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Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease.

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Differential Effects of Levodopa on
Dopaminergic Function in Early and
Advanced Parkinson's Disease
Richard Torstenson, MSc,*t Pet Hartvig, PharmD, PhD,*ts Bengt Liingstrom, PhD,*$
Goran Westerberg, PhD,*$ and Joakim Tedroff, M D , PhD*f
The effect of levodopa on L-["C]DOI'A influx rate was evaluated in patients with early and advanced Parkinson's disease
(PD) by using positron emission tomography (PET). The patients were scanned both drug-free and after a subsequent
therapeutic levodopa infusion. Regional analysis of striatal L-["C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on
the striatal L-[%]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L-["C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of
L-["C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent
in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of
levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings
could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the
understanding of the pathogenesis underlying motor fluctuations.
Torstenson R, Hartvig P, Lhgstrom B, Westerberg G, Tedroff J. Differential effects of levodopa on
dopaminergic function in early and advanced Parkinson's disease. Ann Neurol 1997;41:334-340
For more than 20 years, levodopa has been the most
effective drug treatment for Parkinson's disease (PD).
However, a considerable problem with levodopa treatment is the emergence of drug-induced motor response
complications involving rapid and sometimes unpredictable fluctuations in motor performance as well as
involuntary movements [ 13. Although much effort has
been made to clarify the nature of these fluctuations,
the underlying pathophysiological mechanisms remain
to be elucidated.
In early studies using positron emission tomography
(PET), we could demonstrate a positive correlation between striatal dopaminergic nerve terminal deficiency
and the ability for levodopa to increase synaptic dopamine levels, suggesting an accelerated turnover of levodopa in residual dopaminergic nerve terminals [2, 31.
This is compatible with the view that the "storage capacity" for newly synthesized dopamine is diminished
in advanced PD, leading to high and fluctuating synaptic dopamine concentrations when levodopa is given
The regulation of striatal dopamine synthesis is me-
diated by synaptic dopamine autoreceptors exhibiting
D,-subtype pharmacology. Activation of these autoreceptors results in inhibitory regulation of dopamine
synthesis and release [4]. It has recently been shown
that L-DOPA itself displays autoreceptor antagonisticlike effects [5-7].Such effects are demonstrated by the
ability of L-DOPA to increase dopamine and noradrenaline release in vitro [6] and increase presynaptic synthesis of dopamine [7].Using in vivo or in vitro techniques in animals with experimental nigral lesions,
the autoreceptor-mediated inhibition of dopamine terminal activity has been shown to be reduced [8] or
maintained [9, lo]. Hence, it is conceivable that oral
levodopa medication could give rise to complex
neuromodulatory effects in a structurally damaged nigrostriatal projection, which may have mechanistic importance for the clinical syndrome of motor fluctuations.
In the present study, we have used PET and
L-[' 'CIDOPA to specifically measure presynaptic dopaminergic function in vivo. The rate of striatal
r,-["C]DOPA influx is a measure of the functional
From the *Uppsala Universiry PET Centre, ?Hospital Pharmacy,
$Department of Neurology, University Hospital, and SSubfemtomole Biorecognition Project, Uppsala Universiry, Uppsala, Sweden;
and §Research and Development Corporation of Japan.
Address correspondence to D r Tedroff, Department of Neurology,
University Hospital and PET Centre, Uppsala University, S-751 85
Uppsala, Sweden.
Received Apr 29, 1996, and in revised form Aug 21. Accepted for
publication Aug 23, 1996.
Copyright 0 1997 by the American Neurological Association
Table 1. Details of Patients
Advanced PD
Early P D
Age (yr)
Duration of
Disease (yr)
Hoehn &
LD 800, SEL 10, APO inj
LD 500, BROM 5 mg X 3
LD 1600, SEL 5
LD 1000
LD 1400, SEL 10, BROM 5 mg
LD 300
LD 300
PRAM 1 mg X 3
No medication
LD 300
“All values are daily doses in milligrams.
LD = levodopa + decarboxylase inhibitor; BROM = bromocriptine; PRAM
pramipexole; SEL
selegiline; APO inj
state of the presynaptic dopaminergic system [7, 11131. W e therefore investigated the functional state of
the residual dopaminergic terminals in patients with
both early and advanced PD by using L-[”C]DOPA
a n d PET both after levodopa withdrawal a n d during a
therapeutic levodopa infusion.
Patients and Methods
Patient Selection
Ten patients with idiopathic PD who had given their informed consent to participate were included in the study.
Diagnosis of PD was established according to generally accepted criteria [ 141. Two clinically distinct groups of patients
were selected, one group comprising 5 patients, with early
I’D (mean age, 63 2 8.5 years) with a Hoehn and Yahr [15]
disability score of 1 to 2, and a mean duration of clinical PD
of 2.8 years. The second group comprised 5 patients with
advanced PD (mean age, 64 2 8.8 years), a Hoehn and Yahr
disability score of 4 to 5, and a mean duration of clinical PD
of 16.8 years. For patient details, see Table 1. These patients
all had a history of frequent levodopa-induced motor response complications.
All patients had a primary positive and subsequently sustained levodopa response. One patient with early PD was
untreated at the time of investigation but was shown to be
levodopa responsive when therapy was initiated. None of the
patients had signs of cognitive impairment or a history of
levodopa-induced psychiatric side effects. The study was approved by the Ethics Committee of the Faculty of Medicine,
Uppsala University, and by the Isotope Committee of the
University Hospital, Uppsala.
Preparation of Levodopa Solution
Fresh 5 mg/ml solutions of levodopa were prepared in the
Hospital Pharmacy by adding levodopa to a 5% glucose solution. The p H was then adjusted to 3.0 to 3.5, and sodium
pyrosulfite was added to a concentration of 0.5 mglml as
antioxidant. Solutions were protected from light until administered to the patient.
Scanning Procedure
After an overnight fast, the patients were allowed a light
snack and coffee or tea for breakfast. A venous cannula was
inserted in an antecubital vein. Antiparkinsonian drugs had
been withdrawn and allowed for elimination from plasma for
at least 5 half-lives according to the following regimen: Levodopa medication was withdrawn 12 hours and dopamine
agonists (eg, bromocriptine or pramipexole) at least 48 hours
before PET scanning. Patients who were taking deprenyl
took the last dose 24 hours before PET scanning.
The patients were scanned twice with a 2-hour interval,
first drug free (called “off” scan) and then after levodopa
administration (called “on” scan). The patients were pretreated with carbidopa 100 mg orally 1 hour before the first
scan and then with an additional 50 mg immediately after
this scan. This carbidopa dosage does not significantly inhibit cerebral levodopa decarboxylation [ 161. Beginning 20
to 35 minutes before the second PET scan, levodopa was
administered intravenously in successive bolus injections of
0.5 mg/kg given once every minute to a total dose of 2 mg/
kg. Immediately after bolus injection, a constant rate levodopa infusion (2 mg/kg/hr) was started and continued
throughout the second scan.
The patients were allowed to move freely between scans.
The levodopa infusion was administered using a syringe
pump (Harvard apparatus, Model 22).
Radiochemical Synthesis
The synthesis of L-[”C]DOPA was performed by a combination of organic synthesis and multienzymatic processes
[ 171. After purification using semipreparative liquid chromatography, the fraction containing L - [ ~ - ” C ] D O P Awas collected and pH adjusted to about 4.5. The final solution was
filtered through a 0.22-pm sterile filter. Identity and radiochemical purity of z-[p-”C]DOPA, were determined by liquid chromatography. The radiochemical purity was always
higher than 98%. The specific radioactivity was 5 to 10
GBq/pnol at the time of injection. The average radioactive
dose of the tracer injected to the patient was 377 C 7 2
Torstenson et al: Differential Levodopa Effects in I’D
Positron Emission Tomography
Studies on brain radioactivity distribution were performed
with the patient positioned with the head in the positron
emission tomograph (GE 2048- 15B Plus, General Electric
Medical Systems, Uppsala, Sweden). The radioactivity was
measured in 15 transaxial slices 6.8 mm apart and with an
in-plane resolution of 5 mm 1181. The patient was placed in
the tomograph with the head resting on a plastic U-shaped
support. Fixation was achieved by using an inflatable cushion
surrounding the inner surface of the support. The head was
adjusted to the detectors of the tomograph with the middle
slice parallel to the orbitomeatal line. Scanning began at the
start of i.-["C]UOPA injection and continued for 60 minutes (time frames: 10 x 60, 10 X 120, and ? X 200 seconds). The first and second scans were always separated by at
least 120 minutes. In Patient 1, both scans were shortened at
the patient's demand (the last three 120-second frames were
not scanned).
PET images were reconstructed from data collected from
each time frame, using a contour-finding algorithm for attenuation correction [ 1 ?], and filtered with a 4.2-mm Hanning filter. Summation images were constructed for each
scan by using data collected 20 to GO minutes after tracer
injection by the use of computer software supplied with the
Realignment of PET Scans and Region of
lzterest Drawizgs
A realignment method was used to prevent movements between scans from causing artificial increases or decreases in
the influx consrant of L-("C:]DOPA [20]. In brief, the
method is based on using a mask of one reference data set
(eg, baseline) made from voxels with a high signal-to-noise
ratio in cornparison with the sample data set (eg, perturbation). 'The result of the comparison is a matrix against which
both data sets are resliced. Following this procedure, an average image was formed using the summation images from
the two realigned data sets. A11 regions of interest (ROIs)
were then drawn in this averaged summation image.
All ROIa were drawn upon visual inspection of the images, and the positions of the ROIs were compared with a
brain atlas [21]. A circular ROI with a diameter of 0.9 cm
was used to delineate the caudate nucleus. The left and right
caudate values were averaged, and mean values of two slices
were used. The putamen ROls were delineated with a fixed
geometry defined froin the brain atlas in the left and right
side of the brain, shrunk or expanded to the area of 3.6 to
4.8 cin' and then averaged. The putamen KOIs were drawn
in two continuous slices showing the highest striatum to surrounding brain radiocontrast, covering a ventral and a dorsal
part of putamen. For the extrastriatal analysis of tracer uptake, three KOIs were defined, the dorsolateral prefrontal
cortcx, the niesial prefrontal cortex, and the thalamus. These
ROls were drawn on the same slices as the striatal ROIs.
The dorsolateral prefrontal cortcz RUl was drawn with a
cortex function in the data-handling &ware, using a line
with defined thickness of 1 cm, which was then mirrored
(reflected) to the opposite side of the brain. The values of
both sides of the brain and the two adjacent slices were averaged. The mesial prefrontal cortex ROI was drawn as a
336 Annals of Neurology
Vol 41
No 3
March 1997
circular ROI with the diameter of 2.0 cm. Values of the two
adjacent slices were averaged. The thalamus ROI was drawn
with a freehand function in the right hemisphere with an
area of 1.2 to 2.2 cm2 and mirrored to the opposite side.
The average value of both the thalamus ROIs was used. The
whole set of ROIs was then transferred to the two realigned
data sets and used in the calculations.
Time-activity cui-ves were generated and used to reconstruct
the images and analyze striatal influx rate, ie, the rate of specific conversion of I.-[' 'CIDOPA. The reconstruction uses
the same mathematical background as the multiple time
graphical analysis described previously [22]. This method
effectively generates a linear description of striatal L["C]DOPA increase from 5 minutes of real time after injection. Occipital cortex in three adjacent slices (total area, 1216.5 cm') was chosen as the reference tissue and used as the
input function. The slope (ie, k, value) was deterniined by
linear regression analysis using weighted least-square analysis
from data collected 5 to 60 minutes of real time after tracer
injection. Each data point was used after calculation of a
weight factor by the empirical formula for calculation of the
standard deviation for a given pixel [23]. No correction was
made for difference in intercept, as this has been shown to be
close to 1 for L-["C]DOPA 1241. The k3 value represents the
rate constant for striatal utilization of I ~ - [ ''CIDOPA radioactivity and is shown to represent the rate constant for transport and conversion of the tracer to ["C]dopamine within
the region of interest [22]. A blinded evaluation of the images was made twice by different researchers to avoid subjective estimations of the images.
Statistical Analysis
For comparison of the subregion of striatum and the two
states of disease, the software STATISTICA for Windows
(StatSoft Inc), version 5.0, was used to perform an analysis
of variance with repeated measure and a block design. The
level of significance was set to p < 0.05.
All the patients responded clinically to treatment with
a bolus injection and infusion of levodopa. The advanced PD patients converted from the "off" state to
the "on" state within 5 to 10 minutes after the first
bolus dose. All the patients with advanced PD exhibited dyskinesias to a certain degree during the second
PET scan, but none of the patients with mild PD did.
Two of the early PD patients reported feeling a transient nausea.
The regional striatal L-["C]DOPA influx rate constants (eg, k3 values) are shown in Table 2. The baseline h3 values from the advanced PD patients were significantly lower in all the subregions of the striatum
compared with the baseline h3 values in the early PD
patients ( p < 0.01). The highest /z3 values were found
in rhe caudate nucleus in both patient groups. Analysis
of striatal subregions showed a marked difference in
Table 2. Summary of L-["C]DOPA Injux Rate, eg, k, Value in Subregions of Striaturn and the
Relative Changes of This k, Value Compared with Raseline ("'Off" State) Scan
Advanced PD (n = 5)
Baseline (off state)
Levodopa infiision (on state)
Early I'D (n = 5 )
Baseline (off state)
Levodopa infusion (on state)
Caudate Nucleus
Putamen Ventral Slice
Putamen Dorsal Slice
0.01230 t 0.0019
0.01232 ? 0.0020
0.00812 t 0.0012
0.01016 i 0.0009"
0.00556 -C 0.0029
0.00776 i 0.0031"
0.01720 t 0.0030
0.01610 ? 0.0023
0.01366 t 0.0029
0.01218 t 0.0021"
( - 1 1%)
0.01 1 2 4 t 0.0040
0.00870 t 0.0038"
(- 23%)
Values are mean 2 SD; n = 5 in each patient category. All the baseline values in advanced I'D patients in dl striatal subregions were lower
compared with the early I'D patients (ANOVA, p < 0.01).
"Significant effect from levodopa infusions (ANOVA, p
< 0.05) and
group difference in effect from levodopa infusion (ANOVA; interaction,
p < 0.05) was found.
Parkinson's disease; ANOVA
analysis of variance.
levodopa-induced L-[' 'CIDOPA influx rate in the two
groups of patients (Fig). In the caudate nucleus, the
levodopa infusion did not affect this rate differently,
whereas in the putamen, levodopa infusion had significantly different effects ( p < 0.05) in the two patient
groups (see Table 2). We also observed a tendency to a
ventral-dorsal gradient of change that is opposite in the
two patient groups. Patients with advanced PD showed
an increased L-["C]DOPA influx rate in the putamen
after levodopa infusion (dorsal slice, 40%; ventral slice,
25%). In patients with early PD, on the other hand,
levodopa decreased this rate in the putamen (dorsal
slice, -23%; ventral slice, - 11%).
No significant changes induced by levodopa were
found in the extrastriatal regions analyzed (Table 3). It
Change of L-["C]DOPA inJux rate, eg, k, value induced by
levodopa infision ron state) compared with unrnedicated
state ("'off" state). Values are mean t SO; n = 5 in each
patient categoy. PD = Parkinson i disease.
Early PD
Ventral slice
Dorsal slice
should be pointed out that in both groups of patients,
a small decrease in the k3 value could be observed in
the mesial prefrontal cortex region ( p < 0.05). The
results from the 3 selegiline-treated PD patients did
not markedly differ from the other 2 advanced patients
in any of the analyzed regions.
As seen in Table 2, the two groups of patients displayed significant differences in L-["C] DOPA influx
rate in striatal subregions. In all patients, a rostrocaudal
as well as a ventrodorsal gradient in this influx rate was
observed. These findings correspond to neuropathological indices of neuronal loss in PD obtained from postmortem analysis [25]. In such studies, a general finding
is that the ventrolateral tier of the substantia nigra,
which projects to the dorsal and posterior part of the
putamen, seems to be more vulnerable to the pathological process in idiopathic PD. Also, measurements
of dopamine concentrations postmortem have consistently shown a relative sparing of dopamine in the caudate nucleus as well as a ventrodorsal gradient in dopamine loss in the putamen [26-281. As discussed
above, baseline values of the L-[' 'CIDOPA influx rate
in the investigated PD patients correspond well to distribution of structural deficits obtained by postmortem
analysis. The effects induced by levodopa as measured
in the present investigation are, however, not easily understood.
There seem to be two major factors governing the
L-[' 'CJDOPA influx rate, the integrity of the presynaptic dopaminergic system, which constitutes the structural prerequisite for uptake and decarboxylation, and
the functional tone of this system. The activity of the
enzyme mediating the conversion of I -DOPA to dopamine, aromatic L-amino acid decarboxylase (AADC),
has recently been shown to be regulated by physiological stimuli and corrclates with presynaptic dopaminer-
Torstenson et al: Differential Levodopa Effecrs in PD
Tnble 3. Summary of L-[’IC]
DOPA ln$?ux Rate, eg, k, Value in Extrastrintal Regions (Dorsolnternl Prefiontal Cortex, Mesinl
Prefiontal Cortex, and Thalamus) and the Relative Changes of the k, Value Compared with Baseline (“OffState) Scan
Advanced PD (n
Prefrontal Correx
Mesial Prefrontal
0.00492 t 0.0012
0.00482 t 0.0009
0.00686 t 0.0016
0.0063 5 0.0006“
0.00503 t- 0.0019
0.00494 t 0.001 1
(- 2%)
0.00492 t 0.0002
0.00465 t 0.0009
(- 6 % )
0.0068 -C 0.0010
0.00581 t 0.0012”
0.00537 i 0.0023
0.00501 -t 0.0019
Baseline (“off” state)
Levodopa infusion (“on” state)
Early PD (n = 5 )
Baseline (“off” state)
Levodopa infusion (“on” state)
Values are mean 2 SD; n
5 in each patient category.
“Significant effect from levodopa infiisions (ANOVA, p < 0.05).
I’D = Parkinson’s disease; ANOVA = analysis of variance.
gic tone. A short latency change in the enzyme’s activity can be induced that cannot be explained by
increased protein synthesis [27, 301. A disruption of
dopaminergic neurotransmission by dopamine D o r
D,-receptor antagonists increases AADC activity,
whereas pretreatment with the dopamine agonist bromocriptine decreases the activity of the enzyme [30].
We assume that this behavior is the physiological basis
for any change measured by L-[”C]DOPA, since the
retention of this tracer is crucially dependent on
AADC activity [16, 221.
It is generally accepted that the functional tone of
the presynaptic dopaminergic system is controlled by
inhibitory autoreceptors located on presynaptic dopaminergic nerve terminals [4], regulating synthesis
and/or release of dopamine. This inhibitory effect of
dopamine autoreceptor stimulation also seems to involve the I - [ ’ ‘CIDOPA influx rate, since pretreatment
with dopamine agonists like cabergoline [1 11 and apomorfine (Torstenson R, unpublished results) decreases
the L-[~’C]DOPAinflux rate. There is increasing evidence that L-DOPA itself exerts neuromodulatory
properties with dopamine antagonist-like effects when
administered in therapeutic concentrations [5, 61. Such
dopamine antagonist-like effects can be measured by
PET as an increase in the L-[”C]DOPA influx rate.
Moreover, bR-erythro-5,6,7,8-tetrahydrobiopterin(RBH,) administration has been shown to elicit the
I-[”C]DOPA influx rate, which can be further potentiated by the coadministration of tyrosine [13]. It is
conceivable that levodopa itself mediates this excitatory
influence, since levodopa increases the influx rate for
L-[”C]DOPA by approximately 20% in healthy monHence, apart from the structural integrity,
keys [7].
there appear to be at least two factors governing the
rate of I - [ ’ ~ C ] D O P A
influx, ie, the intrinsic activity of
the dopamine autoreceptor, regulating synthesis and/or
release, and the counteracting excitatory action mediated by L-DOPA or R-BH,.
338 Annals of Neurology
Vol 41
No 3
March 1997
Thus, when levodopa is administered, the net effect
on L-[’IC]DOPA influx rate can be assumed to be different in the healthy and in the degenerated state, due
to differences in decarboxylation capacity, storage, release, and metabolism of dopamine. In the structurally
intact nigrostriatal system, levodopa does not appreciably affect extracellular dopamine levels due to a preserved capacity for reuptake, storage, and metabolism
[31]. It can thus be assumed that in healthy monkeys,
acute levodopa administration does not markedly affect
the intrinsic activity of the inhibitory dopamine autoreceptor. In PD, however, where dopaminergic degeneration gives rise to increasing extracellular dopamine
levels in response to levodopa [2, 311, the modulating
effects on the presynaptic dopaminergic system to such
drug administration must be assumed to be different
from that in the healthy state.
The finding in our study of a preferential levodopamodulating effect in the putamen indicates that loss of
dopaminergic nerve terminals is associated with not
only an acceleration of dopamine release [a] but also
the induction of a dysregulatory state. In the early PD
patients who had comparatively mild dopaminergic
deficits, the net effect of levodopa was inhibitory on
L-[”C]DOPA influx rate, indicating that the increase
in dopamine induced by levodopa did affect the autoreceptor function. In the advanced PD patients, the net
effect of levodopa was excitatory on the rate of
L-[”C]DOPA influx with the most pronounced effect
in the dorsal putamen. We speculate that in these regions, loss of inhibitory feedback will allow levodopa to
exert its excitatory influence. We support this hypothesis on experimental evidence where dopamine autoreceptor dysfunction may occur as a consequence
of dopaminergic degeneration or excessive dopamine
stimulation, which occurs in advanced PD. Such experimental evidence includes dopaminergic autoreceptor
subsensitivity after dopamine depletion, eicher by pharmacological means such as after reserpine administra-
tion [32] or by 1-methyl-4-phenylpyridinium (MPP+)
lesioning [S]. Dopamine autoreceptor subsensitivity has
also been shown to occur after excessive dopamine
stimulation such as after acute or chronic amphetamine
administration [33, 341. Another possible explanation
for this excitatory effect of levodopa could be a differential response to the drug in another interacting neurotransmitter system in the striatum, eg, the glutamate
system [35]. It is noticeable that in more structurally
preserved regions such as the caudate nucleus, the thalamus, and the prefrontal cortex [36],levodopa did not
affect L-[”C]DOPA influx rate in either of the patient
categories. The only effect induced by levodopa was
observed in the mesial prefrontal cortex, where the
L-[”C]DOPA influx rate was decreased in both patient
The clinical response profile of levodopa undergoes a
marked shift in the advancement of PD, ultimately
leading to what is generally described as motor response complications [37-401. Such changes constitute
a shift of the levodopa dose-response curve to the left
[37], a decreased equilibration half-life between the
plasma and effect compartment, a shorter effect duration of each dose, a shift from a hyperbolic to a sigmoid profile of dose-response curve [38, 331, and, finally, a shortening of the time for levodopa to induce
peak response [40]. In a recent review by Nutt and
Holford [41], these various response alterations are
summarized and imposed on pharmacodynamic modeling. It is evident that the seemingly chaotic and unpredictable pharmacology of levodopa in PD can reasonably be described by means of pharmacodynamic
modeling. However, the mechanisms underlying these
alterations are largely unknown. The storage hypothesis
has gained widespread acceptance to underlie some aspects of the motor fluctuation dilemma. Clearly, the
results of the present investigation go well in line with
this hypothesis, but they also touch on the important
question on how levodopa may induce dynamic
changes in receptor tone in various states of PD.
Whether these changes are restricted to presynaptic elements cannot be elucidated with the present experimental protocol. It is known that proteins like neuroreceptors take on a number of conformations and that
the relative proportions of the various conformations
change according to an “energy landscape” [42].It is
tempting to speculate that the behavioral sensitization
to dopaminergic stimulation occurring with the advancement of PD is represented by a shift in the relative proportions of the various conformations of dopamine receptors in this energy landscape. In this
context, the addition of dopamine agonists to levodopa
treatment in PD may be beneficial in terms of reducing the development of dopamine autoreceptor dysfunction. Moreover, in further drug development,
drugs that act to alter the neuromodulatory effects of
levodopa should be considered.
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effect, advanced, dopaminergic, differential, disease, parkinson, function, early, levodopa
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