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Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson's disease PET evidence of increased dopamine turnover.

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Biochemical Variations in the Synaptic Level
of Dopamine Precede Motor Fluctuations in
Parkinson’s Disease: PET Evidence of
Increased Dopamine Turnover
Raúl de la Fuente-Fernández, MD,1 Jian-Qiang Lu, MD, PhD,1 Vesna Sossi, PhD,2 Salma Jivan, BSc,2
Michael Schulzer, MD, PhD,1 James E. Holden, PhD,3 Chong S. Lee, MD, FRCPC,1 Thomas J. Ruth, PhD,2
Donald B. Calne, DM, FRCPC,1 and A. Jon Stoessl, MD, FRCPC1
Motor fluctuations are a major disabling complication in the treatment of Parkinson’s disease. To investigate whether
such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, we studied prospectively
patients in the early stages of Parkinson’s disease with a follow-up after at least 3 years of levodopa treatment. At
baseline, 3 positron emission tomography (PET) scans using [11C]raclopride before and after (1 hour and 4 hours) orally
administered levodopa were performed on the same day for each patient. Patients who developed “wearing-off ” fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [11C]raclopride binding
potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, 1 hour postlevodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable
responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 hours. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically
apparent “wearing-off ” phenomena. The rapid increase in synaptic levels of dopamine observed in fluctuators suggests
that increased dopamine turnover might play a relevant role in levodopa-related motor complications.
Ann Neurol 2001;49:298 –303
Patients with idiopathic parkinsonism, or Parkinson’s
disease (PD) initially have a good response to levodopa.1,2 However, most levodopa-treated patients develop motor response complications (motor fluctuations and dyskinesias) with time. Thus, 50% of PD
patients experience motor complications after 3 to 5
years of levodopa treatment.2 Usually, the first problem
that levodopa-treated patients encounter is a progressive shortening in the duration of the action of levodopa (“wearing-off” fluctuations). Modifications in the
dosing schedule (ie, taking more frequent doses of
levodopa) can initially help alleviate “wearing-off” fluctuations. Many patients with “wearing-off” fluctuations develop later oscillations in mobility, unrelated to
the timing of levodopa ingestion (“on-off” fluctuations) as well as levodopa-induced dyskinesias.
Despite much effort, still little is known about the
pathogenesis of “wearing-off” fluctuations.2,3 Both presynaptic4 and postsynaptic5 mechanisms may be impli-
cated. It has long been speculated that this end-of-dose
deterioration depends largely on the size of the lesion
to the nigrostriatal dopaminergic system.1,4 According
to this notion, as the number of nigral cells declines
with disease progression, the capacity of the nigrostriatal system to synthesize and store dopamine from exogenous levodopa also diminishes. Nevertheless, in a
recent 2-hour [18F]fluorodopa positron emission tomography (PET) study, we found a considerable overlap in the [18F]fluorodopa uptake rate (Ki) between
“wearing-off” fluctuators and stable responders.6 Because 2-hour Ki values are highly correlated with the
number of cells in the substantia nigra and with striatal
dopamine levels,7 this result suggested that differences
in the damage to the nigrostriatal dopaminergic system
might not be sufficient to explain motor fluctuations.
However, striatal radioactivity has been shown to be
much lower in fluctuators than in stable patients 4
hours after [18F]fluorodopa injection.8 Accordingly, we
From the 1Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre, and 2TRIUMF, University of British Columbia, Vancouver, BC, Canada; and 3University of Wisconsin, Madison, WI.
Address correspondence to Dr Stoessl, Neurodegenerative Disorders
Centre, Vancouver Hospital and Health Sciences Centre, Purdy Pavilion, 2221 Wesbrook Mall, V6T 2B5 Vancouver, BC, Canada.
E-mail: jstoessl@interchange.ubc.ca
Received Jul 18, 2000, and in revised form Sep 13. Accepted for
publication Oct 19, 2000.
298
© 2001 Wiley-Liss, Inc.
proposed that “wearing-off” fluctuations may be related to increased dopamine turnover.6 This would explain the occurrence of motor fluctuations despite substantial overlap in dopamine synthesis and storage
capacity. To explore this hypothesis, we estimated by
[11C]raclopride PET the synaptic levels of dopamine
derived from exogenous levodopa 1 hour and 4 hours
after oral levodopa administration. This method is
based on the ability of dopamine to compete with
[11C]raclopride for binding to dopamine D2/D3 receptors.9–13 Because changes in dopamine turnover may
precede clinically manifest motor fluctuations, we designed a prospective study with baseline motor and
PET examinations and a follow-up period corresponding to 3 years of levodopa therapy.
Materials and Methods
Eight PD patients with stable response to levodopa were
studied and followed up regularly at our Movement Disorder
Clinic for a minimum of 3 years of levodopa therapy. There
were 7 men and 1 woman (mean age, 58.62 years; SD,
10.97 years). All patients met the clinical criteria for definite
PD14 and had responded well to treatment with levodopa.
Quantitative measurements based on the Modified Columbia
Scale (MCS)15 during the “off ” state (after 12–18 hours
without medications) and [11C]raclopride PET scans were
performed at baseline. At that time, duration of PD was 5 ⫾
0.89 years, and duration of levodopa therapy was 1.62 ⫾
0.83 years. In addition to levodopa, 3 patients were also taking selegiline, which was withdrawn 24 hours before assessments (MCS and PET). There were no other relevant medications. At the end of the follow-up, patients were classified
as fluctuators or stable responders according to standard clinical criteria4 without prior knowledge of the PET results.
Those patients who were experiencing predictable end-ofdose motor deterioration (“wearing off ”) every 3 hours or
less when on optimum medication with levodopa were defined as fluctuators.
PET Protocol
All patients underwent three consecutive [11C]raclopride
PET scans on the same day according to the following protocol: first scan (baseline), 12 to 18 hours after withdrawal of
medication; second scan, 1 hour after oral administration (on
an empty stomach) of standard-release 250/25 mg of levodopa/carbidopa; and third scan, 4 hours after levodopa. Patients were pretreated with domperidone whenever there was
a history of nausea after levodopa treatment. The reproducibility of [11C]raclopride PET has previously been shown to
be very high.16 Changes in [11C]raclopride BP observed 1
hour after levodopa administration correspond to [11C]raclopride displacement induced by dopamine derived from exogenous levodopa. In a PD patient not included in this study,
we found that a single injection of apomorphine (0.06 mg/
kg) given subcutaneously led to a decrease of 16% in
[11C]raclopride BP. However, 2 hours later the [11C]raclopride BP had returned to 97% of its baseline value. This
indicates that dopamine D2 receptors recover rapidly after
stimulation. Therefore, we can assume that most of the
changes in [11C]raclopride BP observed at the fourth-hour
scan in the present study should also represent displacement
of [11C]raclopride by concurrent synaptic dopamine derived
from exogenous levodopa.13
All PET scans were performed in three-dimensional (3D)
mode using an ECAT 953B/31 tomograph (Siemens Canada/
CTI, Knoxville, TN). Attenuation correction was achieved
by performing a 15-minute transmission scan using 68Ge
rods. For assessment of D2 binding, 16 sequential scans were
obtained over 60 minutes, starting at the time of injection of
5 mCi of [11C]raclopride (mean ⫾ SEM specific activity ⫽
2724 ⫾ 227 Ci/mmol at ligand injection). The 3D emission
data were reconstructed using previously described algorithms with corrections for scatter and detector normalization.17,18 An integrated image with 31 planes, each 3.37 mm
thick, was made from the emission data (from 30 – 60 minutes) for each subject. One circular region of interest (ROI)
of 61.2 mm2 was positioned by inspection on each caudate
nucleus and adjusted to maximize the average ROI activity.
Three circular ROIs of 61.2 mm2 were placed without overlap along the axis of each putamen and were similarly adjusted. The background activity was averaged from a single
elliptical ROI (2107 mm2) drawn over the cerebellum on
each of two contiguous axial planes. The BP (Bmax/Kd) was
determined using a graphical approach and a tissue input
function as described by Logan et al.19 All subjects gave written informed consent. The study was approved by the University of British Columbia ethics committee.
Statistical Analysis
PET analyses focused exclusively on putamen [11C]raclopride
BP. Unless otherwise stated, putamen [11C]raclopride BP refers to mean values based on putamen [11C]raclopride BP
ipsilateral and contralateral to the more affected body side.
Continuous data were analyzed by parametric or nonparametric methods, as appropriate. A two-way repeated measures analysis of covariance (ANCOVA) was used to compare
levodopa-induced effects on [11C]raclopride BP among fluctuators and stable responders, adjusting for baseline values
(ie, [11C]raclopride BP before administration of levodopa).
Differences in [11C]raclopride BP between the first- and
fourth-hour scans were also compared for the two groups by
analysis of covariance (ANCOVA), adjusting for baseline
[11C]raclopride BP values. Data are summarized as mean ⫾
standard deviation (SD) unless otherwise stated.
Results
At 3 years of chronic levodopa treatment, 4 patients
had developed motor fluctuations (“wearing-off” phenomena), and 4 still had a stable response to levodopa.
Three fluctuators were also experiencing levodopainduced dyskinesias. Fluctuations occurred 1 to 2.5
years (1.75 ⫾ 0.87 years) after the PET study. Two
stable responders have currently been followed for 4.5
years, and they remain free of motor fluctuations. Baseline clinical characteristics are summarized in Table 1.
Fluctuators were younger than stable responders (51 ⫾
5.10 years vs 66.25 ⫾ 9.98 years; p ⬍ 0.05), but there
were no other significant between-group differences at
de la Fuente-Fernández et al: Dopamine Turnover and Motor Fluctuations
299
Table 1. Clinical Characteristics at Baseline Examinations
(1–2.5 yr before Fluctuators Developed “Wearing-Off ”
Phenomena)
Stable Responders Fluctuators
Male/female
3/1
Age (yr)
66.25 ⫾ 9.98
Duration of PD (yr) 5.25 ⫾ 0.87
Duration of LD
2 ⫾ 0.71
treatment (yr)
LD dose (mg/day)
375 ⫾ 86.60
MCS-OFF
14.25 ⫾ 8.30
4/0
51 ⫾ 5.10a
4.75 ⫾ 0.96
1.25 ⫾ 0.87
412.50 ⫾ 143.61
9 ⫾ 6.68
a
p ⬍ 0.05; there were no other significant between-group differences.
LD ⫽ levodopa; MCS-OFF ⫽ Modified Columbia Scale score for
limbs during the off state; PD ⫽ Parkinson’s disease.
baseline examinations. At the end of the follow-up,
fluctuators had more than doubled their daily levodopa
intake, from 412.50 ⫾ 143.61 mg to 871.25 ⫾
596.47 mg, whereas stable responders remained on a
very similar dose (375 ⫾ 86.60 mg vs 412.50 ⫾ 43.30
mg). There were no between-group differences in body
weight ( p ⫽ 0.36).
Putamen [11C]raclopride BP values are summarized
in Table 2. Fluctuators and stable responders had similar ( p ⫽ 0.90) [11C]raclopride BP at baseline (before
levodopa administration), which was no different ( p ⫽
0.76) from the [11C]raclopride BP found in agematched normal control subjects (n ⫽ 5). However,
there were between-group differences in the pattern of
changes of [11C]raclopride BP over time (from baseline
to 4 hours after levodopa administration; p ⬍ 0.001 by
repeated-measures ANCOVA; Fig 1). This difference
was present in the putamen both ipsilateral ( p ⬍
0.001) and contralateral ( p ⬍ 0.001) to the more affected body side. One hour after levodopa administration, the reduction in [11C]raclopride BP compared to
baseline was greater in fluctuators than in stable responders ( p ⬍ 0.05). By contrast, at the fourth-hour
scan, the [11C]raclopride BP was significantly higher in
fluctuators (ie, showed a greater return toward baseline
levels) than in stable responders ( p ⬍ 0.01). The mean
difference in [11C]raclopride BP between the first- and
fourth-hour scans was almost of identical magnitude
(but of opposite sign) in the two groups of patients
(adjusted means 0.160 and ⫺0.169 for stable respond-
ers and fluctuators, respectively; between-group differences after adjusting for baseline values by ANCOVA,
p ⬍ 0.01). Two of the 3 patients who were on selegiline at the time of the PET study maintained a stable
response to levodopa treatment for 2 years after stopping selegiline. As shown in Figure 1, these 2 patients
had the typical pattern of PET findings observed in
other stable responders (ie, a small change in BP at 1
hour and a substantial change at 4 hours postlevodopa). The other patient on selegiline at the time
of the PET study developed “wearing-off” fluctuations
during the follow-up and had the typical pattern of
PET findings observed in other fluctuators (see Fig 1).
The same pattern of changes observed in PD patients who developed “wearing-off” fluctuations during
the follow-up period was found when the same PET
protocol was applied to another patient who was already experiencing motor fluctuations (Fig 2).
We estimated the levodopa-induced effects on the
synaptic levels of dopamine as the percent change from
baseline of the [11C]raclopride BP values before and at
both 1 hour and 4 hours after levodopa administration.
This estimate is based on the assumption that there is
a linear relationship between changes in [11C]raclopride BP and synaptic dopamine levels. The estimated
increase in synaptic dopamine levels 1 hour after levodopa administration was 3 times higher in fluctuators
than in stable responders ( p ⬍ 0.05; Fig 3). By contrast, whereas the synaptic levels of dopamine had returned to baseline levels (or below baseline levels) 4
hours after levodopa administration in the fluctuator
group, stable responders still showed increased synaptic
levels of dopamine in the fourth-hour scan ( p ⬍ 0.01;
see Fig 3).
We also applied a compartment-based analysis to the
data20,21 and obtained identical results in [11C]raclopride BP. In addition to the BP, this method provides
an estimate of the ratio of the tracer delivery constants
(R1) of the target (putamen) to the reference region
(cerebellum), which showed no significant betweengroup differences at either 1 hour ( p ⫽ 0.24) or 4
hours ( p ⫽ 0.23) post-levodopa. No correlation was
found between R1 and putamen [11C]raclopride BP
( p ⫽ 0.66).
Table 2. Putamen [11C]raclopride Binding Potential at Baseline Examinations (1–2.5 yr before Fluctuators Developed “WearingOff ” Phenomena)
Stable responders
Fluctuators
First PET Scan
(before 250 mg LD)
Second PET Scan
(1 hr after LD)
Third PET Scan
(4 hr after LD)
2.51 ⫾ 0.39
2.56 ⫾ 0.58
2.45 ⫾ 0.37
2.39 ⫾ 0.47
2.29 ⫾ 0.34
2.56 ⫾ 0.48
LD ⫽ levodopa.
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Fig 1. Putamen [11C]raclopride binding potential before
(baseline) and after (1 hour and 4 hours) orally administered
levodopa (250/25 mg levodopa/carbidopa). Stable responders
were patients 1, 2, 4, and 8. Fluctuators were patients 3, 5,
6, and 7. Patients 2, 4, and 7 were on selegiline at the time
of the positron emission tomography study. Whereas stable responders exhibited a gradual decrease in [11C]raclopride binding potential over the 4 hours post-levodopa administration,
the fluctuator pattern was characterized by a similar amplitude but a transitory decrease in [11C]raclopride binding potential ( p ⬍ 0.001 by repeated-measures analysis of covariance). This pattern of levodopa-induced changes in putamen
[11C]raclopride binding potential preceded by 1 to 2.5 years
the onset of clinically relevant motor fluctuations.
Discussion
PET studies with [11C]raclopride allow us to estimate
changes in the synaptic levels of dopamine in vivo.9–13
Using our paradigm, we exploited the ability of dopamine derived from exogenous levodopa to compete
with [11C]raclopride for dopamine D2/D3 receptors. In
this prospective study, we found that, 1 hour after oral
levodopa administration, the synaptic levels of dopamine were higher in patients who develop “wearingoff” fluctuations during the first 3 years of levodopa
treatment than in stable responders. In contrast, 4
hours after levodopa administration, only stable responders had increased synaptic levels of dopamine. Indeed, at the fourht-hour scan, the [11C]raclopride BP
slightly exceeded baseline values in the fluctuator
group, which might suggest the possibility of levodopainduced presynaptic inhibition of endogenous dopamine release.22–24 Taken together, these findings
clearly support the existence of a link between the stability of synaptic concentrations of dopamine and the
occurrence of “wearing-off” fluctuations. Therefore, at
the biochemical level, “wearing-off” fluctuations may
be present early in the course of the treatment with
levodopa, but clinically relevant fluctuations may become apparent only when the parkinsonism reaches a
certain severity. In addition, our results are consistent
with a view of increased dopamine turnover as an im-
Fig 2. Levodopa-induced changes in putamen [11C]raclopride
binding potential in a 51-year-old patient with motor fluctuations. This patient exhibited the same pattern of [11C]raclopride binding potential changes as that observed in patients
who developed motor fluctuations in the prospective study (see
Fig 1).
portant underlying mechanism of “wearing-off” fluctuations.6 Such an increase in dopamine turnover may
apply not only to exogenously derived dopamine but
also to endogenous dopamine.
Our interpretation of the findings described here is
based on a number of assumptions, the first of which is
that short-term reductions in D2 receptor binding, as
described here, do indeed correspond to increased synaptic levels of dopamine. Reductions in [11C]raclopride
Fig 3. Estimated levodopa-induced changes in the synaptic
level of dopamine. Values are expressed as percent reduction
from baseline of the putamen [11C]raclopride binding potential at both 1 hour and 4 hours after levodopa administration
(250/25 mg levodopa/carbidopa). The estimated increase in
the synaptic levels of dopamine 1 hour after levodopa administration was 3 times higher in patients who developed motor
fluctuations during the follow-up period than in stable responders ( p ⬍ 0.05). By contrast, whereas stable responders
maintained increased levels 4 hours after levodopa administration, the synaptic level of dopamine had dropped below baseline values (zero line in the graph) at the fourth-hour scan in
the fluctuator group ( p ⬍ 0.01).
de la Fuente-Fernández et al: Dopamine Turnover and Motor Fluctuations
301
binding as detected by PET or in [123I]iodobenzamide
binding as measured by single-photon emission computed tomography (SPECT) have been shown to correlate with increases in striatal dopamine release measured by in vivo microdialysis following amphetamine
administration.12,25 A similar reduction in striatal
[11C]raclopride binding following levodopa administration was reported by Tedroff et al,11 but those authors
did not attempt to compare patients with stable to patients with short-lived responses to levodopa, and they
did not examine the time course of this effect. The
graphical method of analysis used here is insensitive to
global changes in cerebral blood flow but could conceivably be affected by a reduction in blood flow localized to the striatum following levodopa administration
unaccompanied by similar reductions in the reference
region (cerebellum). However, we found no correlation
between the [11C]raclopride BP and the blood-tissue
transfer ratio (R1), as estimated by a compartment
based analysis.20,21 In addition, there were no significant between-group differences in blood-tissue transfer
ratio. Therefore, we believe the most plausible explanation for our findings to be changes in synaptic availability of dopamine following levodopa administration.
The increase induced by levodopa is transient in patients who were stable at the time of the study but go
on to develop motor fluctuations within 3 years of initiating levodopa therapy, whereas a more sustained increase is seen in patients who maintain a stable response to levodopa after 3 years of treatment.
We have also assumed that the interaction between
dopamine and [11C]raclopride follows a simple competitive model (ie, both compete for D2 receptors).
There is ample in vivo evidence supporting this assumption.9,10,26 Psychostimulants, such as amphetamine, lead to more prolonged reductions in [11C]raclopride binding than expected by changes in synaptic
dopamine concentrations. This may be explained by
receptor internalization (see Ref 26 for a review). However, the reversibility of the effects of levodopa (in the
fluctuators) and apomorphine shown here suggests that
receptor internalization is unlikely to contribute substantially to our findings. Finally, we recognize that
there may also be between-group differences in the
proportion of D2 receptors in the high-affinity agonist
state.26 For example, the 1-hour results could be explained by a higher proportion of high-affinity receptors in the fluctuator group than in the stable responders. However, this would not explain the overall
pattern of changes (in particular, the 4-hour results),
unless a time-dependent change in affinity were also
introduced.
There is no clear explanation for the differences in
dopamine turnover between fluctuators and stable responders. Both experimental27,28 and human29,30 observations have shown that damage to the nigrostriatal
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March 2001
dopaminergic system is associated with an increase in
dopamine turnover. However, clinical measurements
(MCS) indicated that fluctuators and stable responders
had nigrostriatal lesions of similar severity. There is evidence suggesting that the nigrostriatal projections to
striosomes and striatal matrix may have different rates
of dopamine turnover (higher turnover in the projection to the striatal matrix).31–33 It is unknown whether
differences in the degree of lesion to these two projections may be related to the occurrence of motor fluctuations. Finally—and we consider most plausibly—
changes in dopamine turnover may be age-related. Like
others,34 we have previously found a higher prevalence
of motor fluctuations in early-onset PD patients than
in those with an older age of onset.6 Fluctuators were
also younger than stable responders in the present
study. It may be that in younger patients there is a
greater capacity to increase the rate of turnover of dopamine as a compensatory response to neuronal loss in
the nigrostriatal pathway. If this hypothesis is correct,
“wearing-off” phenomena would represent a paradoxical and deleterious result of an aberrant homeostatic
mechanism. The association between dyskinesia and
“wearing-off” phenomena raises another possibility:
that dyskinesia derives from the abnormally rapid rise
of synaptic dopamine concentration consequent upon a
pathologically increased turnover rate. We are currently
exploring this possibility.
Clinicians have long been concerned with the possibility that chronic treatment with levodopa could be
triggering the development of motor fluctuations in patients with PD.2,35 Our results suggest that “wearingoff” fluctuations are not related directly to treatment
and that the future risk of developing motor fluctuations may be predicted from the time course of response to a single dose of orally administered levodopa.
This study was funded by the Canadian Institutes for Health Research. Raúl de la Fuente-Fernández is supported by the Pacific Parkinson’s Research Institute (Vancouver, Canada) and the British
Columbia Health Research Foundation. Vesna Sossi is supported by
the British Columbia Health Research Foundation.
We thank Jess McKenzie, Teresa Dobko, and members of the
UBC-TRIUMF PET team for assistance with the scans.
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turnover, motor, level, synaptic, variation, dopamine, disease, parkinson, fluctuations, pet, biochemical, increase, evidence, precedes
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