dopa has been
compared in early Parkinson’s disease patients who
have been followed up for a 2- to 5-year period. Clinical assessments have demonstrated that pramipexole,
ropinirole, cabergoline, and pergolide delay the onset
of dopaminergic motor complications, particularly dyskinesia, in comparison with L-dopa therapy.3,4,28,29
However, in each of these studies, initial L-dopa therapy was more effective than the dopamine agonist in
ameliorating signs and symptoms of PD as measured
by the Unified Parkinson Disease Rating Scale (UPDRS). The significance of this finding remains to be
determined, particularly as patients in either group
could receive open-label L-dopa at any time.
In parallel with these clinical outcomes, in vivo imaging using either ␤-CIT/SPECT or F-dopa/PET has
been used to compare surrogate estimates of the progressive loss of dopaminergic neurons in early PD patients treated with either dopamine agonists or L-dopa.
In CALM-PD CIT, a parallel-group double-blind randomized study conducted by the Parkinson Study
Group and sponsored by The Pharmacia Corp and
Boehringer-Ingelheim, 82 PD patients who were part
of the CALM-PD study were imaged with ␤-CIT/
SPECT at baseline and again at 22 (n ⫽ 78), 34 (n ⫽
71), and 46 (n ⫽ 65) months after initial treatment.27
Patients were randomly assigned to receive pramipexole
0.5mg three times per day (1.5–9.5 daily dose) plus
L-dopa placebo (n ⫽ 42) or L-dopa 25/100mg three
times per day (75/300 –150/600 daily dose) plus
pramipexole placebo (n ⫽ 40). For patients with residual disability, the dosage of the blinded study medication could be escalated during the first 10 weeks.
Thereafter, open-label L-dopa could be added to the
blinded treatment for patients in either treatment
group. After 24 months of follow-up, the dosage of the
blinded study drug could be further modified. The primary outcome variable in this study was the percentage
of change from baseline in striatal [123I]␤-CIT uptake
after 46 months. The percentages of change and absolute change in striatal, putamen, and caudate [123I]␤CIT uptake after 22 and 34 months also were assessed.
Comparison of the treatment groups demonstrated that
the rate of reduction in striatal [123I]␤-CIT uptake was
significantly reduced in the group initially treated with
pramipexole compared with the group initially treated
with L-dopa (Fig 1). The percentages of decline from
baseline in the pramipexole and L-dopa groups, respectively, were 7.1 ⫾ 9.0% versus 13.5 ⫾ 9.6% at 22
months ( p ⫽ 0.004); 10.9 ⫾ 11.8% versus 19.6 ⫾
12.4% at 34 months ( p ⫽ 0.009); and 16.0 ⫾ 13.3%
versus 25.5 ⫾ 14.1% at 46 months ( p ⫽ 0.01; Fig 2).
Both putamen and caudate showed a similar reduction
in the percentage of loss of [123I]␤-CIT uptake from
baseline in the pramipexole and L-dopa groups.
In the prospective double-blind REAL-PET study
sponsored by GlaxoSmithKline, 186 untreated PD patients were randomized to receive initial treatment with
either ropinirole or L-dopa. Patients were imaged with
18
F-dopa/PET at baseline and 24 months after initial
treatment. Patients were randomized to each treatment
group in equal numbers. The mean daily doses after 2
years of treatment were 12.2 ⫾ 6.2mg ropinirole and
558.7 ⫾ 180.8mg L-dopa. Supplemental L-dopa could
be added to subjects in either group who experienced
insufficient therapeutic benefit from their blinded
Marek et al: Neuroimaging Studies in PD
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Fig 1. Single-photon emission computed tomography (SPECT) [123I]␤-CIT images of progressive striatal dopamine transporter loss
during the 46-month evaluation period for a representative subject. Note that the loss of activity is more marked in the putamen
than in the caudate. Levels of SPECT activity are color-encoded from low (black) to high (yellow/white).
study drug during the course of the trial. The primary
outcome variable was the percentage of change from
baseline in the putamenal 18F-dopa uptake. Comparison of the treatment groups showed that the percentage of loss from baseline in putamenal 18F-dopa in the
Fig 2. Percentage of reduction from baseline in putamen
F-dopa in L-dopa versus ropinirole-treated patients (REALPET) and in striatal ␤-CIT in L-dopa versus pramipexoletreated patients (CALM-PD CIT). p value was less than 0.05
for all comparison between dopamine agonist and L-dopa.
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2003
ropinirole group was significantly reduced compared
with the L-dopa group: 13 versus 20%, p ⫽ 0.022 (see
Fig 2).26
These imaging studies demonstrate that the rate of
decline in striatal ␤-CIT or F-dopa uptake, markers of
dopamine neuron degeneration, was significantly
slowed in early PD patients treated with a dopamine
agonist compared with L-dopa. The relative slowing in
the rate of decline of [123I]␤-CIT uptake in the
pramipexole group compared with the L-dopa group
was 47% at 22 months, 44% at 34 months, and 37%
at 46 months after initiating treatment. Similarly, the
decline in uptake of F-dopa was reduced by 35% at 24
months in the ropinirole group compared with the
123
L-dopa group. Both [
I]␤-CIT SPECT and 18F-dopa
PET are quantitative biomarkers that provide an estimate of the number of striatal dopamine neurons but
target different aspects of dopaminergic neuron function. As both pramipexole and ropinirole are predominantly D2 dopamine receptor agonists, these data
strongly suggest that treatment with the dopamine agonists pramipexole and ropinirole alters the rate of disease progression in comparison with L-dopa. As there
was no placebo control group, however, it is not possible based on these data to determine if one drug
slowed or the other drug accelerated the rate of dopaminergic degeneration in PD. These studies also dem-
onstrate that in vivo imaging can be used to assess potential disease-modifying drugs in well-controlled,
blinded clinical studies.
Study Design Limitations
Although both the CALM-PD CIT and the REALPET demonstrate a robust and remarkably consistent
reduction in the striatal uptake of biomarkers of nigrostriatal dopaminergic neurons in the dopamine agonist
versus L-dopa groups, these data should be very cautiously interpreted for the effect of dopamine agonists
on disease progression. Several issues in the study design limit interpretation of these data.
One especially important question in longitudinal
studies is whether study dropouts might have biased
study results. Approximately 20% of the study cohort
withdrew from CALM-PD-CIT before the month 46
visit. Analysis of the imaging data from all the 82 subjects enrolled including dropouts using a regressionbased imputation strategy showed very similar results
to the data reported from the completer analysis, making it very unlikely than dropouts effected the study
outcome.30 –39 Approximately 27% of the study cohort
withdrew from the REAL-PET study before the 24month visit. In addition, 11% of the subjects completing the REAL-PET study had 18F-dopa uptake in the
normal range and were eliminated from the analysis.
The individuals enrolled in the REAL-PET study without imaging abnormalities are most likely misdiagnoses
and may reflect problems with the choice of very early
de novo patients in that study.
The effect of study drug dosage was not addressed in
either of these studies. It is uncertain whether the dosage required to obtain symptomatic benefit might have
modified the rate of loss of imaging markers detected
in this study. In addition, the use of open-label L-dopa
in the dopamine agonist groups complicates interpretation of the results. In the CALM-PD CIT study, approximately 75% of patients in the pramipexole group
were supplemented with L-dopa by 46 months, and in
the REAL-PET study approximately 14% of the ropinirole patients were supplemented with L-dopa by 24
months.26,27
Both studies compared two active medications without a placebo group. Therefore, these data cannot distinguish whether the difference in the rate of loss of
[123I]␤-CIT or 18F-dopa uptake between the treatment
groups results from a reduced rate of loss due to
pramipexole or ropinirole, an accelerated rate of loss
due to L-dopa, or both. However, indirect evidence in
the CALM-PD study suggests that it is more likely that
pramipexole reduced the rate of loss rather than exposure to L-dopa having increased the rate of loss of
[123I]␤-CIT uptake. In pilot imaging studies, the annual percentage of loss of [123I]␤-CIT striatal uptake
of untreated PD patients was 6.8%, similar to that ob-
served in the L-dopa group in this study.31 Furthermore, in the CALM-PD CIT the percentage of loss
from baseline of [123I]␤-CIT striatal uptake after 46month follow-up in those subjects initially treated with
pramipexole who did require supplemental L-dopa by
22 months remained reduced compared with those patients initially treated with L-dopa also requiring supplemental L-dopa by 22 months. These imaging data
suggest that treatment with pramipexole reduced the
rate of loss of [123I]␤-CIT uptake despite subsequent
treatment with L-dopa. However, the duration and
dose of exposure to supplemental L-dopa and the effect
of pretreatment with a dopamine agonist on a possible
L-dopa disease-modifying effect has not been fully evaluated. Studies are under way to directly assess the effect of treatment with L-dopa compared with placebo
on the rate of loss of [123I]␤-CIT uptake in early PD
patients that will further elucidate the relative effects of
pramipexole and L-dopa on [123I]␤-CIT uptake.5
Possible Regulation of Imaging Outcomes
A more important limitation in interpreting the results
of these studies is that the difference in the loss of
[123I]␤-CIT and 18F-dopa uptake in the dopamine agonist versus L-dopa groups may be caused by a pharmacological interaction between the dopamine agonist
(pramipexole or ropinirole), L-dopa, or both and the
dopamine transporter or dopamine turnover rather
than slowed or accelerated neuronal degeneration. Preclinical studies suggest that dopamine agonists and
L-dopa might regulate both the dopamine transporter
and dopamine turnover.32,33 However, the relevance of
the preclinical studies to human imaging studies is
questionable because of the short duration of exposure
to drugs, suprapharmacological dosing, and species differences. In a clinical study of 35 PD patients and 16
age-matched controls imaged with [11C]methylphenidate (a dopamine transporter ligand), 18F-dopa, and
[11C]dihydrotetrabenazine (a vesicular transporter ligand), reduction in uptake was greater in dopamine
transporter imaging ⬎ vesicular transporter ⬎ F-dopa,
suggesting that differential regulation of these imaging
targets might occur in a progressively denervated striatum.34 The relative lack of change in 18F-dopa imaging
in aging healthy subjects is consistent with a presumed
upregulation of dopamine turnover in normal aging.35
Clinical studies that directly assessed the short-term
effects of dopamine agonists or L-dopa on imaging outcomes do not show regulation. In the CALM-PD CIT
study, there was no significant change in ␤-CIT uptake
after 10 weeks of treatment with either pramipexole
(dose, 1.5– 4.5mg) or L-dopa (dose, 300 – 600mg) consistent with previous studies evaluating L-dopa effects
after 6 to 12 weeks.27,36,37 In a similar study, treatment with pergolide for 6 weeks also showed no significant changes in ␤-CIT striatal, putamen, or caudate
Marek et al: Neuroimaging Studies in PD
S163
uptake, although there was an insignificant trend toward increased ␤-CIT uptake.38 Finally data assessing
RTI-32, another dopamine transporter ligand, demonstrated significant reductions from baseline in striatal
DAT after 6 weeks of treatment with L-dopa,
pramipexole, and placebo. This pilot study could not
detect differences between the treatment and placebo
groups.39 Although these clinical studies do not demonstrate significant regulation of the dopamine transporter, they do not exclude the possibility of
treatment-induced change in dopamine transporter nor
do they address the possibility that pharmacological effects may emerge in longer term studies. The best strategy to assess long-term regulation is to continue to obtain long-term data in studies such as the CALM-PD
CIT and REAL-PET studies. If dopamine agonist regulation is relevant to these studies, it is likely that dopamine agonists would have different effects on F-dopa
and ␤-CIT, which reflect different dopaminergic properties. Indeed, the consistent treatment effect of dopamine agonists observed in these separate imaging studies measuring related but distinct aspects of
dopaminergic activity argue strongly that the observed
results are not explained by pharmacological effects on
the dopamine transporter or F-dopa uptake but represent a measure of surviving dopamine neurons and terminals.
Fig 3. Model of Parkinson’s disease progression.
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2003
Clinical Imaging Correlation
Slowing the loss of decline in imaging biomarkers of
nigrostriatal function in PD is relevant only if these
imaging changes ultimately result in meaningful, measurable, and persistent changes in clinical function in
PD patients. Several clinical end points designed to assess progressive functional decline in PD have been
used including change from baseline in UPDRS in the
“practically defined off” state or after a drug washout
of up to 2 weeks, time to a milestone such as need for
dopaminergic therapy, or the time to development of
motor complications.2–5,40 These end points reflect the
complex clinical progression of PD symptoms and disability. In several cross-sectional studies of PD cohorts,
the reduction in [123I]␤-CIT or [18F]DOPA correlates
with increasing disease severity measured by the UPDRS.11,41– 44
However, in prior longitudinal studies there has
been no clear correlation between change in either
[123I]␤-CIT or [18F]DOPA uptake and change in UPDRS.17,45 Figure 3 shows a model for PD progression
depicting an idealized change in an imaging marker of
dopamine neuronal degeneration such as [123I]␤-CIT
or [18F]DOPA uptake and in a clinical rating scale
such as the UPDRS. The imaging progression is derived from studies estimating that the preclinical period
for loss of [123I]␤-CIT or [18F]DOPA uptake is 5 to
10 years and that the subsequent progression is slow
but linear for at least 4 years, and then may slow further.17,26,27,31,45 The clinical scale is normal until
symptoms develop and then slowly worsens in association with clinical diagnosis but then improves with
treatment only to very slowly worsen again despite
continued symptomatic treatment.46 This model helps
to explain the poor correlation between [123I]␤-CIT or
[18F]DOPA uptake and UPDRS in longitudinal studies. First, the UPDRS is confounded by the effects of
the patient’s anti-Parkinson medications, both acutely
after initiating therapy and with ongoing treatment.
Even evaluation of the UPDRS in the “defined off”
state or after prolonged washout does not solely reflect
changes due to disease progression, because of the long
duration symptomatic effects of these treatments.40,47
Second, in early PD the temporal patterns for the rate
of loss of dopamine transporter and the change in UPDRS may not be congruent. This is best illustrated by
data demonstrating a loss of approximately 40 to 50%
of striatal [123I]␤-CIT or [18F]DOPA uptake at the
time of diagnosis when clinical symptoms measured by
the UPDRS may be minimal. Third, the UPDRS is a
measure of dopaminergic and nondopaminergic symptoms and is vulnerable to both patient and evaluator
subjectivity.
These data suggest that, particularly in 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
the CALM-PD CIT and REAL-PET studies, there was
no correlation between the percentage of change from
baseline in the imaging outcome and the change from
baseline in UPDRS at 22 to 24 months. However, the
loss of striatal [123I]␤-CIT uptake from baseline was
significantly correlated (r ⫽ ⫺0.40; p ⫽ 0.001) with
the change in UPDRS from baseline at the 46-month
evaluation suggesting that the correlation between clinical and imaging outcomes begins to emerge with
longer monitoring.
Future Directions
The CALM-PD CIT and REAL-PET studies demonstrate that [123I]␤-CIT and [18F]DOPA imaging can
detect treatment-related changes in the progressive loss
of striatal imaging markers in patients with early PD.
These data demonstrate a relative reduction in the rate
of loss of striatal [123I]␤-CIT and [18F]DOPA uptake
of approximately 35 to 47% in subjects initially treated
with pramipexole or ropinirole compared with L-dopa
during a 22- to 46-month evaluation period. These imaging data strongly suggest that treatment with
pramipexole or ropinirole may slow and/or L-dopa may
accelerate the rate of loss of nigrostriatal dopamine
neurons in early PD patients. However, additional preclinical and clinical studies are necessary to further validate the imaging markers and to fully assess whether
dopamine agonists are neuroprotective in PD. These
include nonhuman primate studies in an 1-methyl-4phenyl-1,2,3,4-tetrahydropyridine (MPTP) model to
directly establish the relationship between a decline in
dopaminergic imaging markers and the loss of striatal
neurons so as to fully validate these probes. The next
clinical studies of dopamine agonists initially should
focus on newly diagnosed PD patients so that agonist
treatment could be compared with a placebo group.
Novel study designs such as “delayed start” enabling
the placebo group to be treated with study drug after
an appropriate interval also may encourage recruitment
of a placebo group and may reduce concern about dopamine agonist regulation of the imaging outcomes.
These studies then could be extended to evaluate the
long-term consequences of study drug treatment. Ultimately, it will be crucial to obtain both biological evidence such as slowed loss of a validated imaging biomarker and clinical evidence such as slowed
progression in meaningful clinical end points in longterm clinical trials to obtain convincing data that dopamine agonists or alternative potential diseasemodifying drugs are neuroprotective in PD.
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Discussion
Kordower: Dr Marek reported a reduced rate of decline
in ␤-CIT uptake in patients treated with pramipexole
and FD uptake in those taking ropinirole compared
with L-dopa. Nonetheless, there was no clinical difference in the two populations. Dr Olanow, as a clinical
neurologist, are you more comfortable with clinical
outcome or neuroimaging as a primary outcome variable for a study of neuroprotection in Parkinson’s disease?
Olanow: In the final analysis, I think it is necessary
to show that a drug alters the natural clinical progression of the disease for it to be considered to be neuroprotective. Obviously, we would like to see some clinical indication that the drug has altered the quality of
life of the patient. This may, however, be difficult to
determine in clinical trials as they are currently constructed. Patients take symptomatic drugs that may
mask the clinical expression of underlying neurodegeneration, and considerable compensation may go on in
the basal ganglia such that degenerative changes may
not correlate with clinical deterioration in a linear fashion. It thus may be difficult to use a clinical marker as
an index of underlying neurodegeneration, and it may
take a long time before overt clinical differences become apparent. On the other hand, neuroimaging permits us to objectively quantify differences in a surrogate marker of the nigrostriatal system, but questions
remain about precisely what changes in F-dopa and
␤-CIT uptake measure. Are they truly measures of dopamine terminals or neurons and how much compensation can occur. Furthermore, it is necessary to ensure
that there are no confounding pharmacological effects
responsible for differences between the agonists and
L-dopa. Clearly, these questions need to be answered.
In the final analysis, however, I think clinicians will
want to see some clinical benefit that cannot be explained by symptomatic effect before they will be convinced that a drug is neuroprotective.
Rascol: It is critical for us to determine whether these
agents are really neuroprotective, and I agree that the
data presented does suggest that perhaps they are. Seeing a clinical as well as a neuroimaging change certainly would help to resolve this issue, and perhaps because of the confounding drug effects it may take a
long time before we can see such a clinical change. Is
there any plan to continue to follow your patients and
repeat scans? In addition, have you analyzed your data
to see if there are individual patients who have done
particularly well that might help to validate the results
of imaging?
Marek: We, of course, would love to continue to follow up and image these patients indefinitely because I
agree with you that the information is very valuable.
Approximately one half of these patients have had additional images at this time, and we hope to be able to
continue to scan them. The problem is that it is increasingly hard to get people to come back particularly
as their disease progresses. In addition, the study is no
longer blinded, so that clinical evaluations are less useful. To properly assess long-term clinical change, we
would have to design a new long-term study. Even so,
I think it is worthwhile to continue to try and follow
up the patients who participated in the current trial.
Olanow: Which is the best agent to use for neuroimaging and is least likely to be influenced by compensatory effects: ␤-CIT or F-dopa.
Brooks: Well they behave in a different fashion. In
PD, F-dopa is relatively upregulated, whereas ␤-CIT is
downregulated. Nobody actually knows which is the
true gold standard, and it is interesting that both FD
and ␤-CIT studies indicate a slower rate of deterioration with an agonist compared with L-dopa. In a sense,
these two imaging techniques thus are complementary,
and the fact that both show similar positive results supports the view that the agonists are neuroprotective and
that the results are not caused by artifactual compensatory effects alone. No one has really determined the
relationship between uptake with these agents and the
numbers of surviving nigral neurons or terminals, although preliminary studies with low numbers suggest
that FD-PET uptake does correlate relatively well in
both MPTP monkeys and PD patients.
Marek: I agree that we don’t know the answer and
agree that, because the results in the two studies were
very similar, it suggests that any compensatory effect is
not very great.
Schapira: Can we conclude from these studies then
that dopamine agonists are neuroprotective in PD?
Marek: Because we did not have a placebo control
group, all we can say is that there is a difference in
the rate of decline in FD and ␤-CIT uptake between
the dopamine agonists and L-dopa. We cannot say if
this difference is caused by a neuroprotective effect
of the dopamine agonist or a deleterious effect of
L-dopa.
Schapira: Let me ask the clinicians, do you think
that the data that have been presented will make clinicians re-evaluate when they give a dopamine agonists,
that is, at time of diagnosis versus when they develop
functional disability?
Rascol: I am very impressed by these data, and they
certainly support my inclination to initiate symptomatic therapy in the appropriate patient with a dopamine agonist to reduce the risk of inducing motor
complications. However, there is not enough data at
the current time to convince me to start a dopamine
agonist at the time of diagnosis as a neuroprotective
agent.
Olanow: I agree that the neuroimaging data do not
permit one to conclude that the agonists are neuroprotective, but the results are consistent with this effect.
Given that there is now a body of scientific information suggesting that agonists can protect dopamine
neurons in a variety of model systems and that they are
not likely to induce motor complications when given
as monotherapy, I would be inclined to at least discuss
Marek et al: Neuroimaging Studies in PD
S167
the issue with patients and recommend using them at
diagnosis particularly in younger PD patients.
Stocchi: I am somewhere in between. This data will
certainly reinforce my decision to start symptomatic
treatment with a dopamine agonist, but I am rather
conservative and I am not sure the current information
will move me to use the agonists immediately (ie, at
the time of diagnosis). My main concern is that I do
not know which dose to use and whether there might
be long-term adverse events.
Jenner: That is an issue we had to address in designing the monkey studies as well. My suggestion is that
we should start with a lower doses and see what you
can get.
Brooks: I am not sure that I agree. Some patients
actually deteriorate with low-dose dopamine agonists
because they stimulate autoreceptors on presynaptic
neurons and turn off endogenous dopamine synthesis
and release.
Olanow: I would be inclined to use doses that already have been established in clinical practice to be
safe and well tolerated. From a neuroprotective point
of view, dose may not be that critical; as in laboratory
studies, you often see comparable protection across a
broad range of doses.
Schapira: What about side effects?
Olanow: From the standpoint of side effects, in the
early stages of the disease agonist-induced side effects
tend not to be serious and to occur primarily during
the titration phase. You will have to deal with these
side effects at some time point or other. I don’t think
they are of sufficient concern that if one accepts the
notion that the drug may be neuroprotective it warrants delaying introduction for a year or two.
Stocchi: I am not so concerned about the lack of
change in clinical features in the studies that were presented and think that neuroimaging is likely a more
sensitive marker of neuronal degeneration. So, I do believe that the changes on imaging studies that have
been presented are telling us something about what is
going on in the brain when we use these different
drugs. Let me clarify my earlier comment. Although I
might delay introducing an agonist if a patient has only
minimal symptomatology that causes them no disability, most patients I see at diagnosis already have some
disturbing features, which is why they came to see me.
In such an individual, I would discuss the issue with
the patient and the family and recommend that they
take the drug if there are no contraindications. This
also helps me in choosing the dose, as I can titrate to
the lowest dose that controls the clinical features. I
don’t think there is a specific clinical marker that allows us to say this is the right point to start treatment,
and clinical judgment is required.
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Annals of Neurology
Vol 53 (suppl 3)
2003
Marek: Perhaps this is a moot point. Most patients
are started on treatment for clinical disability within 1
year of diagnosis. If you think the drug may be neuroprotective, and if side effects are not a major issue,
why not start at the time of diagnosis if you think the
drug might be neuroprotective?
Olanow: There has also been at least some data suggesting that rate of progression in the early stages of
Parkinson’s disease may be faster than in the later
stages of the disease. In any event, it seems logical to
me to start a drug that you think is neuroprotective at
the earliest time point you can, even preclinically if you
could define who is at risk. The issue remains, is the
evidence available sufficient to allow you to conclude
that the drug is likely to be neuroprotective. Bear in
mind that clinical studies are not easy to perform, and
it may be that we will not have additional clinical information for many years to come.
Marek: I think it is a mindset issue. Right now, patients may not seek an early diagnosis because they say
why should I bother—what is the difference? Should
we be much more aggressive about telling people they
need to seek a diagnosis early and get treated early?
Olanow: I agree. First of all, the average person has
symptoms for at least a year before diagnosis is made.
Second, the average person, once diagnosis is made,
does not require symptomatic therapy for probably 12
to 18 months. We have no definite information in
terms of what happens to that patient during those 2
to 2.5 years. Bear in mind that Parkinson’s disease progression is not linear but rather reflects a series of steplike deteriorations. It therefore may be that it is best to
introduce a neuroprotective therapy during this early
time window before decompensation has occurred.
Rascol: I am still concerned about the risk of side
effects, and without some clinical indication that the
drug has changed the natural outcome of the disease, I
prefer to delay therapy until there is clinical disability.
Olanow: I think that is fair and what you propose is
perfectly correct. What I am saying is that a strong
argument can be brought forward saying that if, in
fact, these drugs are neuroprotective, or if we think
they might be, we should get them on board as soon as
possible. Not only should we be starting them as soon
as we make the diagnosis, we should be making a concerted effort to diagnose PD sooner and indeed to define preclinical patients who are at risk so we can start
neuroprotective therapies earlier. At the present time,
we do not have a definite answer, and two reasonable
positions can be put forward. One would not initiate a
dopamine agonist as a neuroprotective agent until
more data are available. The other argues that the clinical and scientific information currently available is
enough to suggest that the drug likely is neuroprotective and it is appropriate to initiate therapy at the time
of diagnosis. Both positions are reasonable, and, as
with so many medical decisions, it is a matter of clinical judgment and patient philosophy.
Schapira: I agree with Warren in saying that there is
a reasonable hypothesis for considering that the earlier
you start a dopamine agonist the better it might be. It
is important to consider that you may be targeting not
only functioning nerve cells but also those that are alive
and dysfunctional. Laboratory studies in cell culture
models and MPTP monkeys demonstrate the potential
of dopamine agonists to provide protective effects and
support the notion that the earlier you give the drug
the more likely you may be to protect remaining dopamine neurons.
Marek et al: Neuroimaging Studies in PD
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