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PET studies and motor complications in Parkinson's disease
REVIEW PET studies and motor complications in Parkinson's disease David J. Brooks Parkinson's disease (PD) patients with motor complications show a greater reduction in putamen
[ISF]dopa uptake on positron emission tomography (PET) compared with sustained responders to c-dopa, although individual ranges overlap considerably.This implies that, although loss of putamen dopamine storage predisposesmotor complications in PD, it cannot be the only factor determining timing of onset. Additional PET studies suggest that loss of striatal dopamine storage capacity along with pulsatile exposure to exogenous c-dopa results in pathologically raised synaptic dopamine levels and derangedbasal ganglia opioid transmission.This, rather than altered dopamine receptor binding, then causes inappropriate overactivity of basal ganglia-frontal projections, resulting in breakthrough involuntary movements. Trends Neurosci.
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exposure to this pro-drug ~. The onset of the beneficial clinical response to oral k-dOpa becomes more rapid with disease advancement, but the duration of the clinical effect become progressively shorter and less predictable 2. The mechanisms underlying these 'wearing-off' and unpredictable ' o n - o f f ' p h e n o m e n a remain unclear. Possible factors include a loss of ability of the deafferented striatum to buffer and regulate dopamine release after administration of oral L-dOpa, and unpredictable absorption of L-dopa from the gastrointestinal tract. Levodopa-induced dyskinesias (LIDs) can be choreic or dystonic and tend to be most evident when peak plasma levels of L-dopa are achieved (peak-dose dyskinesia), or at the onset and end of the effect of each L-dopa administration (diphasic dyskinesia). The timing of onset of LIDs in PD appears, in part, to be related to disease severity; dyskinesias develop within weeks of k-dOpa exposure in patients with long-standing untreated PD or severe parkinsonism caused by the nigral toxin 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine (MPTP) 3. It has been suggested that the loss of nigrostriatal dopamine projections associated with PD results in 'supersensitivity' of deafferented postsynaptic striatal dopamine D1 and D2 receptors. Subsequent exposure to high and pulsatile levels of exogenous dopamine via long-term intermittent oral administration of L-dopa then leads to the occurrence of dyskinesias 4'5. Although the dopamine-receptor-supersensitivity model for LIDs is attractive, there are two lines of evidence against it. First, if intact monkeys are exposed to high enough oral doses of L-dopa, dyskinesias can result 6. Second, studies on animal models of PD with toxininduced nigral lesions suggest that striatal D2-receptor upregulation is transient and Dl-receptor binding is unaltered or reduced <7-1°(J. Tedroff, PhD thesis, Uppsala University, 1990). Given this, it seems more likely that dyskinesias arise from downstream pharmacological changes in the basal ganglia that result from exposure of dopamine receptors to high non-physiological levels
of exogenous L-dOpa and dopamine, rather than from changes in striatal dopamine receptor availability (see Olanow et al. n in this supplement). In support of this, it has been reported that, although the threshold for response of parkinsonism to L-dopa remains relatively constant with disease progression, the threshold for inducing dyskinesias decreases 4. The likelihood of developing either fluctuating motor responses or dyskinesias can be significantly reduced by maintaining de novo PD patients on dopamine-agonist monotherapy, rather than L-dOpa1>1s. As these agents are D2-receptor selective, it has been argued that dyskinesias could arise owing to overstimulation of D1 receptors. However, pulsatile administration of D1- and D2-receptor agonists can induce dyskinesias in MPTPlesioned monkeys in the absence of L-dopa priming 16. Postmortem studies on striatal dopamine D1- and D2receptor binding in PD have concentrated on endstage patients who invariably were experiencing motor complications. As a rule, these chronically treated endstage cases show normal or mildly reduced levels of striatal D1- and D2-receptor binding 17. The endogenous opioid peptides enkephalin and dynorphin are present in high levels in the basal ganglia. The monosynaptic striatal-internal pallidal (GPi) projections of the direct pathway contain dynorphin and GABA, whereas the striatal-external pallidal (GPe) projections that make up the first stage of the indirect polysynaptic pathway to the GPi contain enkephalin and GABA~s'~9(see also Obeso e t al. 2° in this supplement). High levels of enkephalin and dynorphin, and increased expression of preproenkephalin mRNA, have been reported in the striatum and pallidum of animal lesion models of PD with L-dopa-induced dyskinesias 2>24. Dynorphin has highest affinity for opioid K receptors and inhibits release of glutamate in the GPi (Ref. 25), whereas enkephalin has highest affinity for opioid 8 receptors and inhibits release of GABA in the GPe (Refs 26,27). Current models of basal-ganglia connectivity suggest that the net effect of raised levels of enkephalin in the GPe and of dynorphin in the GPi will be to reduce the normal inhibitory GABA-mediated
David L Brooks is at the MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK W 1 2 ONN.
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PPROXIMATELY SO°N of Parkinson's disease (PD) patients will experience a fluctuating motor response A to oral L-dopa along with dyskinesias after five years of
see front matter © 2000 Elsevier Science Ltd. All rights reserved.
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remaining neurons increases in parallel with striatal deafferentation. Lee and colleagues have compared [~SFldopa, p*C]DHTBZ and plC]MP Glu PET findings in established PD (Ref. 36). They have shown that all three PET approaches discriminate D1 receptors | ~ D2 andA2Areceptors alu 100% of PD cases from control ) cases, but putamen [lSF]dopa upGABA GABA,SP I take was relatively raised and t DYNtD ~ ENKI'F1 Glu Glu [HC]methylphenidate binding relaI' tively reduced, compared with {Dopamine []~C]DHTBZ binding. They suggest I Ventral that levels of vesicular monoamine I thalamus o transporter binding give the truest reflection of remaining dopamineGABAI ~ terminal density in PD owing to GABA relative upregulation of DDC activity and downregulation of DAT binding to compensate for the lower ..... G/u .... ~( GPi/SNr @...... levels of endogenous dopamine present in the synaptic cleft in PD. Basal ganglia, Parkinson's disease and levodopa therapy: TINS supplement Patients with fluctuating responses to >dopa show significantly lower Fig. 1. Basal ganglia connectivity in Parkinson's disease with dyskinesias. Thickened lines indicate abnormally increased neurotransmission and dotted lines indicate abnormally decreased neurotransmission. Glutamate pathways putamen [~UF]dopa uptake than are shown in red, GABA pathways are shown in blue and dopamine pathways are shown in green. Abbreviations: those with early disease and with sustained therapeutic responses 3s'39. A2A , adenosine A2A; D Y N t dynorphin; ENK, enkephalin; GABA, gammaaminobutyric acid; Glu, glutamate; GPe, external pallidum; GPi, intemal pallidum; PPN, pedunculopontine nucleus; SNc, substantia nigra compacta; SNr, substantia nigra A confounding factor when trying reticulata; SP, substance P; STN, subthalamic nucleus. to compare presynaptic dopamineterminal function in PD patients output from GPi to ventral thalamus and motor cortical with and without motor complications is that the former areas, thus promoting involuntary movements ]gy tend to have an earlier age of onset, more severe disease, (Fig. 1). Microelectrode recordings from the GPi of longer disease duration and a greater cumulative monkeys with LIDs are in support of this viewpoint as exposure to >dopa. De la Fuente-Fernfindez and colabnormal burst firing at a diminished frequency has leagues addressed this problem in two ways 39. First, been reported 28. Additionally, apomorphine-induced they used analysis of covariance (ANCOVA) to factor dyskinesias in PD are associated with a reduction in GPi out effects of age at onset and disease duration in firing 29. The main frontal projection areas of the basal groups of fluctuators and non-fluctuators. Second, they ganglia are the supplementary motor area (SMA), the matched subgroups of fluctuators and non-fluctuators arcuate premotor cortex (PMC) and the dorsal prefrontal for age of onset and disease duration. They found that cortex (DPFC). It would, therefore, seem a plausible mean putamen [~SF]dopa uptake was 28% lower in PD hypothesis that LIDs arise in association with inappro- patients with motor complications compared with priate overactivity of these frontal projection areas. those without, but that there was considerable overlap of the two individual ranges (Fig. 2). They concluded that, although loss of striatal dopamine-terminal funcFollowing intravenous administration, [lSF]6-fluoro- tion predisposes PD patients towards development of dopa and 6-[nC]L-dopa are taken up by the terminals of L-dopa-associated complications, it cannot alone be the nigrostriatal dopamine projections and converted to responsible for determining the timing of onset of motor [~SF]- and [11C]dopa, respectively 3°m. The rate of striatal fluctuations and involuntary movements. [18F]- and [11C]dopa accumulation, measured by PET, Torstensen and colleagues have examined the effects therefore directly reflects the activity of dopa decarboxyl- of intravenous boluses of >dopa at pharmacologically ase (DDC) in dopamine terminals 3z. Putamen [lSF]dopa effective levels (2 mg/kg) on striatal [HC]dopa uptake uptake decreases with the clinical progression of PD in early and advanced PD patients 4°. Levodopa admin(Ref. 33), correlating closely with the severity of istration reduced dorsal putamen p~C]dopa uptake by bradykinesia and rigidity 34. 23% in patients with early disease, but increased uptake The PET tracers [11C]CIT-FEand [llC]methylphenidate by 40% in advanced cases with motor complications. (MP) both bind to the dopamine transporter (DAT) on Levodopa was found to have no significant effect on nigrostriatal terminals and provide markers of their func- caudate [~lC]dopa uptake where dopamine-terminal tional integrity 3s,g6.The tracer [llC]dihydrotetrabenazine function was relatively preserved. In a follow-up study, (DHTBZ) is a marker of vesicle m o n o a m i n e transporter they showed that subcutaneously administered therfunction 37. Tedroff and colleagues have compared rela- apeutically effective doses of the dopamine D1- and tive levels of striatal DAT binding and DDC activity in PD D2-receptor agonist, apomorphine, downregulated using [11C]CIT-FEand [llC]dopa PET (Ref. 35). They found dorsal putamen [llC]dopa uptake by 28% in early PD that DDC activity was relatively upregulated compared patients, but had no significant effect on DDC activity with DAT binding, and that this was most marked in the in advanced cases4L They hypothesized that the posterior putamen where dopamine denervation is inhibitory autoreceptor function of the remaining greatest. This suggests that dopamine turnover in the dopamine terminals becomes upregulated in the puta-
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men in early PD. This autoreceptor upregulation results in downregulation of DDC activity in the presence of clinically effective doses of exogenous L-dOpa or dopamine agonists such as apomorphine. Dopamine tone in early PD is maintained in this way at physiological levels, allowing a sustained treatment response. As PD advances, however, the continuing degeneration of nigrostriatal terminals in the dorsal putamen causes this adaptive autoreceptor upregulation to be lost, resulting in ineffective control of dopamine tone and onset of motor fluctuations. At the same time, high levels of exogenous L-dOpa (and not, interestingly, dopamine agonists), act to increase putamen DDC activity by an uncertain mechanism, which causes synaptic dopamine levels to swing pathologically high and promotes onset of dyskinesias. Postsynaptic dopamine function At least five different sub-types of dopamine receptors have now been described. They broadly fall into Dl-type receptors (D1 and D5), which activate adenyl cyclase, and D2-type receptors (D2, D3 and D4), which either inhibit or have no effect on this enzyme. The striatum contains mainly D1- and D2-receptor subtypes and these play a primary role in modulating locomotor function. PET studies with spiperone-based tracers, and single photon emission computed tomography (SPECT) studies with [123I]IBZMhave reported normal levels of striatal D2-receptor binding in untreated PD patients later shown to be L-dopa or a p o m o r p h i n e responsive 42'43. By contrast, [11C]raclopride PET studies in de novo PD patients have shown 10-20% increases in D2-receptor-site availability in the p u t a m e n contralateral to the more affected limbs 4446. [l~C]raclopride binding inversely correlates with [18F]dopa uptake 47. These findings suggest that putamen D2-receptor availability in untreated PD patients is mildly upregulated and caudate D2 binding, where dopamine-terminal function is relatively preserved, remains normal. Studies with [~C]methylspiperone PET and [~23I]IBZM SPECT have reported both normal 48-s° and reduced striatal D2 binding in chronically treated PD patients. Serial [HC]raclopride PET has shown that the mildly increased putamen [~lC]raclopride binding seen in de novo PD patients normalizes after several months of exposure to L-dopa4s'sl. Chronically L-dopaexposed PD cases continue to show normal levels of putamen D2-receptor binding, but caudate D2-receptor binding is reduced by around 20% (Refs 46,52). These findings correlate well with in vitro reports of striatal dopamine D2-receptor binding based on postmortem material from end-stage patients s3. [uC]SCH23390 is an antagonist of Dl-type receptor sites, binding reversibly during the time course of PET. In de novo hemiparkinsonian patients later shown to be L-dopa responsive, [~C]SCH23390 PET shows no relative upregulation of putamen binding contralateral to the affected limbs, suggesting that D1 binding remains at a normal level 54. By contrast, PD patients who have been exposed to L-dopa for several years show a 20% reduction in striatal Dl-receptor binding 46. Turjanski and colleagues examined striatal dopaminereceptor availability in subgroups of eight L-dopaexposed dyskinetic and ten non-dyskinetic patients 46, These subgroups were age-matched (dyskinetic, 49-74 years; non-dyskinetic, 42-78 years) and had similar clinical disease durations (dyskinetic, 3-10 years;
R~ w
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TABLE I. D I- and D2-receptor binding potentials (BPs) in dyskinetic and non-dyskinetic individuals with Parkinson's disease (PD) Caudate BP
Controls Non-dysldnetic PD Dyskinetic PD
Putamen BP
DI receptor (mean-+SD)
D2 receptor (mean_+SD)
1.25_+0.17 I.I 1+0.14
2.25+0.13
1.25+0.13
2.35+_0.14
1,90+_0.19 ~ 1.88_+0.2 P
1.14+0.09 1.12+-0.21
2,22+0.13 2.45_+0.28
1.06+_0.23
DI receptor (mean_+SD)
D2 receptor (mean_SD)
ap<0.05. Adapted from Ref.46.
non-dyskinetic, 3-9 years). There were non-significant trends towards greater disease severity [mean motor Unified Parkinson's Disease Rating Scale (UPDRS) 19 versus 13] and higher daily L-dOpa dosage (560 mg vs 450 rag) in the dyskinesia subgroup. Mean caudate a n d p u t a m e n Dl-receptor binding and putamen D2receptor binding were normal for both the dyskinetic a n d the non-dyskinetic PD subgroups, and caudate D2-receptor binding was reduced by around 15% (see Table 1). Similar findings have been reported where striatal d o p a m i n e D1- and D2-receptor binding is similar in fluctuating ss and dyskinetic s(' PD patients compared w i t h sustained responders. In these studies, ANCOVA was used to factor out the confounding effects of differences in age of onset and disease duration between the PD subgroups. These studies suggest that onset of motor complications in PD is not primarily associated with alterations in striatal dopamine-receptor availability. [llC]raclopride PET can provide an indirect marker of changes in levels of dopamine in the synaptic cleft of the striatum. An intravenous bolus of 0.3 mg/kg m e t a m p h e t a m i n e causes a 24% reduction in putamen [11C]raclopride binding in normal subjects owing to the dopamine released st. Tedroff and colleagues used [2,C]raclopride PET to examine L-dopa-induced changes in synaptic dopamine levels in I'D (Ref. 58). The patients were divided into two subgroups: those with early hemi-disease and those with advanced disease exhibiting fluctuating treatment responses and LIDs. A total dose of 3 mg/kg L-dopa was administered as an intravenous bolus; this resulted in a clinical response in all the PD patients. After the infusion of L-dopa, the early cases showed a 10% fall in [*~C]raclopride binding in the posterior dorsal putamen. No effect on [l~C]raclopride binding was seen in the asymptomatic putamen contralateral to the unaffected limbs. The advanced PD cases showed falls in posterior and anterior dorsal putamen [11C]raclopride binding after ~-dopa (23% and 20% respectively). The reductions in putamen [I1C]raclopride binding correlated with disease severity assessed without medication with the UPDRS. These findings indicate that severe loss of dopamine terminals in advanced PD leads to excessive levels of synaptic dopamine when exogenous c-dopa is administered. This reflects a combination of upregulation of striatal dopamine synthesis and release by those terminals remaining, along with severe loss of dopamine transporters preventing dopa m i n e re-uptake. This is more likely to be the explanation for the more rapid response of advanced PD patients to oral L-dOpa, rather than changes in postsynaptic dopamine D1- and D2-receptor binding, and m a y also be a factor in promoting onset of dyskinesias. TINS Vol. 23, No. 10 (Suppl.), 2 0 0 0
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TABLE 2. Uptake ratios (region-occipital) for [JlC]diprenorphine in Parkinson's disease (PD)
Controls Non-dyskinetic PD DyskineticPD
n
Caudate (mean--SD)
Putamen (mean---SD)
Thalamus (mean---SD)
10 7 6
2.76+0.40 2.64-+0.40 2.37_+0.80 a
2.62_+0.70 2.42-+0.30 1.97+0.40 b
2.81_+0.40 2.62+_0.30 2.31 +0.70 b
"P<0.05 versus controls. bP<0.001 versus controls and non-dyskinetic PD. Adapted from Ref. 67.
Opioid binding The caudate and p u t a m e n contain a dense population of m e d i u m spiny projection neurons that cotransmit opioids in addition to GABA in the pallidum 19. Striatal projections to GPe contain enkephalin w h i c h binds m a i n l y to 8 opioid-receptor sites and inhibits GABA release in the GPe (Ref. 26). Striatal projections to GPi transmit d y n o r p h i n w h i c h binds to K opioid-receptor sites and inhibits glutamate release from STN afferents to the GPi (Ref. 25). It is t h o u g h t that phasic firing of striatopallidal projection neurons results primarily in GABA release and m o r e sustained firing causes additional m o d u l a t o r y opioid release. The caudate and putamen also contain high densities of I*, K, and 8 opioidreceptor sites s9. These receptors are located b o t h presynaptically on dopamine, where they regulate dopamine release, and postsynaptically on interneurones and m e d i u m spiny projection neurons to pallidum terminals6°,6L Postmortem studies have shown reductions in nigral I* and K opioid-receptor sites in end-stage treated PD patients 62,63. There is n o w strong evidence from both postmortem studies and toxic lesioned animal models of this disorder to support the presence of deranged opioid transmission in the basal ganglia of PD. At postmortem, end-stage-treated PD patients show raised levels of pallidal preproenkephalin 64. In rats lesioned with the nigral toxin 6-hydroxydopamine, there are raised levels of striatal enkephalin and preproenkephalin expression, and p r o d y n o r p h i n expression is suppressed 27'6s. W h e n such animals are made hyperkinetic or dyskinetic after
0.008 -
[]
[] 0.006 -
Fluctuators Non-fluctuators * P = 0.053
t-
0.004 -
0.002 -
0.000 Caudate
I
Putamen
Basal ganglia, Parkinson's disease and levodopa therapy: TINS supplement
Fig. 2. Striatal [~SF]dopauptake in Parkinson's disease(PD). Putamen dopa decarboxylase(DDC)
activity is reduced in PD patients with fluctuating motor responses to L-dopa (red) compared with those with sustained motor responses to L-dopa~9(blue). Ki is an influx constant.
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chronic exposure to pulsatile doses of i,-dopa, further overexpression of striatal preproenkephalin is seen in addition to raised expression of prodynorphin. LevodopanaYve MPTP-lesioned m o n k e y s are also reported to show raised striatal enkephalin and reduced substance P mRNA expression23,24; exposure to L-dOpa for one m o n t h failed to normalize striatal preproenkephalin mRNA expression and substance P mRNA expression became elevated. [nC]diprenorphine PET is a non-selective marker of I*, ~, and 8 opioid sites and its binding has been shown to be sensitive to levels of e n d o g e n o u s opioids 66. If raised basal ganglia levels of enkephalin and dynorp h i n are associated with LIDs, PD patients with m o t o r complications would be expected to show reduced b i n d i n g of [uC]diprenorphine c o m p a r e d with those with sustained treatment responses. Piccini and colleagues 67 studied six PD patients with m o t o r fluctuations and LIDs and seven patients without dyskinesias (two had m o t o r fluctuations). Mean age, disease and treatment duration, and daily > d o p a dosage were not significantly different (see Table 2). Mean H o e h n and Yahr scores for the two groups were similar (1.85 _+ 0.7 sustained versus 2.25 _+ 0.5 dyskinetic). Significant reductions in [nC]dipren0rphine b i n d i n g in caudate, putamen, thalamus and anterior cingulate in the dyskinetic patients were observed, c o m p a r e d with the sustained responders (Fig. 3). Table 2 shows the magnitude of these reductions in the basal ganglia. Figure 4 shows that individual levels of p u t a m e n p~C]diprenorphine uptake correlate inversely with dyskinesia severity as determined with part 4 of the UPDRS. These in viva PET findings support the presence of elevated levels of endogenous opioids in the basal ganglia of dyskinetic PD patients and suggest that this, rather t h a n a primary alteration in dopamine-receptor binding, contributes to the appearance of involuntary m o v e m e n t s 67.
Activation studies Localization of regional cerebral activation during tasks, manifested as increases in levels of regional cerebral blood flow (rCBF), can be detected using H2[~sO] PET. W h e n n o r m a l subjects make m o v e m e n t s of a joystick in freely selected directions with their right h a n d while paced by a tone, there are associated rCBF increases in contralateral sensorimotor cortex (SMC) and lentiform nucleus, and bilaterally in anterior cingulate cortex, supplementary m o t o r area (SMA), lateral premotor cortex (PMC), and dorsolateral prefrontal cortex (DLPFC) 6s. Self-paced extensions of the index finger result in a similar pattern of activation 69. W h e n PD patients, scanned after stopping their medication for 12 h, perform the same two m o t o r tasks, n o r m a l levels of activation of SMC, PMC and lateral parietal association areas are seen, but there is impaired activation of the contralateral lentiform nucleus, and also of anterior cingulate, SMA and DLPFC. These are the cortical areas that receive a major input from the basal ganglia. It is t h o u g h t that the dorsolateral prefrontal cortex plays a crucial role in m o t o r decision making and working m e m o r y whereas the supplementary m o t o r area prepares volitional m o t o r programmes once selected. By contrast, lateral premotor cortex is believed to have a primary role in facilitating m o t o r responses to external visual and auditory stimuli. An inability to activate SMA and DLPFC during freely selected m o v e m e n t s could explain the difficulty that PD patients experience in
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Fig. 3. [~lC]diprenorphine uptake in dyskinetic Parkinson's disease (PD). A statistical parametric map overlaying the location of PD regions onto a magnetic resonance (MR) template in standard stereotactic space indicates that significant reductions in [7~C]diprenorphineuptake are present in dyskinetic PD /(a) saggital, (b) coronal and (c) transaxial views]. Opioid binding is reduced in the basal ganglia, thalamus and anterior cingulate areas. Reproduced,with permission,from Ref. 67.
initiating such movements. Samuel and colleagues have recently reported that PD patients overactivate lateral p r e m o t o r and parietal areas while performing learned sequential finger m o v e m e n t s in order to compensate for impaired SMA function 7°. If akinesia in PD results from a failure to activate the basal ganglia to SMA and DLPFC projections, t h e n dopamine-replacement therapy ought to restore activation of this system. W h e n the c o m b i n e d D1- and D2-receptor agonist a p o m o r p h i n e is given subcutaneously to PD patients, resolution of their akinesia during performance of freely chosen joystick movements is associated with selective increases in SMA and DLPFC blood flow, providing further evidence for the role of these stuctures in the generation of volitional movements
71,72.
To determine the functional a n a t o m y that underlies peak-dose dyskinesias in PD, Piccini and colleagues have studied three right-handed PD patients w h o were selected because t h e y had predictable onset 7~ and duration of L-dopa-induced involuntary m o v e m e n t s that were restricted to the right arm. All three patients switched ' o n ' about 1S mins after the administration of a single oral dose of 200 mg :-dopa, and dyskinesias of the right arm began 1S-2S rains later as plasma levels peaked. Twelve rCBF measurements were performed for each subject: two at rest (scans 1 and 12) and ten while performing paced joystick m o v e m e n t s in freely chosen directions with the right h a n d (scans 2-11). Patients started the session off medication, L-dOpa was given between scans 2 and 3, and by scans 4 and S the patients were o n b u t without dyskinesias, and from scans 6 to 12 the patients were on and dyskinetic. Comparison of rCBF levels during rest with dyskinesias versus rest w i t h o u t dyskinesias showed relative activation of m o t o r cortex, lateral and mesial premotor areas, DLPFC and the basal ganglia during dyskinesias (Fig. S). Voluntary m o v e m e n t (paced joystick movements with the right h a n d in freely chosen directions) led to activation of the contralateral basal ganglia, primary m o t o r cortex, SMA and ipsilateral cerebellum in the PD patients. Comparison of dyskinetic versus non-dyskinetic states during voluntary m o v e m e n t revealed relatively higher levels of rCBF in the basal ganglia, the m o t o r cortex, lateral and mesial p r e m o t o r areas, DLPFC - a similar finding to that associated with dyskinesias at rest. Areas that showed a correlation between levels of rCBF and dyskinesia severity were lateral and mesial premotor areas, DLPFC, and the basal ganglia.
These H2[lsO] PET activation findings suggest that dyskinesias are associated with inappropriate overactivity of the basal ganglia - premotor - prefrontal projections. They also correlate with an [133Xe]SPECT activation study where a comparison of rCBF levels between dyskinetic and non-dyskinetic subgroups of PD patients performing learned sequential finger m o v e m e n t s w h e n ' o n ' showed relative overactivity of m o t o r cortex and lateral and mesial p r e m o t o r areas TM. The presence of abnormally raised basal ganglia and frontal activation during dyskinesias is reminiscent of the pattern of overactivity seen w h e n patients with dystonia (both idiopathic and acquired) perform joystick movements in freely chosen directions 7s'76.Indeed, D Y T I dystonia gene carriers have been shown to have relatively raised basal ganglia, p r e m o t o r and prefrontal glucose metabolism even at rest 77. This suggests that in b o t h LIDs and dystonia there is an inappropriate increase in traffic through the basal-ganglia frontal circuitary resulting in breakthrough of involuntary movements. Such an observation correlates with the hypothesis that the basal ganglia play a role in filtering and focusing m o t o r programmes,
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Fig. 4. Putamen:occiptal ~ I C]diprenorphine uptake ratios in Parkinson's disease (PD). The ratio of putamen:occiptal [TJC]diprenorphine uptake versus dyskinesia severity was measured 60-90 mins after tracer administration in PD patients. This was rated with part IV of the motor Unified Parkinson's Disease Rating Scale (UPDRSy. The graph shows that opioid receptor binding in the putamen decreases as dyskinesia severity increases.
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of rCBF measured with Hs[~sO] PET are d e t e r m i n e d by integrated synaptic activity in brain structures rather t h a n o u t p u t n e u r o n firing rates ~°. The globus pallidus has few i n t e r n e u r o n s and thus synaptic activity in the GPe and GPi will primarily reflect levels of striatal input, w h i c h is inhibitory. Increased pallidal rCBF in the presence of dyskinesias and d y s t o n i a therefore suggests an increased level of i n h i b i t o r y striatal i n p u t a n d is in a g r e e m e n t with the o b s e r v a t i o n t h a t intrinsic GPi n e u r o n a l firing is d i m i n i s h e d d u r i n g apomorp h i n e - i n d u c e d dyskinesias.
SMA
Basal ganglia
Prefrontal cortex
Basalganglia,Parkinson'sdiseaseandlevodopatherapy:TINSsupplement
Fig. 5. Regional cerebral activation during dyskinesias at rest. Increased levels of regional cerebral blood flow (rCBF) in the lentifrom nucleus, the motor, premotor and prefrontal cortex measured with positron emission tomography (PET) are associated with the presence of involuntary movements 73. Abbreviation: SMA, supplemenatry motor area. and t h a t an i n a p p r o p r i a t e increase in firing leads to a failure of the filtering m e c h a n i s m . The observation that b o t h dyskinesias and dystonia can be dramatically reduced after medial p a l l i d o t o m y and pallidal s t i m u l a t i o n is of interest because these procedures act to restore levels of p r e m o t o r and prefrontal a c t i v a t i o n in akinefic PD (Ref. 78) whereas excessive p r e m o t o r a c t i v a t i o n is n o r m a l i z e d in dystonia 79. The f i n d i n g of increased l e n t i f o r m nucleus rCBF appears, superficially, to contradict findings reported from single-unit pallidal recordings p e r f o r m e d prior to p a l l i d o t o m y w i t h PD patients. Lozano and colleagues have reported t h a t d o p a m i n e agents relieve akinesia by decreasing GPi and s u b t h a l a m i c nucleus activity while increasing GPe activity, and that a p o m o r p h i n e - i n d u c e d dyskinesias are associated w i t h further r e d u c t i o n s in GPi firing 29. However, it should be reiterated t h a t levels
Concluding
remarks
To date, m o s t studies o n the p h a r m a c o l o g y of dyskinesias have i n v o l v e d p o s t m o r t e m material from treated end-stage PD patients or toxic-lesion animal models. PET has the advantage of a l l o w i n g in viva measurements of neurotransmitter binding and cerebral m e t a b o l i s m to be performed at all stages of disease and can indirectly measure changes in synaptic d o p a m i n e and o p i o i d levels. The findings of the PET studies reviewed in this article suggest t h a t m o t o r complications arise in PD because pulsatile L-dopa administ r a t i o n results in p a t h o l o g i c a l l y h i g h levels of synaptic d o p a m i n e as the disease advances. These changes in synapfic d o p a m i n e levels result in a b n o r m a l l y raised levels of basal ganglia e n k e p h a l i n and d y n o r p h i n , and reduced levels of striatal and t h a l a m i c o p i o i d receptor availability o w i n g to increased o c c u p a n c y by the e n d o g e n o u s opioids. This, in turn, results in reduced inhibitory o u t p u t from the GPi and inappropriate overactivity of the basal-ganglia frontal p r o j e c t i o n areas allowing breakthrough involuntary movements. For further discussion o n this topic see Box 1.
Box I. Discussion Obeso: Are changes occurring in the striatum or pallidum in dyskinesia? Brooks: Changes are likely to be present in both areas. Levels of blood flow primarily reflect synaptic activity. The pallidum has few interneurons and so the finding of increased pallidal blood flow during dyskinesia suggests that inhibitory input to pallidum from the striatum is raised. This would be in accord with the single unit patient and animal model data that has reported decreased internal pallidal (GPi) firing during dyskinesias. O b e s o : During normal movement, there is activation of dorsolateral prefrontal cortex. Is there less activation of this region with movement in dyskinetic patients? Brooks: If anything, the opposite. Non-dyskinetic Parkinson's disease (PD I patients deactivate prefrontal areas if the task is complex. In dyskinetic patients, we saw aberrant activation of these areas but, I suspect that it's not productive activation and that it represents inappropriate synaptic activity. Waiters: It is appropriate to note that prefrontal areas and supplementary motor areas (SMA) send glutamatergic projections to the subthalamic nucleus {STN). If they are overactive as you indicate, they could contribute to the increased metabolic and physiologic activity in the STN. And, to the extent that this activation represents dysfunctional activity, this could induce an altered firing pattern in the STN, and disruption of this altered pattern could account for the benefit seen with deep brain stimulation (DBS) of the STN.
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Brooks: Bear in mind that when we see increased activation with positron emission tomography (PET), the actual firing frequency per se may not be increased - it may represent aberrant burst firing. Chase: Can you separate the GPi from the the striatalexternal pallidat ~GPe~on PET? Brooks: State of the art systems have 3 mm resolution, so you can certainly separate pallidum from striatum, We're just on the borderline of being able to separate the internal and external segments of the pallidum. Chase: If you can't. I think your results could be confounded. If, for exam pie, one of those structure goes up and the other goes down. you end up with an average. Brooks: I accept that. The whole question of pallidal metabolism is open to question as it reflects input from multiple sites such as striatum. STN, and cortex. If we really want to examine pallidal output with PK[. we have to examine ventral thalamic metabolism. Graybieh In what part of the cingulate gyms do you see changes in opioid binding. There are a number of motor areas in what used to be thought of as limbic cingulate cortex. Recordings from neurons in this region respond to movement. intention to move, and selection of movement. Brooks: There is increased binding in the motor regions in area 24, but it seems to extend into anterior cingulate region 32 as well. Graybiel: If receptors are internalized, how does that affect binding on PET?
D.J. Brooks
References 1 Nutt, J.G. (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neul"oh~y 40, 340-345 2 Nutt, J.G. and Holford, N.H.G. (1996) The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann. NeuroL 39, 561-573 3 Langston, J.W. et al. (1983) Chronic parkinsonism in h u m a n s due to a product of meperidine-analog synthesis. Science 219, 979-980 4 Mouradian, M.M. et aL (1989) Pathogenesis of dyskinesias in Parkinson's disease. Ann. Neurol. 25, 523 526 5 Boyce, S. et al. (1990) Nigrostriatal damage is required for induction of dyskinesias by L-dopa in squirrel monkeys. Clin. Neuropharmacol. 13, 448-458 6 Pearce, R.K.B. etal. (1995) Altered striataI preproenkephalin mRNA levels in normal macaque monkeys (Maraca fascicularis) with dyskinesias induced by chronic l.-dopa administration. Br. J. Phalrnacol. 116, 78-95 7 Murata, M. and Kanazawa, 1. (1993) Repeated L-dopa administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat. Neurosci. Res. Commun. 16, 15-23 8 Fuxe, K. etal. (1981) Characterisation of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides. J. Neural Transm. 51, 3-37 9 Alexander, G.M. etal. (1993) Changes in brain dopamine-receptors in MPTP parkinsonian monkeys following L-dopa treatment. Brain Res. 625, 276-282 10 Przedborski, S. etal. (1991) Unilateral MPTP-induced parkinsonism in monkeys - a quantitative autoradiographic study of dopamineD1 and dopamine-D2 receptors and reuptake sites. Neurochirurgie 37, 377-382 11 Olanow, C.W. et aL (2000) Continuous dopamine-receptor stimulation in early Parkinson's disease. Trends Neurosci. 23 (Suppl. Basal ganglia, Parkinson's disease and levodopa therapy), $117-$126 12 Lees, A.J. and Stern, G.M. (1981) Sustained bromocriptine therapy in previously untreated patients with Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 44, 1020-1023 13 Montastruc, J.L. et al. (1994) A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkiuson's disease: a five year follow-up. I. Neurol. Neurosurg. Psychiatry 57, 1034-1038 14 Rinne, U.K. et al. (1998) Early treatment of Parkiuson's disease with cabergoline delays the onset of motor complications. Results
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of a double-blind levodopa controlled trial. The PKDS009 study group. Drugs $5, 23-30 Rascol, O. et al. (2000) Dyskinesia in Parkinson's disease: A S-year study of ropinirole versus levodopa. N e w Engl. I. Med. 342, 1484-1491 Blanchet, P. et al. (1993) Differential effect of selective D-I and D2-dopamine receptor agonists on ievodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys. ]. Pharmacol. Exp. Ther. 267, 27S-279 Playford, E.D. and Brooks, D.J. (1992) In vivo and in vitro studies of the dopamine system in m o v e m e n t disorders. Cerebrovasc. Brain Metab. Rev. 4, 144 171 Haber, S. and Watson, S.J. (198S) The comparative distribution of enkephalin, dynorphin, and substance P in the h u m a n globus pallidus and basal forebrain. Neuroscience 14, 1001 1024 Penney, J.B., Jr and Young, A.B. (1986) Striatal inhomogeneities a n d basal ganglia function. Mov. Disord. 1, 3-15 Obeso, J.A. et al. (2000) Pathophysiology of the basal ganglia in Parkinson's disease. Trends Neurosci. 23 (Suppl. Basal ganglia, Parkinson's disease and levodopa therapy), $8-$19 Engberg, T.M. et al. (1991) Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats. Brain Res. 552, 113-118 Taylor, M.D. et al. (1992) Effects of unilateral 6-hydroxydopamine lesion and prolonged L-3,4-dihydroxyphenylalanine treatment on peptidergic systems in rat basal ganglia. Bur. I. Pharmacol. 219, 183-192 Jolkkonen, J. et aL (1995) c-dopa reverses altered gene expression of substance P but n o t enkephalin in the caudate-putamen of c o m m o n marmosets treated with MPTP. Mol. Brain Res. 32, 297-307 Lavoie, B. etal. (1991) Effects of dopamine denervation on striatal peptide expression in parkinsonian monkeys. Can. }. Neurol. ScL 18, 373-375 Maneuf, Y.P. et al. (1995) Functional implications of K-opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease. Brain Res. 683, 102-108 Maneuf, Y.P. et al. (1994) On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp. Neurol. 125, 65-71 Henry, B. and Brotchie, J.M. (1996) Potential of opioid antagonists in the treatment of levodopa-induced dyskinesias in Parkinson's disease. Drugs and Aging 9, 149-158
Box I. Discussion B r o o k s : T h i s varies b e t w e e n tracers. If D2 r e c e p t o r s are i n t e r n a l i z e d M a r c Laruelle h a s r e p o r t e d t h a t o n e d o e s n ' t see i n t r a c e l l u l a r b i n d i n g o f [nC]raclopride. H o w e v e r | H C ] S C H 2 3 3 9 0 c a n b i n d t o D l - r e c e p t o r b i n d i n g sites i n t h e c y t o p l a s m a n d so its u p t a k e s h o u l d n o t b e sensitive t o internalization. H i r s c h : W e h a v e s h o w n t h a t t h e r e is i n t e r n a l i z a t i o n o f t h e D 1 receptor after d o p a m i n e r g i c t r e a t m e n t . However. in a PD p a t i e n t w h o c a m e to a u t o p s y after b e i n g off L-dopa for 1 - 2 days. we saw m a n y D1 r e c e p t o r s in t h e c y t o p l a s m a n d a l m o s t n o r m a l levels at t h e s y n a p t i c m e m b r a n e , It is difficult to k n o w w h a t t h e f u n c t i o n of t h i s receptor in t h e c y t o p l a s m is, b u t o n e m i g h t a s s u m e t h a t t h e y are recycled i n t o t h e s y n a p t i c m e m b r a n e to be s t i m u l a t e d again. A n d t h i s t r a n s f e r f r o m t h e c y t o p l a s m to t h e m e m b r a n e c a n be v e r y fast. C a n we rule o u t t h e possibility t h a t s u c h c h a n g e s c o n t r i b u t e to t h e d e v e l o p m e n t of t h e d y s k i n e s i a ? Brooks: I d o n ' t k n o w for sure. As [ n C ] S C H 2 3 3 9 0 c a n b i n d to D l - r e c e p t o r b i n d i n g sites in t h e c y t o p l a s m its striatal u p t a k e reflects b o t h surface a n d i n t e r n a l i z e d p o p u l a t i o n s . PET studies w i t h this tracer s u g g e s t t h a t striatal D l - r e c e p t o r b i n d i n g is s i m i l a r in d y s k i n e t i c a n d n o n - d y s k i n e t i c PD t h o u g h t h e relative levels of receptor i n t e r n a l i z a t i o n c o u l d c o n c e i v a b l y differ. [11C]raclopride u p t a k e o n l y reflects t h e external D2 p o p u l a t i o n w h i c h a g a i n is similar in dyskinetic a n d n o n - d y s k i n e t i c PD. Rascol: I ' m s u r p r i s e d t h a t it is so difficult to s h o w supers e n s i t i v i t y of d o p a m i n e receptors w h e n y o u s h o w it so
RE-VIEW
- PET studies in Parkinson's disease
(cont'd)
n i c e l y w i t h o p i a t e receptors. Are t h e s e r e c e p t o r s r e g u l a t e d differently, or is d o p a m i n e t r e a t m e n t a c o n f o u n d i n g bias? B r o o k s : D o p a m i n e t r e a t m e n t is a c o n f o u n d e r . In u n t r e a t e d PD p a t i e n t s , D2 receptors are u p r e g u l a t e d b y 1 0 - 2 0 % , b u t this disappears with chronic therapy. Olanow: Are t h e r e differences o n PET in older a n d y o u n g e r PD p a t i e n t s to e x p l a i n w h y y o u n g e r p a t i e n t s h a v e a n i n c r e a s e d risk of d e v e l o p i n g d y s k i n e s i a ? B r o o k s : T h e r e is a fall i n b o t h d o p a m i n e t r a n s p o r t e r a n d p o s t s y n a p t i c - r e c e p t o r b i n d i n g as y o u b e c o m e older, h o w ever. o p i a t e b i n d i n g increases. It m a y be t h a t in s o m e w a y t h a t t h e s e a g e i n g c h a n g e s are p r o t e c t i v e a g a i n s t d y s k i n e s i a development, possibly by influencing glutamate NMDA site p h o s p h o r y l a t i o n . H i r s c h : In p a r k i n s o n i a n s y n d r o m e s , s u c h as p r o g r e s s i v e s u p r a n u c l e a r palsy (PSP), t h e r e are d o p a m i n e r g i c lesions, b u t t h e s e p a t i e n t s d o n o t d e v e l o p dyskinesia, p o s s i b l y b e c a u s e t h e y h a v e o t h e r l e s i o n s in t h e basal g a n g l i a circuitry w h i c h p r e v e n t its e x p r e s s i o n . It m a y be t h a t elderly PD p a t i e n t s have non-dopaminergic lesions that prevent dyskinesia w h i l e y o u n g e r subjects h a v e p u r e d o p a m i n e r g i c lesions. O l a n o w : If y o u r h y p o t h e s i s is correct, y o u w o u l d e x p e c t d y s k i n e s i a s to g r a d u a l l y d i s a p p e a r as t h e PD p a t i e n t s age a n d d e v e l o p m o r e n o n - d o p a m i n e r g l c lesions. But as far as I k n o w . d y s k i n e s i a s t e n d to persist. O b e s o : I agree. I h a v e s e e n p a t i e n t s in t h e i r 80s w h o h a v e h a d PD for m a n y years a n d still h a v e d y s k i n e s i a severe e n o u g h to w a r r a n t c o n s i d e r a t i o n of surgery.
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[ISF]dopa uptake on positron emission tomography (PET) compared with sustained responders to c-dopa, although individual ranges overlap considerably.This implies that, although loss of putamen dopamine storage predisposesmotor complications in PD, it cannot be the only factor determining timing of onset. Additional PET studies suggest that loss of striatal dopamine storage capacity along with pulsatile exposure to exogenous c-dopa results in pathologically raised synaptic dopamine levels and derangedbasal ganglia opioid transmission.This, rather than altered dopamine receptor binding, then causes inappropriate overactivity of basal ganglia-frontal projections, resulting in breakthrough involuntary movements. Trends Neurosci.
(2000) 23 (Suppl.), S101-$108
exposure to this pro-drug ~. The onset of the beneficial clinical response to oral k-dOpa becomes more rapid with disease advancement, but the duration of the clinical effect become progressively shorter and less predictable 2. The mechanisms underlying these 'wearing-off' and unpredictable ' o n - o f f ' p h e n o m e n a remain unclear. Possible factors include a loss of ability of the deafferented striatum to buffer and regulate dopamine release after administration of oral L-dOpa, and unpredictable absorption of L-dopa from the gastrointestinal tract. Levodopa-induced dyskinesias (LIDs) can be choreic or dystonic and tend to be most evident when peak plasma levels of L-dopa are achieved (peak-dose dyskinesia), or at the onset and end of the effect of each L-dopa administration (diphasic dyskinesia). The timing of onset of LIDs in PD appears, in part, to be related to disease severity; dyskinesias develop within weeks of k-dOpa exposure in patients with long-standing untreated PD or severe parkinsonism caused by the nigral toxin 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine (MPTP) 3. It has been suggested that the loss of nigrostriatal dopamine projections associated with PD results in 'supersensitivity' of deafferented postsynaptic striatal dopamine D1 and D2 receptors. Subsequent exposure to high and pulsatile levels of exogenous dopamine via long-term intermittent oral administration of L-dopa then leads to the occurrence of dyskinesias 4'5. Although the dopamine-receptor-supersensitivity model for LIDs is attractive, there are two lines of evidence against it. First, if intact monkeys are exposed to high enough oral doses of L-dopa, dyskinesias can result 6. Second, studies on animal models of PD with toxininduced nigral lesions suggest that striatal D2-receptor upregulation is transient and Dl-receptor binding is unaltered or reduced <7-1°(J. Tedroff, PhD thesis, Uppsala University, 1990). Given this, it seems more likely that dyskinesias arise from downstream pharmacological changes in the basal ganglia that result from exposure of dopamine receptors to high non-physiological levels
of exogenous L-dOpa and dopamine, rather than from changes in striatal dopamine receptor availability (see Olanow et al. n in this supplement). In support of this, it has been reported that, although the threshold for response of parkinsonism to L-dopa remains relatively constant with disease progression, the threshold for inducing dyskinesias decreases 4. The likelihood of developing either fluctuating motor responses or dyskinesias can be significantly reduced by maintaining de novo PD patients on dopamine-agonist monotherapy, rather than L-dOpa1>1s. As these agents are D2-receptor selective, it has been argued that dyskinesias could arise owing to overstimulation of D1 receptors. However, pulsatile administration of D1- and D2-receptor agonists can induce dyskinesias in MPTPlesioned monkeys in the absence of L-dopa priming 16. Postmortem studies on striatal dopamine D1- and D2receptor binding in PD have concentrated on endstage patients who invariably were experiencing motor complications. As a rule, these chronically treated endstage cases show normal or mildly reduced levels of striatal D1- and D2-receptor binding 17. The endogenous opioid peptides enkephalin and dynorphin are present in high levels in the basal ganglia. The monosynaptic striatal-internal pallidal (GPi) projections of the direct pathway contain dynorphin and GABA, whereas the striatal-external pallidal (GPe) projections that make up the first stage of the indirect polysynaptic pathway to the GPi contain enkephalin and GABA~s'~9(see also Obeso e t al. 2° in this supplement). High levels of enkephalin and dynorphin, and increased expression of preproenkephalin mRNA, have been reported in the striatum and pallidum of animal lesion models of PD with L-dopa-induced dyskinesias 2>24. Dynorphin has highest affinity for opioid K receptors and inhibits release of glutamate in the GPi (Ref. 25), whereas enkephalin has highest affinity for opioid 8 receptors and inhibits release of GABA in the GPe (Refs 26,27). Current models of basal-ganglia connectivity suggest that the net effect of raised levels of enkephalin in the GPe and of dynorphin in the GPi will be to reduce the normal inhibitory GABA-mediated
David L Brooks is at the MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK W 1 2 ONN.
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PPROXIMATELY SO°N of Parkinson's disease (PD) patients will experience a fluctuating motor response A to oral L-dopa along with dyskinesias after five years of
see front matter © 2000 Elsevier Science Ltd. All rights reserved.
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remaining neurons increases in parallel with striatal deafferentation. Lee and colleagues have compared [~SFldopa, p*C]DHTBZ and plC]MP Glu PET findings in established PD (Ref. 36). They have shown that all three PET approaches discriminate D1 receptors | ~ D2 andA2Areceptors alu 100% of PD cases from control ) cases, but putamen [lSF]dopa upGABA GABA,SP I take was relatively raised and t DYNtD ~ ENKI'F1 Glu Glu [HC]methylphenidate binding relaI' tively reduced, compared with {Dopamine []~C]DHTBZ binding. They suggest I Ventral that levels of vesicular monoamine I thalamus o transporter binding give the truest reflection of remaining dopamineGABAI ~ terminal density in PD owing to GABA relative upregulation of DDC activity and downregulation of DAT binding to compensate for the lower ..... G/u .... ~( GPi/SNr @...... levels of endogenous dopamine present in the synaptic cleft in PD. Basal ganglia, Parkinson's disease and levodopa therapy: TINS supplement Patients with fluctuating responses to >dopa show significantly lower Fig. 1. Basal ganglia connectivity in Parkinson's disease with dyskinesias. Thickened lines indicate abnormally increased neurotransmission and dotted lines indicate abnormally decreased neurotransmission. Glutamate pathways putamen [~UF]dopa uptake than are shown in red, GABA pathways are shown in blue and dopamine pathways are shown in green. Abbreviations: those with early disease and with sustained therapeutic responses 3s'39. A2A , adenosine A2A; D Y N t dynorphin; ENK, enkephalin; GABA, gammaaminobutyric acid; Glu, glutamate; GPe, external pallidum; GPi, intemal pallidum; PPN, pedunculopontine nucleus; SNc, substantia nigra compacta; SNr, substantia nigra A confounding factor when trying reticulata; SP, substance P; STN, subthalamic nucleus. to compare presynaptic dopamineterminal function in PD patients output from GPi to ventral thalamus and motor cortical with and without motor complications is that the former areas, thus promoting involuntary movements ]gy tend to have an earlier age of onset, more severe disease, (Fig. 1). Microelectrode recordings from the GPi of longer disease duration and a greater cumulative monkeys with LIDs are in support of this viewpoint as exposure to >dopa. De la Fuente-Fernfindez and colabnormal burst firing at a diminished frequency has leagues addressed this problem in two ways 39. First, been reported 28. Additionally, apomorphine-induced they used analysis of covariance (ANCOVA) to factor dyskinesias in PD are associated with a reduction in GPi out effects of age at onset and disease duration in firing 29. The main frontal projection areas of the basal groups of fluctuators and non-fluctuators. Second, they ganglia are the supplementary motor area (SMA), the matched subgroups of fluctuators and non-fluctuators arcuate premotor cortex (PMC) and the dorsal prefrontal for age of onset and disease duration. They found that cortex (DPFC). It would, therefore, seem a plausible mean putamen [~SF]dopa uptake was 28% lower in PD hypothesis that LIDs arise in association with inappro- patients with motor complications compared with priate overactivity of these frontal projection areas. those without, but that there was considerable overlap of the two individual ranges (Fig. 2). They concluded that, although loss of striatal dopamine-terminal funcFollowing intravenous administration, [lSF]6-fluoro- tion predisposes PD patients towards development of dopa and 6-[nC]L-dopa are taken up by the terminals of L-dopa-associated complications, it cannot alone be the nigrostriatal dopamine projections and converted to responsible for determining the timing of onset of motor [~SF]- and [11C]dopa, respectively 3°m. The rate of striatal fluctuations and involuntary movements. [18F]- and [11C]dopa accumulation, measured by PET, Torstensen and colleagues have examined the effects therefore directly reflects the activity of dopa decarboxyl- of intravenous boluses of >dopa at pharmacologically ase (DDC) in dopamine terminals 3z. Putamen [lSF]dopa effective levels (2 mg/kg) on striatal [HC]dopa uptake uptake decreases with the clinical progression of PD in early and advanced PD patients 4°. Levodopa admin(Ref. 33), correlating closely with the severity of istration reduced dorsal putamen p~C]dopa uptake by bradykinesia and rigidity 34. 23% in patients with early disease, but increased uptake The PET tracers [11C]CIT-FEand [llC]methylphenidate by 40% in advanced cases with motor complications. (MP) both bind to the dopamine transporter (DAT) on Levodopa was found to have no significant effect on nigrostriatal terminals and provide markers of their func- caudate [~lC]dopa uptake where dopamine-terminal tional integrity 3s,g6.The tracer [llC]dihydrotetrabenazine function was relatively preserved. In a follow-up study, (DHTBZ) is a marker of vesicle m o n o a m i n e transporter they showed that subcutaneously administered therfunction 37. Tedroff and colleagues have compared rela- apeutically effective doses of the dopamine D1- and tive levels of striatal DAT binding and DDC activity in PD D2-receptor agonist, apomorphine, downregulated using [11C]CIT-FEand [llC]dopa PET (Ref. 35). They found dorsal putamen [llC]dopa uptake by 28% in early PD that DDC activity was relatively upregulated compared patients, but had no significant effect on DDC activity with DAT binding, and that this was most marked in the in advanced cases4L They hypothesized that the posterior putamen where dopamine denervation is inhibitory autoreceptor function of the remaining greatest. This suggests that dopamine turnover in the dopamine terminals becomes upregulated in the puta-
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men in early PD. This autoreceptor upregulation results in downregulation of DDC activity in the presence of clinically effective doses of exogenous L-dOpa or dopamine agonists such as apomorphine. Dopamine tone in early PD is maintained in this way at physiological levels, allowing a sustained treatment response. As PD advances, however, the continuing degeneration of nigrostriatal terminals in the dorsal putamen causes this adaptive autoreceptor upregulation to be lost, resulting in ineffective control of dopamine tone and onset of motor fluctuations. At the same time, high levels of exogenous L-dOpa (and not, interestingly, dopamine agonists), act to increase putamen DDC activity by an uncertain mechanism, which causes synaptic dopamine levels to swing pathologically high and promotes onset of dyskinesias. Postsynaptic dopamine function At least five different sub-types of dopamine receptors have now been described. They broadly fall into Dl-type receptors (D1 and D5), which activate adenyl cyclase, and D2-type receptors (D2, D3 and D4), which either inhibit or have no effect on this enzyme. The striatum contains mainly D1- and D2-receptor subtypes and these play a primary role in modulating locomotor function. PET studies with spiperone-based tracers, and single photon emission computed tomography (SPECT) studies with [123I]IBZMhave reported normal levels of striatal D2-receptor binding in untreated PD patients later shown to be L-dopa or a p o m o r p h i n e responsive 42'43. By contrast, [11C]raclopride PET studies in de novo PD patients have shown 10-20% increases in D2-receptor-site availability in the p u t a m e n contralateral to the more affected limbs 4446. [l~C]raclopride binding inversely correlates with [18F]dopa uptake 47. These findings suggest that putamen D2-receptor availability in untreated PD patients is mildly upregulated and caudate D2 binding, where dopamine-terminal function is relatively preserved, remains normal. Studies with [~C]methylspiperone PET and [~23I]IBZM SPECT have reported both normal 48-s° and reduced striatal D2 binding in chronically treated PD patients. Serial [HC]raclopride PET has shown that the mildly increased putamen [~lC]raclopride binding seen in de novo PD patients normalizes after several months of exposure to L-dopa4s'sl. Chronically L-dopaexposed PD cases continue to show normal levels of putamen D2-receptor binding, but caudate D2-receptor binding is reduced by around 20% (Refs 46,52). These findings correlate well with in vitro reports of striatal dopamine D2-receptor binding based on postmortem material from end-stage patients s3. [uC]SCH23390 is an antagonist of Dl-type receptor sites, binding reversibly during the time course of PET. In de novo hemiparkinsonian patients later shown to be L-dopa responsive, [~C]SCH23390 PET shows no relative upregulation of putamen binding contralateral to the affected limbs, suggesting that D1 binding remains at a normal level 54. By contrast, PD patients who have been exposed to L-dopa for several years show a 20% reduction in striatal Dl-receptor binding 46. Turjanski and colleagues examined striatal dopaminereceptor availability in subgroups of eight L-dopaexposed dyskinetic and ten non-dyskinetic patients 46, These subgroups were age-matched (dyskinetic, 49-74 years; non-dyskinetic, 42-78 years) and had similar clinical disease durations (dyskinetic, 3-10 years;
R~ w
e
TABLE I. D I- and D2-receptor binding potentials (BPs) in dyskinetic and non-dyskinetic individuals with Parkinson's disease (PD) Caudate BP
Controls Non-dysldnetic PD Dyskinetic PD
Putamen BP
DI receptor (mean-+SD)
D2 receptor (mean_+SD)
1.25_+0.17 I.I 1+0.14
2.25+0.13
1.25+0.13
2.35+_0.14
1,90+_0.19 ~ 1.88_+0.2 P
1.14+0.09 1.12+-0.21
2,22+0.13 2.45_+0.28
1.06+_0.23
DI receptor (mean_+SD)
D2 receptor (mean_SD)
ap<0.05. Adapted from Ref.46.
non-dyskinetic, 3-9 years). There were non-significant trends towards greater disease severity [mean motor Unified Parkinson's Disease Rating Scale (UPDRS) 19 versus 13] and higher daily L-dOpa dosage (560 mg vs 450 rag) in the dyskinesia subgroup. Mean caudate a n d p u t a m e n Dl-receptor binding and putamen D2receptor binding were normal for both the dyskinetic a n d the non-dyskinetic PD subgroups, and caudate D2-receptor binding was reduced by around 15% (see Table 1). Similar findings have been reported where striatal d o p a m i n e D1- and D2-receptor binding is similar in fluctuating ss and dyskinetic s(' PD patients compared w i t h sustained responders. In these studies, ANCOVA was used to factor out the confounding effects of differences in age of onset and disease duration between the PD subgroups. These studies suggest that onset of motor complications in PD is not primarily associated with alterations in striatal dopamine-receptor availability. [llC]raclopride PET can provide an indirect marker of changes in levels of dopamine in the synaptic cleft of the striatum. An intravenous bolus of 0.3 mg/kg m e t a m p h e t a m i n e causes a 24% reduction in putamen [11C]raclopride binding in normal subjects owing to the dopamine released st. Tedroff and colleagues used [2,C]raclopride PET to examine L-dopa-induced changes in synaptic dopamine levels in I'D (Ref. 58). The patients were divided into two subgroups: those with early hemi-disease and those with advanced disease exhibiting fluctuating treatment responses and LIDs. A total dose of 3 mg/kg L-dopa was administered as an intravenous bolus; this resulted in a clinical response in all the PD patients. After the infusion of L-dopa, the early cases showed a 10% fall in [*~C]raclopride binding in the posterior dorsal putamen. No effect on [l~C]raclopride binding was seen in the asymptomatic putamen contralateral to the unaffected limbs. The advanced PD cases showed falls in posterior and anterior dorsal putamen [11C]raclopride binding after ~-dopa (23% and 20% respectively). The reductions in putamen [I1C]raclopride binding correlated with disease severity assessed without medication with the UPDRS. These findings indicate that severe loss of dopamine terminals in advanced PD leads to excessive levels of synaptic dopamine when exogenous c-dopa is administered. This reflects a combination of upregulation of striatal dopamine synthesis and release by those terminals remaining, along with severe loss of dopamine transporters preventing dopa m i n e re-uptake. This is more likely to be the explanation for the more rapid response of advanced PD patients to oral L-dOpa, rather than changes in postsynaptic dopamine D1- and D2-receptor binding, and m a y also be a factor in promoting onset of dyskinesias. TINS Vol. 23, No. 10 (Suppl.), 2 0 0 0
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TABLE 2. Uptake ratios (region-occipital) for [JlC]diprenorphine in Parkinson's disease (PD)
Controls Non-dyskinetic PD DyskineticPD
n
Caudate (mean--SD)
Putamen (mean---SD)
Thalamus (mean---SD)
10 7 6
2.76+0.40 2.64-+0.40 2.37_+0.80 a
2.62_+0.70 2.42-+0.30 1.97+0.40 b
2.81_+0.40 2.62+_0.30 2.31 +0.70 b
"P<0.05 versus controls. bP<0.001 versus controls and non-dyskinetic PD. Adapted from Ref. 67.
Opioid binding The caudate and p u t a m e n contain a dense population of m e d i u m spiny projection neurons that cotransmit opioids in addition to GABA in the pallidum 19. Striatal projections to GPe contain enkephalin w h i c h binds m a i n l y to 8 opioid-receptor sites and inhibits GABA release in the GPe (Ref. 26). Striatal projections to GPi transmit d y n o r p h i n w h i c h binds to K opioid-receptor sites and inhibits glutamate release from STN afferents to the GPi (Ref. 25). It is t h o u g h t that phasic firing of striatopallidal projection neurons results primarily in GABA release and m o r e sustained firing causes additional m o d u l a t o r y opioid release. The caudate and putamen also contain high densities of I*, K, and 8 opioidreceptor sites s9. These receptors are located b o t h presynaptically on dopamine, where they regulate dopamine release, and postsynaptically on interneurones and m e d i u m spiny projection neurons to pallidum terminals6°,6L Postmortem studies have shown reductions in nigral I* and K opioid-receptor sites in end-stage treated PD patients 62,63. There is n o w strong evidence from both postmortem studies and toxic lesioned animal models of this disorder to support the presence of deranged opioid transmission in the basal ganglia of PD. At postmortem, end-stage-treated PD patients show raised levels of pallidal preproenkephalin 64. In rats lesioned with the nigral toxin 6-hydroxydopamine, there are raised levels of striatal enkephalin and preproenkephalin expression, and p r o d y n o r p h i n expression is suppressed 27'6s. W h e n such animals are made hyperkinetic or dyskinetic after
0.008 -
[]
[] 0.006 -
Fluctuators Non-fluctuators * P = 0.053
t-
0.004 -
0.002 -
0.000 Caudate
I
Putamen
Basal ganglia, Parkinson's disease and levodopa therapy: TINS supplement
Fig. 2. Striatal [~SF]dopauptake in Parkinson's disease(PD). Putamen dopa decarboxylase(DDC)
activity is reduced in PD patients with fluctuating motor responses to L-dopa (red) compared with those with sustained motor responses to L-dopa~9(blue). Ki is an influx constant.
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chronic exposure to pulsatile doses of i,-dopa, further overexpression of striatal preproenkephalin is seen in addition to raised expression of prodynorphin. LevodopanaYve MPTP-lesioned m o n k e y s are also reported to show raised striatal enkephalin and reduced substance P mRNA expression23,24; exposure to L-dOpa for one m o n t h failed to normalize striatal preproenkephalin mRNA expression and substance P mRNA expression became elevated. [nC]diprenorphine PET is a non-selective marker of I*, ~, and 8 opioid sites and its binding has been shown to be sensitive to levels of e n d o g e n o u s opioids 66. If raised basal ganglia levels of enkephalin and dynorp h i n are associated with LIDs, PD patients with m o t o r complications would be expected to show reduced b i n d i n g of [uC]diprenorphine c o m p a r e d with those with sustained treatment responses. Piccini and colleagues 67 studied six PD patients with m o t o r fluctuations and LIDs and seven patients without dyskinesias (two had m o t o r fluctuations). Mean age, disease and treatment duration, and daily > d o p a dosage were not significantly different (see Table 2). Mean H o e h n and Yahr scores for the two groups were similar (1.85 _+ 0.7 sustained versus 2.25 _+ 0.5 dyskinetic). Significant reductions in [nC]dipren0rphine b i n d i n g in caudate, putamen, thalamus and anterior cingulate in the dyskinetic patients were observed, c o m p a r e d with the sustained responders (Fig. 3). Table 2 shows the magnitude of these reductions in the basal ganglia. Figure 4 shows that individual levels of p u t a m e n p~C]diprenorphine uptake correlate inversely with dyskinesia severity as determined with part 4 of the UPDRS. These in viva PET findings support the presence of elevated levels of endogenous opioids in the basal ganglia of dyskinetic PD patients and suggest that this, rather t h a n a primary alteration in dopamine-receptor binding, contributes to the appearance of involuntary m o v e m e n t s 67.
Activation studies Localization of regional cerebral activation during tasks, manifested as increases in levels of regional cerebral blood flow (rCBF), can be detected using H2[~sO] PET. W h e n n o r m a l subjects make m o v e m e n t s of a joystick in freely selected directions with their right h a n d while paced by a tone, there are associated rCBF increases in contralateral sensorimotor cortex (SMC) and lentiform nucleus, and bilaterally in anterior cingulate cortex, supplementary m o t o r area (SMA), lateral premotor cortex (PMC), and dorsolateral prefrontal cortex (DLPFC) 6s. Self-paced extensions of the index finger result in a similar pattern of activation 69. W h e n PD patients, scanned after stopping their medication for 12 h, perform the same two m o t o r tasks, n o r m a l levels of activation of SMC, PMC and lateral parietal association areas are seen, but there is impaired activation of the contralateral lentiform nucleus, and also of anterior cingulate, SMA and DLPFC. These are the cortical areas that receive a major input from the basal ganglia. It is t h o u g h t that the dorsolateral prefrontal cortex plays a crucial role in m o t o r decision making and working m e m o r y whereas the supplementary m o t o r area prepares volitional m o t o r programmes once selected. By contrast, lateral premotor cortex is believed to have a primary role in facilitating m o t o r responses to external visual and auditory stimuli. An inability to activate SMA and DLPFC during freely selected m o v e m e n t s could explain the difficulty that PD patients experience in
O.J. B r o o k s -
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PET studies in Parkinson's disease
Fig. 3. [~lC]diprenorphine uptake in dyskinetic Parkinson's disease (PD). A statistical parametric map overlaying the location of PD regions onto a magnetic resonance (MR) template in standard stereotactic space indicates that significant reductions in [7~C]diprenorphineuptake are present in dyskinetic PD /(a) saggital, (b) coronal and (c) transaxial views]. Opioid binding is reduced in the basal ganglia, thalamus and anterior cingulate areas. Reproduced,with permission,from Ref. 67.
initiating such movements. Samuel and colleagues have recently reported that PD patients overactivate lateral p r e m o t o r and parietal areas while performing learned sequential finger m o v e m e n t s in order to compensate for impaired SMA function 7°. If akinesia in PD results from a failure to activate the basal ganglia to SMA and DLPFC projections, t h e n dopamine-replacement therapy ought to restore activation of this system. W h e n the c o m b i n e d D1- and D2-receptor agonist a p o m o r p h i n e is given subcutaneously to PD patients, resolution of their akinesia during performance of freely chosen joystick movements is associated with selective increases in SMA and DLPFC blood flow, providing further evidence for the role of these stuctures in the generation of volitional movements
71,72.
To determine the functional a n a t o m y that underlies peak-dose dyskinesias in PD, Piccini and colleagues have studied three right-handed PD patients w h o were selected because t h e y had predictable onset 7~ and duration of L-dopa-induced involuntary m o v e m e n t s that were restricted to the right arm. All three patients switched ' o n ' about 1S mins after the administration of a single oral dose of 200 mg :-dopa, and dyskinesias of the right arm began 1S-2S rains later as plasma levels peaked. Twelve rCBF measurements were performed for each subject: two at rest (scans 1 and 12) and ten while performing paced joystick m o v e m e n t s in freely chosen directions with the right h a n d (scans 2-11). Patients started the session off medication, L-dOpa was given between scans 2 and 3, and by scans 4 and S the patients were o n b u t without dyskinesias, and from scans 6 to 12 the patients were on and dyskinetic. Comparison of rCBF levels during rest with dyskinesias versus rest w i t h o u t dyskinesias showed relative activation of m o t o r cortex, lateral and mesial premotor areas, DLPFC and the basal ganglia during dyskinesias (Fig. S). Voluntary m o v e m e n t (paced joystick movements with the right h a n d in freely chosen directions) led to activation of the contralateral basal ganglia, primary m o t o r cortex, SMA and ipsilateral cerebellum in the PD patients. Comparison of dyskinetic versus non-dyskinetic states during voluntary m o v e m e n t revealed relatively higher levels of rCBF in the basal ganglia, the m o t o r cortex, lateral and mesial p r e m o t o r areas, DLPFC - a similar finding to that associated with dyskinesias at rest. Areas that showed a correlation between levels of rCBF and dyskinesia severity were lateral and mesial premotor areas, DLPFC, and the basal ganglia.
These H2[lsO] PET activation findings suggest that dyskinesias are associated with inappropriate overactivity of the basal ganglia - premotor - prefrontal projections. They also correlate with an [133Xe]SPECT activation study where a comparison of rCBF levels between dyskinetic and non-dyskinetic subgroups of PD patients performing learned sequential finger m o v e m e n t s w h e n ' o n ' showed relative overactivity of m o t o r cortex and lateral and mesial p r e m o t o r areas TM. The presence of abnormally raised basal ganglia and frontal activation during dyskinesias is reminiscent of the pattern of overactivity seen w h e n patients with dystonia (both idiopathic and acquired) perform joystick movements in freely chosen directions 7s'76.Indeed, D Y T I dystonia gene carriers have been shown to have relatively raised basal ganglia, p r e m o t o r and prefrontal glucose metabolism even at rest 77. This suggests that in b o t h LIDs and dystonia there is an inappropriate increase in traffic through the basal-ganglia frontal circuitary resulting in breakthrough of involuntary movements. Such an observation correlates with the hypothesis that the basal ganglia play a role in filtering and focusing m o t o r programmes,
3,5 3.00
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o
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1.00.5 0 Dyskinesia severity Basal ganglia, Parkinson's disease and levodopa therapy: TINS supplement
Fig. 4. Putamen:occiptal ~ I C]diprenorphine uptake ratios in Parkinson's disease (PD). The ratio of putamen:occiptal [TJC]diprenorphine uptake versus dyskinesia severity was measured 60-90 mins after tracer administration in PD patients. This was rated with part IV of the motor Unified Parkinson's Disease Rating Scale (UPDRSy. The graph shows that opioid receptor binding in the putamen decreases as dyskinesia severity increases.
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of rCBF measured with Hs[~sO] PET are d e t e r m i n e d by integrated synaptic activity in brain structures rather t h a n o u t p u t n e u r o n firing rates ~°. The globus pallidus has few i n t e r n e u r o n s and thus synaptic activity in the GPe and GPi will primarily reflect levels of striatal input, w h i c h is inhibitory. Increased pallidal rCBF in the presence of dyskinesias and d y s t o n i a therefore suggests an increased level of i n h i b i t o r y striatal i n p u t a n d is in a g r e e m e n t with the o b s e r v a t i o n t h a t intrinsic GPi n e u r o n a l firing is d i m i n i s h e d d u r i n g apomorp h i n e - i n d u c e d dyskinesias.
SMA
Basal ganglia
Prefrontal cortex
Basalganglia,Parkinson'sdiseaseandlevodopatherapy:TINSsupplement
Fig. 5. Regional cerebral activation during dyskinesias at rest. Increased levels of regional cerebral blood flow (rCBF) in the lentifrom nucleus, the motor, premotor and prefrontal cortex measured with positron emission tomography (PET) are associated with the presence of involuntary movements 73. Abbreviation: SMA, supplemenatry motor area. and t h a t an i n a p p r o p r i a t e increase in firing leads to a failure of the filtering m e c h a n i s m . The observation that b o t h dyskinesias and dystonia can be dramatically reduced after medial p a l l i d o t o m y and pallidal s t i m u l a t i o n is of interest because these procedures act to restore levels of p r e m o t o r and prefrontal a c t i v a t i o n in akinefic PD (Ref. 78) whereas excessive p r e m o t o r a c t i v a t i o n is n o r m a l i z e d in dystonia 79. The f i n d i n g of increased l e n t i f o r m nucleus rCBF appears, superficially, to contradict findings reported from single-unit pallidal recordings p e r f o r m e d prior to p a l l i d o t o m y w i t h PD patients. Lozano and colleagues have reported t h a t d o p a m i n e agents relieve akinesia by decreasing GPi and s u b t h a l a m i c nucleus activity while increasing GPe activity, and that a p o m o r p h i n e - i n d u c e d dyskinesias are associated w i t h further r e d u c t i o n s in GPi firing 29. However, it should be reiterated t h a t levels
Concluding
remarks
To date, m o s t studies o n the p h a r m a c o l o g y of dyskinesias have i n v o l v e d p o s t m o r t e m material from treated end-stage PD patients or toxic-lesion animal models. PET has the advantage of a l l o w i n g in viva measurements of neurotransmitter binding and cerebral m e t a b o l i s m to be performed at all stages of disease and can indirectly measure changes in synaptic d o p a m i n e and o p i o i d levels. The findings of the PET studies reviewed in this article suggest t h a t m o t o r complications arise in PD because pulsatile L-dopa administ r a t i o n results in p a t h o l o g i c a l l y h i g h levels of synaptic d o p a m i n e as the disease advances. These changes in synapfic d o p a m i n e levels result in a b n o r m a l l y raised levels of basal ganglia e n k e p h a l i n and d y n o r p h i n , and reduced levels of striatal and t h a l a m i c o p i o i d receptor availability o w i n g to increased o c c u p a n c y by the e n d o g e n o u s opioids. This, in turn, results in reduced inhibitory o u t p u t from the GPi and inappropriate overactivity of the basal-ganglia frontal p r o j e c t i o n areas allowing breakthrough involuntary movements. For further discussion o n this topic see Box 1.
Box I. Discussion Obeso: Are changes occurring in the striatum or pallidum in dyskinesia? Brooks: Changes are likely to be present in both areas. Levels of blood flow primarily reflect synaptic activity. The pallidum has few interneurons and so the finding of increased pallidal blood flow during dyskinesia suggests that inhibitory input to pallidum from the striatum is raised. This would be in accord with the single unit patient and animal model data that has reported decreased internal pallidal (GPi) firing during dyskinesias. O b e s o : During normal movement, there is activation of dorsolateral prefrontal cortex. Is there less activation of this region with movement in dyskinetic patients? Brooks: If anything, the opposite. Non-dyskinetic Parkinson's disease (PD I patients deactivate prefrontal areas if the task is complex. In dyskinetic patients, we saw aberrant activation of these areas but, I suspect that it's not productive activation and that it represents inappropriate synaptic activity. Waiters: It is appropriate to note that prefrontal areas and supplementary motor areas (SMA) send glutamatergic projections to the subthalamic nucleus {STN). If they are overactive as you indicate, they could contribute to the increased metabolic and physiologic activity in the STN. And, to the extent that this activation represents dysfunctional activity, this could induce an altered firing pattern in the STN, and disruption of this altered pattern could account for the benefit seen with deep brain stimulation (DBS) of the STN.
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Brooks: Bear in mind that when we see increased activation with positron emission tomography (PET), the actual firing frequency per se may not be increased - it may represent aberrant burst firing. Chase: Can you separate the GPi from the the striatalexternal pallidat ~GPe~on PET? Brooks: State of the art systems have 3 mm resolution, so you can certainly separate pallidum from striatum, We're just on the borderline of being able to separate the internal and external segments of the pallidum. Chase: If you can't. I think your results could be confounded. If, for exam pie, one of those structure goes up and the other goes down. you end up with an average. Brooks: I accept that. The whole question of pallidal metabolism is open to question as it reflects input from multiple sites such as striatum. STN, and cortex. If we really want to examine pallidal output with PK[. we have to examine ventral thalamic metabolism. Graybieh In what part of the cingulate gyms do you see changes in opioid binding. There are a number of motor areas in what used to be thought of as limbic cingulate cortex. Recordings from neurons in this region respond to movement. intention to move, and selection of movement. Brooks: There is increased binding in the motor regions in area 24, but it seems to extend into anterior cingulate region 32 as well. Graybiel: If receptors are internalized, how does that affect binding on PET?
D.J. Brooks
References 1 Nutt, J.G. (1990) Levodopa-induced dyskinesia: review, observations, and speculations. Neul"oh~y 40, 340-345 2 Nutt, J.G. and Holford, N.H.G. (1996) The response to levodopa in Parkinson's disease: imposing pharmacological law and order. Ann. NeuroL 39, 561-573 3 Langston, J.W. et al. (1983) Chronic parkinsonism in h u m a n s due to a product of meperidine-analog synthesis. Science 219, 979-980 4 Mouradian, M.M. et aL (1989) Pathogenesis of dyskinesias in Parkinson's disease. Ann. Neurol. 25, 523 526 5 Boyce, S. et al. (1990) Nigrostriatal damage is required for induction of dyskinesias by L-dopa in squirrel monkeys. Clin. Neuropharmacol. 13, 448-458 6 Pearce, R.K.B. etal. (1995) Altered striataI preproenkephalin mRNA levels in normal macaque monkeys (Maraca fascicularis) with dyskinesias induced by chronic l.-dopa administration. Br. J. Phalrnacol. 116, 78-95 7 Murata, M. and Kanazawa, 1. (1993) Repeated L-dopa administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat. Neurosci. Res. Commun. 16, 15-23 8 Fuxe, K. etal. (1981) Characterisation of normal and supersensitive dopamine receptors: effects of ergot drugs and neuropeptides. J. Neural Transm. 51, 3-37 9 Alexander, G.M. etal. (1993) Changes in brain dopamine-receptors in MPTP parkinsonian monkeys following L-dopa treatment. Brain Res. 625, 276-282 10 Przedborski, S. etal. (1991) Unilateral MPTP-induced parkinsonism in monkeys - a quantitative autoradiographic study of dopamineD1 and dopamine-D2 receptors and reuptake sites. Neurochirurgie 37, 377-382 11 Olanow, C.W. et aL (2000) Continuous dopamine-receptor stimulation in early Parkinson's disease. Trends Neurosci. 23 (Suppl. Basal ganglia, Parkinson's disease and levodopa therapy), $117-$126 12 Lees, A.J. and Stern, G.M. (1981) Sustained bromocriptine therapy in previously untreated patients with Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 44, 1020-1023 13 Montastruc, J.L. et al. (1994) A randomised controlled study comparing bromocriptine to which levodopa was later added, with levodopa alone in previously untreated patients with Parkiuson's disease: a five year follow-up. I. Neurol. Neurosurg. Psychiatry 57, 1034-1038 14 Rinne, U.K. et al. (1998) Early treatment of Parkiuson's disease with cabergoline delays the onset of motor complications. Results
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of a double-blind levodopa controlled trial. The PKDS009 study group. Drugs $5, 23-30 Rascol, O. et al. (2000) Dyskinesia in Parkinson's disease: A S-year study of ropinirole versus levodopa. N e w Engl. I. Med. 342, 1484-1491 Blanchet, P. et al. (1993) Differential effect of selective D-I and D2-dopamine receptor agonists on ievodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys. ]. Pharmacol. Exp. Ther. 267, 27S-279 Playford, E.D. and Brooks, D.J. (1992) In vivo and in vitro studies of the dopamine system in m o v e m e n t disorders. Cerebrovasc. Brain Metab. Rev. 4, 144 171 Haber, S. and Watson, S.J. (198S) The comparative distribution of enkephalin, dynorphin, and substance P in the h u m a n globus pallidus and basal forebrain. Neuroscience 14, 1001 1024 Penney, J.B., Jr and Young, A.B. (1986) Striatal inhomogeneities a n d basal ganglia function. Mov. Disord. 1, 3-15 Obeso, J.A. et al. (2000) Pathophysiology of the basal ganglia in Parkinson's disease. Trends Neurosci. 23 (Suppl. Basal ganglia, Parkinson's disease and levodopa therapy), $8-$19 Engberg, T.M. et al. (1991) Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats. Brain Res. 552, 113-118 Taylor, M.D. et al. (1992) Effects of unilateral 6-hydroxydopamine lesion and prolonged L-3,4-dihydroxyphenylalanine treatment on peptidergic systems in rat basal ganglia. Bur. I. Pharmacol. 219, 183-192 Jolkkonen, J. et aL (1995) c-dopa reverses altered gene expression of substance P but n o t enkephalin in the caudate-putamen of c o m m o n marmosets treated with MPTP. Mol. Brain Res. 32, 297-307 Lavoie, B. etal. (1991) Effects of dopamine denervation on striatal peptide expression in parkinsonian monkeys. Can. }. Neurol. ScL 18, 373-375 Maneuf, Y.P. et al. (1995) Functional implications of K-opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson's disease. Brain Res. 683, 102-108 Maneuf, Y.P. et al. (1994) On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp. Neurol. 125, 65-71 Henry, B. and Brotchie, J.M. (1996) Potential of opioid antagonists in the treatment of levodopa-induced dyskinesias in Parkinson's disease. Drugs and Aging 9, 149-158
Box I. Discussion B r o o k s : T h i s varies b e t w e e n tracers. If D2 r e c e p t o r s are i n t e r n a l i z e d M a r c Laruelle h a s r e p o r t e d t h a t o n e d o e s n ' t see i n t r a c e l l u l a r b i n d i n g o f [nC]raclopride. H o w e v e r | H C ] S C H 2 3 3 9 0 c a n b i n d t o D l - r e c e p t o r b i n d i n g sites i n t h e c y t o p l a s m a n d so its u p t a k e s h o u l d n o t b e sensitive t o internalization. H i r s c h : W e h a v e s h o w n t h a t t h e r e is i n t e r n a l i z a t i o n o f t h e D 1 receptor after d o p a m i n e r g i c t r e a t m e n t . However. in a PD p a t i e n t w h o c a m e to a u t o p s y after b e i n g off L-dopa for 1 - 2 days. we saw m a n y D1 r e c e p t o r s in t h e c y t o p l a s m a n d a l m o s t n o r m a l levels at t h e s y n a p t i c m e m b r a n e , It is difficult to k n o w w h a t t h e f u n c t i o n of t h i s receptor in t h e c y t o p l a s m is, b u t o n e m i g h t a s s u m e t h a t t h e y are recycled i n t o t h e s y n a p t i c m e m b r a n e to be s t i m u l a t e d again. A n d t h i s t r a n s f e r f r o m t h e c y t o p l a s m to t h e m e m b r a n e c a n be v e r y fast. C a n we rule o u t t h e possibility t h a t s u c h c h a n g e s c o n t r i b u t e to t h e d e v e l o p m e n t of t h e d y s k i n e s i a ? Brooks: I d o n ' t k n o w for sure. As [ n C ] S C H 2 3 3 9 0 c a n b i n d to D l - r e c e p t o r b i n d i n g sites in t h e c y t o p l a s m its striatal u p t a k e reflects b o t h surface a n d i n t e r n a l i z e d p o p u l a t i o n s . PET studies w i t h this tracer s u g g e s t t h a t striatal D l - r e c e p t o r b i n d i n g is s i m i l a r in d y s k i n e t i c a n d n o n - d y s k i n e t i c PD t h o u g h t h e relative levels of receptor i n t e r n a l i z a t i o n c o u l d c o n c e i v a b l y differ. [11C]raclopride u p t a k e o n l y reflects t h e external D2 p o p u l a t i o n w h i c h a g a i n is similar in dyskinetic a n d n o n - d y s k i n e t i c PD. Rascol: I ' m s u r p r i s e d t h a t it is so difficult to s h o w supers e n s i t i v i t y of d o p a m i n e receptors w h e n y o u s h o w it so
RE-VIEW
- PET studies in Parkinson's disease
(cont'd)
n i c e l y w i t h o p i a t e receptors. Are t h e s e r e c e p t o r s r e g u l a t e d differently, or is d o p a m i n e t r e a t m e n t a c o n f o u n d i n g bias? B r o o k s : D o p a m i n e t r e a t m e n t is a c o n f o u n d e r . In u n t r e a t e d PD p a t i e n t s , D2 receptors are u p r e g u l a t e d b y 1 0 - 2 0 % , b u t this disappears with chronic therapy. Olanow: Are t h e r e differences o n PET in older a n d y o u n g e r PD p a t i e n t s to e x p l a i n w h y y o u n g e r p a t i e n t s h a v e a n i n c r e a s e d risk of d e v e l o p i n g d y s k i n e s i a ? B r o o k s : T h e r e is a fall i n b o t h d o p a m i n e t r a n s p o r t e r a n d p o s t s y n a p t i c - r e c e p t o r b i n d i n g as y o u b e c o m e older, h o w ever. o p i a t e b i n d i n g increases. It m a y be t h a t in s o m e w a y t h a t t h e s e a g e i n g c h a n g e s are p r o t e c t i v e a g a i n s t d y s k i n e s i a development, possibly by influencing glutamate NMDA site p h o s p h o r y l a t i o n . H i r s c h : In p a r k i n s o n i a n s y n d r o m e s , s u c h as p r o g r e s s i v e s u p r a n u c l e a r palsy (PSP), t h e r e are d o p a m i n e r g i c lesions, b u t t h e s e p a t i e n t s d o n o t d e v e l o p dyskinesia, p o s s i b l y b e c a u s e t h e y h a v e o t h e r l e s i o n s in t h e basal g a n g l i a circuitry w h i c h p r e v e n t its e x p r e s s i o n . It m a y be t h a t elderly PD p a t i e n t s have non-dopaminergic lesions that prevent dyskinesia w h i l e y o u n g e r subjects h a v e p u r e d o p a m i n e r g i c lesions. O l a n o w : If y o u r h y p o t h e s i s is correct, y o u w o u l d e x p e c t d y s k i n e s i a s to g r a d u a l l y d i s a p p e a r as t h e PD p a t i e n t s age a n d d e v e l o p m o r e n o n - d o p a m i n e r g l c lesions. But as far as I k n o w . d y s k i n e s i a s t e n d to persist. O b e s o : I agree. I h a v e s e e n p a t i e n t s in t h e i r 80s w h o h a v e h a d PD for m a n y years a n d still h a v e d y s k i n e s i a severe e n o u g h to w a r r a n t c o n s i d e r a t i o n of surgery.
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