REVIEW
Central Pharmacokinetics of Levodopa: Lessons From Imaging Studies A. Jon Stoessl* Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia & Vancouver Coastal Health, 2221 Wesbrook Mall, Vancouver, BC CANADA V6T 2B5
ABSTRACT:
Functional imaging may be particularly helpful for the assessment of levodopa (L-dopa) response and long-term complications of therapy in Parkinson’s disease. Radiotracer imaging allows the quantitative determination of regional changes in blood flow and glucose metabolism, as well as alterations in brain connectivity and network activation and changes in dopamine receptors, non-dopaminergic neurotransmitter systems, and to a lesser extent, signaling pathways downstream to dopamine receptors. The focus of the present article, however, is the application of positron emission tomography (PET) to study the central pharmacokinetics of L-dopa. Radioligands with limited affinity for the dopamine D2 receptor are sensitive to changes in the levels of synaptic dopamine and can accordingly provide helpful insights into the magnitude and time course of dopamine release after L-dopa. Prolonged fluorodopa PET scans can be used to estimate the rate of dopamine turnover. Studies performed with
these techniques have demonstrated increased dopamine turnover and increased but shorter duration release of dopamine after L-dopa as Parkinson’s disease (PD) progresses, increased release of dopamine in patients with L-dopa–induced dyskinesia, and that aberrant patterns of dopamine release may actually predict the future development of motor fluctuations. Taken together, the studies provide in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. Similar approaches can be used to study the non-motor complications of PD C 2014 International Parkinson and and its treatment. V Movement Disorder Society
K e y W o r d s : Dopamine; dopamine release; dopamine turnover; dopamine transporter; serotonin; positron emission tomography
Imaging studies can provide numerous helpful insights into the complications of levodopa (L-dopa) therapy. The present article focuses on positron emission tomography (PET) studies of presynaptic dopaminergic function. Although studies in animal models have consistently provided clear evidence for the importance of changes that occur downstream to dopamine receptors, these have for the most part been
more difficult to characterize in vivo, given the relative lack of relevant radiotracers. Studies of cerebral blood flow or metabolism, addressed elsewhere in this volume, although neurochemically not specific, provide complementary information.
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The integrity of presynaptic dopamine function is typically assessed using radiotracers that bind to the vesicular monoamine transporter type 2 (VMAT2) or the membrane dopamine transporter (DAT), or 18Ffluorodopa, which is taken up by monoaminergic neurons, decarboxylated to 18F-fluorodopamine, and packaged in synaptic vesicles. Vesicular monoamine transporter type 2 is labeled with 11C-dihydrotetrabenazine or its 18F analog; the DAT can be studied using a host of tropane (cocaine-like) compounds labeled with 123I or 99mTc for SPECT, and with 11C or 18Ftropanes or with 11C-d-threo-methylphenidate for PET (Fig. 1). All three approaches provide indirect
*Correspondence to: A. Jon Stoessl, Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia & Vancouver Coastal Health, 2221 Wesbrook Mall, Vancouver, BC CANADA V6T 2B5. E-mail: [email protected]
Funding agencies: This study was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation, the Michael Smith Foundation for Health Research, the National Parkinson Foundation, the Pacific Alzheimer Research Foundation, the Pacific Parkinson’s Research Institute and the Canada Research Chairs program. Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 7 August 2014; Accepted: 1 September 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26046
Methodological Approaches
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FIG. 1. Cartoon depicting determination of dopamine (DA) function. The presynaptic neuron can be labeled with 18F-DOPA, which is converted to 18F-DA and stored in synaptic vesicles. The vesicular monoamine transporter type 2 (VMAT2) can be labeled with 11C-dihydrotetrabenazine (DTBZ) or its 18F analog, and the DAT transporter (DAT) can be labeled with a variety of 11C- , 18F (PET), 123I, or 99mTc (SPECT) tropanes (cocaine analogs), or with 11C-d-threo-methylphenidate (PET). Dopamine D2 receptors can be labeled with low-affinity ligands (11C-raclopride for PET, 123I-iodobenzamide [IBZM] for SPECT) whose binding is subject to competition from synaptic DA0.
measures of dopaminergic nerve terminal function, and accordingly all result in similar abnormalities in Parkinson’s disease, namely, an asymmetric reduction of tracer uptake that affects the striatum with a graded abnormality that is maximum in the caudal putamen. Using all three approaches, disease progression (ie, tracer uptake) is best described by an exponential function, as is seen in postmortem studies. Thus, for most purposes such as the identification of dopaminergic dysfunction for diagnosis or the assessment of disease progression, all three approaches provide similar information. However, subtle differences are found between the approaches, based on the physiological processes that they target. The VMAT2 binding is thought to be less subject to compensatory or pharmacologically mediated regulation than either DAT binding or fluorodopa (F-DOPA) uptake. In early disease, DAT binding is reduced relative to VMAT2 binding, presumably reflecting downregulation of the DAT in an effort to maintain adequate dopamine in the synapse. In contrast, F-DOPA uptake is increased relative to VMAT2 binding in early disease, possibly reflecting increased activity in L-aromatic amino acid decarboxylase, ie, increased dopamine synthesis1,2 (Fig. 2). These relatively subtle differences between radiotracer approaches are seen in early disease stages only, but they may be highly relevant in understanding the pathophysiology of treatment-related complications of Parkinson’s disease (PD). Furthermore, F-DOPA is taken up by serotonin and norepinephrine neurons and is not specific to dopamine neurons, and its uptake reflects the unidirectional transport of 18F-fluo-
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rodopamine into synaptic vesicles and not just the decarboxylation of 18F-fluorodopa to 18F-fluorodopamine. These points are critical in the interpretation of imaging studies and their relevance to understanding the complications of therapy. Finally, one of the most effective ways to study the function of the presynaptic dopamine neuron is to use a tracer that binds to postsynaptic dopamine receptors. The binding of ligands such as 11C-raclopride, which has relatively weak affinity for D2/D3 receptors, is subject to competition from endogenous dopamine. Thus, increased dopamine release will result in reduced 11C-raclopride binding, and this property can provide tremendous insights into altered central pharmacokinetics of L-dopa and the relationship to complications of therapy. Although limited in size, post-mortem studies conducted in humans who have undergone functional imaging demonstrate a good correlation between FDOPA uptake3 or DAT binding4 and nigral dopamine cell counts. Studies conducted in animal models of PD have resulted in somewhat more variable results. Although tracer uptake has been shown to correlate with striatal levels of dopamine, the relationship to nigral cell counts has been somewhat more variable,
FIG. 2. Changes in dopamine processing over the course of PD. In early disease, FD (F-DOPA) uptake (green line) is increased relative to VMAT2 binding (DTBZ; blue line), while DAT binding (MP uptake, red line) is reduced. Y-axis values are the proportion of age-expected healthy control values (i.e., 1 5 100% of normal, 0.5 5 50%, etc.). These differences converge over time. Reproduced from Nandhagopal et al.2
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possibly reflecting the relatively limited loss of nigral neurons in some protocols using 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP).5 The differential involvement of VMAT2 binding, F-DOPA uptake, and DAT binding has also been called into question based on a study conducted in MPTP-treated nonhuman primates.6 However, the MPTP model results in relatively acute toxicity as opposed to PD, in which progression is much more indolent, thereby affording a much greater opportunity for compensatory changes.
Assessment of Dopamine Release As noted, changes in 11C-raclopride binding after an intervention can be used to surmise the effects of that intervention on dopamine release. At usual doses, amphetamine results in dopamine release by reversal of the DAT. Thus, dopamine release (estimated by percent decrease in 11C-raclopride binding after amphetamine) is directly correlated with the number of surviving dopamine neurons as estimated by F-DOPA uptake.7 The situation with L-dopa is somewhat more complex. Changes in 11C-raclopride binding can be demonstrated after oral8 or intravenous9 L-dopa, but, in contrast to amphetamine, the magnitude of dopamine release after L-dopa administration increases with increased duration and severity of disease (Fig. 3). Although this may seem paradoxical, it is actually very much in keeping with the findings reported using microdialysis in rats with partial 6hydroxydopamine lesions, whereas substantial dopamine release is seen only when the lesion is greater than 80%.10 Interestingly, imaging studies have demonstrated evidence for a prolonged effect of L-dopa therapy on 11Craclopride binding. Thobois et al.11 studied patients with advanced PD who had undergone subthalamic nucleus deep brain stimulation surgery. Although all subjects were imaged after 12-hour medication withdrawal, those patients in whom DBS afforded longterm withdrawal of dopaminergic medication demonstrated increased D2 binding in the putamen, as is seen in early, untreated PD. In patients who required ongoing medication, D2 binding in the putamen was comparable to healthy control levels, whereas binding in these subjects was reduced to slightly subnormal levels in the caudate nucleus. Similar findings have been reported in patients with PD caused by parkin mutation. Early reports suggested reductions in 11Craclopride binding,12 with scans again conducted after 12 hours of medication withdrawal. A follow-up study conducted in treatment-na€ıve parkin mutants revealed increased binding.13 Increased 11C-raclopride binding in treatment-na€ıve subjects probably represents a combination of receptor upregulation and reduced occupancy by endogenous dopamine.14 Whereas acute
FIG. 3. Dopamine release (% change in RAC BP 5 raclopride binding potential) increases with disease duration in both the caudate (upper) and putamen (lower). Reproduced from de la Fuente-Fernandez et al.19
reductions in 11C-raclopride binding can readily be explained by increases in synaptic dopamine,15,16 longer-term reductions might reflect receptor downregulation. Internalized D2 receptors appear to bind 11Craclopride to a degree similar to receptors localized on the cell surface, but sustained dopaminergic stimulation might presumably result in long-term reductions in total receptor number.
Dopamine Release After L-Dopa A number of classical studies examining the relationship between plasma L-dopa levels and motor response duration in PD have demonstrated that peripheral pharmacokinetic factors are unlikely to explain motor fluctuations in most patients.17,18 Using 11 C-raclopride PET, de la Fuente-Fernandez et al.8 showed that central pharmacokinetics of L-dopa– derived dopamine are indeed altered. In fact, an abnormal pattern of dopamine release was seen in those patients with a stable response to L-dopa who later went on to develop motor fluctuations8 (Fig. 4). Patients who had a modest reduction in 11C-raclopride binding that was sustained for at least 4 hours after oral administration of L-dopa maintained a stable clinical response for at least 3 years after they were studied. In contrast, those patients who showed an early large increase in dopamine release that was poorly sustained went on to develop motor response fluctuations within 3 years of study. This supports a model
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FIG. 4. Changes in the pattern of DA release in response to L-dopa anticipate the future development of motor fluctuations. The left panel demonstrates raclopride binding in eight PD patients, all of whom had a stable response at the time of study. Note that in in four patients (Nos. 1, 2, 4, 8), there is a small reduction in raclopride binding 1 hour after levodopa, which is sustained or of greater magnitude 4 hours later. In the other patients, there is a larger but more transient decline in raclopride binding. The latter pattern is associated with the future development of motor fluctuations 3 years later (right panel). Modified from de la Fuente-Fernandez et al.8
in which altered central pharmacokinetics of L-dopa characterized by short-duration release of substantial amounts of dopamine and thereby pulsatile stimulation of dopamine receptors are the necessary underpinning for future complications that also may reflect changes downstream to dopamine receptors. In contrast to dopamine release after amphetamine, dopamine release after L-dopa increases with disease duration19 (Fig. 3). This may reflect a number of factors, including impaired vesicular storage of dopamine as disease progresses, reduced reuptake of dopamine because of loss of DAT sites on surviving dopamine nerve terminals, and synthesis of dopamine by nondopaminergic neurons. Regardless of mechanism, this means that advanced disease is associated with a higher magnitude of dopamine release after L-dopa that is, however, of reduced duration. This pattern is associated with dyskinesias19 (Fig. 5), as well as the degree of clinical improvement after medication.20 Patients with younger onset of PD are more prone to fluctuations in motor function and dyskinesias in response to L-dopa. In fact, we have found that the degree of dopamine denervation at disease onset is more severe in those with younger age of onset, even though disease progresses more slowly in these individuals.21 This presumably reflects stronger compensatory mechanisms in those with young disease onset. Although some of this compensation may be attributable to engagement of nondopaminergic networks, increased dopamine turnover is another potential mechanism. Dopamine turnover can be estimated using PET by performing 18F-DOPA scans for longer times. During a traditional 90-minute F-DOPA scan, tracer uptake is unidirectional in healthy individuals, reflecting tracer conversion to 18F-fluorodopamine and its storage in synaptic vesicles. This unidirectional
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transport is reflected in the determination of the influx constant (Ki or Kocc) based on multiple time graphical analysis. However, even in healthy individuals, more prolonged scan times of 4 hours will be associated with egress of 18F-fluorodopamine from synaptic vesicles and loss of unidirectional tracer kinetics.
FIG. 5. In a subject with L-dopa–induced dyskinesias, L-dopa induces a marked reduction in raclopride binding from baseline (left) to 1 hour later (right) (upper panel). In patients with L-dopa–induced dyskinesias, the reduction in raclopride binding, corresponding to increased DA release, is of much greater magnitude but shorter duration compared with those with a stable response to medication. Modified from de la Fuente-Fernandez et al.19
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FIG. 6. Model of aberrant release proposed by Carta et al.28 In the intact striatum, DA levels are regulated by reuptake via the DAT and D2 autoreceptors on DA nerve terminals (A). In PD, L-dopa is converted to DA in serotonergic nerve terminals, but the lack of D2 autoreceptors and of reuptake via the DAT lead to high but poorly sustained levels of DA in the synapse (B). Aberrantly high DA release can be dampened by using drugs that stimulate 5HT1A and 5HT1B autoreceptors (C). Reproduced from Carta et al.28
The rate of loss can be estimated by kinetic modeling.22,23 A simpler and essentially equivalent approach is to determine tracer distribution volume using an alternate graphical method that assumes that a state of equilibrium is achieved over the time of the scan (i.e., that tracer uptake is not unidirectional).24 The tracer distribution volume is inversely related to dopamine turnover. Using this approach, for a given degree of dopamine denervation, dopamine turnover is higher in younger PD patients.25 This would contribute to increased oscillations in dopamine release and more pulsatile stimulation of dopamine receptors. By using multi-tracer PET, it also can be shown that dopamine turnover is inversely proportional to the degree to which the DAT is downregulated.26 The logical extension of this is that while downregulation of the dopamine transporter might serve to preserve synaptic dopamine levels in the short-term, this may lead to increased dopamine turnover in the longer term, with subsequent increase in dyskinesias. This is indeed what we found. When correcting for the degree of dopamine denervation based on VMAT2 binding, dyskinetic patients had lower levels of DAT binding.27
Indeed, the effects of dopamine denervation on Ldopa–induced dopamine release are similar to those of DAT blockade.10 Whether the use of DAT blocking agents in PD is associated with a higher risk of longterm complications is not clear.
The Role of Serotonergic Neurons In recent years, increased evidence has appeared in support of the view that in PD, L-dopa–derived dopamine is produced in serotonergic neurons. These neurons express L-aromatic amino acid decarboxylase and have the capacity to store dopamine in synaptic vesicles, but they do not express either DAT or dopamine autoreceptors; hence, synthesis and release of dopamine are not regulated. Lack of DAT means that released dopamine cannot be taken back up for subsequent re-use. This model, proposed by Carta et al.28 (Fig. 6), is entirely compatible with the findings we have reported using 11C-raclopride PET. In support of their model, Carta et al. showed that in animals with 6-hydroxydopamine lesions, L-dopa–induced
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dyskinesia was suppressed either by concurrent lesions of serotonin neurons (induced by the selective neurotoxin 5,7-dihydroxytryptamine) or by treatment with serotonergic somatodendritic (5HT1A) or terminal (5HT1B) autoreceptor agonists. The hypothesis gained further support from the demonstration that in PD patients with dyskinesias after neural transplantation, the grafts expressed much higher levels of the serotonin transporter than is seen in either healthy control or typical PD striatum.29 More recently, the same authors have demonstrated that dyskinetic PD subjects have a greater decline in 11C-raclopride binding after L-dopa than do nondyskinetic patients and furthermore, that Ldopa–induced dopamine release is suppressed by the 5HT1A agonist buspirone.30 The degree to which buspirone suppressed L-dopa–induced dopamine release in these patients was directly correlated with the density of serotonin innervation, as determined by PET with the 5HT transporter ligand 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile (11C-DASB). However, although PD subjects all had reduced striatal 11 C-DASB binding compared with healthy controls, no clear relationship was found between 5HT transporter binding and the presence or severity of L-dopa–induced dyskinesias. This negative finding was unexpected and at first glance appears to run counter to the model proposed by Carta and colleagues. As noted, however, altered central pharmacokinetics of L-dopa set the stage for future trouble by contributing to pulsatile stimulation of dopamine receptors and subsequent downstream effects. Thus, the critical question is not so much the difference in 5HT transporter binding between those who currently have dyskinesia and those who do not, but rather, whether 5HT transporter binding can predict the future development of dyskinesias.
Non-motor Complications Finally, the present article has focused on the relationship between altered central pharmacokinetics of L-dopa and the emergence of motor complications. However, similar considerations may apply to the development of behavioral complications. In patients with dopamine dysregulation syndrome, L-dopa– derived dopamine release is increased in the ventral striatum compared with those without this complication.31 Gambling or even exposure to visual cues results in increased ventral striatal dopamine release in PD patients prone to impulse control disorders.32,33 This increase in dopamine release is in keeping with the reductions in DAT binding that have been reported in association with these disorders.
Concluding Comments Dopamine release is of greater magnitude but shorter duration in patients with advanced PD. This
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undoubtedly contributes to pulsatile stimulation of dopamine receptors and the emergence of motor and, quite likely, non-motor complications. Radiotracer imaging has been particularly helpful for identifying and quantifying changes in the pattern of dopamine release and dopamine turnover and more recently have provided support for the view that these arise at least in part from conversion of L-dopa to dopamine in serotonergic neurons as dopaminergic neurons are lost. Although not the focus of the current article, future studies may address changes that occur downstream to dopamine receptors34 and their potential role in these complications. Additionally, developments in hybrid PET–magnetic resonance imaging imaging may allow the concurrent determination of changes in neurotransmitter function and alterations in blood flow and brain network activation.35 Acknowledgements: We thank our many colleagues who have contributed to this work, especially Drs. Raul de la Fuente-Fernandez, Vesna Sossi, Ramchandiran Nandhagopal, and Andre Troiano, Dr. Thomas Ruth and the UBC-TRIUMF PET program, and Jessamyn McKenzie.
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Tedroff J, Pedersen M, Aquilonius SM, Hartvig P, Jacobsson G, Langstrom B. Levodopa-induced changes in synaptic dopamine in patients with Parkinson’s disease as measured by [11 C] raclopride displacement and PET. Neurology 1996;46:1430-1436.
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Abercrombie ED, Bonatz AE, Zigmond MJ. Effects of L-DOPA on extracellular dopamine in striatum of normal and 6hydroxydopamine-treated rats. Brain Res 1990;525:36-44.
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Scherfler C, Khan NL, Pavese N, et al. Striatal and cortical preand postsynaptic dopaminergic dysfunction in sporadic parkinlinked parkinsonism. Brain 2004;127:1332-1342.
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Sossi V, Doudet DJ, Holden JE. A reversible tracer analysis approach to the study of effective dopamine turnover. J Cereb Blood Flow Metab 2001;21:469-476.
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Sossi V, Fuente-Fernandez R, Schulzer M, Adams J, Stoessl J. Agerelated differences in levodopa dynamics in Parkinson’s: implications for motor complications. Brain 2006;129:1050-1058.
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Sossi V, Fuente-Fernandez R, Schulzer M, Troiano AR, Ruth TJ, Stoessl AJ. Dopamine transporter relation to dopamine turnover in Parkinson’s disease: a positron emission tomography study. Ann Neurol 2007;62:468-474.
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Troiano AR, Fuente-Fernandez R, Sossi V, et al. PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology 2009;72:1211-1216.
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Central Pharmacokinetics of Levodopa: Lessons From Imaging Studies A. Jon Stoessl* Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia & Vancouver Coastal Health, 2221 Wesbrook Mall, Vancouver, BC CANADA V6T 2B5
ABSTRACT:
Functional imaging may be particularly helpful for the assessment of levodopa (L-dopa) response and long-term complications of therapy in Parkinson’s disease. Radiotracer imaging allows the quantitative determination of regional changes in blood flow and glucose metabolism, as well as alterations in brain connectivity and network activation and changes in dopamine receptors, non-dopaminergic neurotransmitter systems, and to a lesser extent, signaling pathways downstream to dopamine receptors. The focus of the present article, however, is the application of positron emission tomography (PET) to study the central pharmacokinetics of L-dopa. Radioligands with limited affinity for the dopamine D2 receptor are sensitive to changes in the levels of synaptic dopamine and can accordingly provide helpful insights into the magnitude and time course of dopamine release after L-dopa. Prolonged fluorodopa PET scans can be used to estimate the rate of dopamine turnover. Studies performed with
these techniques have demonstrated increased dopamine turnover and increased but shorter duration release of dopamine after L-dopa as Parkinson’s disease (PD) progresses, increased release of dopamine in patients with L-dopa–induced dyskinesia, and that aberrant patterns of dopamine release may actually predict the future development of motor fluctuations. Taken together, the studies provide in vivo validation for the hypothesis that pulsatile stimulation of dopamine receptors plays a critical role in the emergence of long-term motor complications of therapy. Similar approaches can be used to study the non-motor complications of PD C 2014 International Parkinson and and its treatment. V Movement Disorder Society
K e y W o r d s : Dopamine; dopamine release; dopamine turnover; dopamine transporter; serotonin; positron emission tomography
Imaging studies can provide numerous helpful insights into the complications of levodopa (L-dopa) therapy. The present article focuses on positron emission tomography (PET) studies of presynaptic dopaminergic function. Although studies in animal models have consistently provided clear evidence for the importance of changes that occur downstream to dopamine receptors, these have for the most part been
more difficult to characterize in vivo, given the relative lack of relevant radiotracers. Studies of cerebral blood flow or metabolism, addressed elsewhere in this volume, although neurochemically not specific, provide complementary information.
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The integrity of presynaptic dopamine function is typically assessed using radiotracers that bind to the vesicular monoamine transporter type 2 (VMAT2) or the membrane dopamine transporter (DAT), or 18Ffluorodopa, which is taken up by monoaminergic neurons, decarboxylated to 18F-fluorodopamine, and packaged in synaptic vesicles. Vesicular monoamine transporter type 2 is labeled with 11C-dihydrotetrabenazine or its 18F analog; the DAT can be studied using a host of tropane (cocaine-like) compounds labeled with 123I or 99mTc for SPECT, and with 11C or 18Ftropanes or with 11C-d-threo-methylphenidate for PET (Fig. 1). All three approaches provide indirect
*Correspondence to: A. Jon Stoessl, Pacific Parkinson’s Research Centre, Djavad Mowafaghian Centre for Brain Health, University of British Columbia & Vancouver Coastal Health, 2221 Wesbrook Mall, Vancouver, BC CANADA V6T 2B5. E-mail: [email protected]
Funding agencies: This study was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation, the Michael Smith Foundation for Health Research, the National Parkinson Foundation, the Pacific Alzheimer Research Foundation, the Pacific Parkinson’s Research Institute and the Canada Research Chairs program. Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article. Received: 7 August 2014; Accepted: 1 September 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26046
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FIG. 1. Cartoon depicting determination of dopamine (DA) function. The presynaptic neuron can be labeled with 18F-DOPA, which is converted to 18F-DA and stored in synaptic vesicles. The vesicular monoamine transporter type 2 (VMAT2) can be labeled with 11C-dihydrotetrabenazine (DTBZ) or its 18F analog, and the DAT transporter (DAT) can be labeled with a variety of 11C- , 18F (PET), 123I, or 99mTc (SPECT) tropanes (cocaine analogs), or with 11C-d-threo-methylphenidate (PET). Dopamine D2 receptors can be labeled with low-affinity ligands (11C-raclopride for PET, 123I-iodobenzamide [IBZM] for SPECT) whose binding is subject to competition from synaptic DA0.
measures of dopaminergic nerve terminal function, and accordingly all result in similar abnormalities in Parkinson’s disease, namely, an asymmetric reduction of tracer uptake that affects the striatum with a graded abnormality that is maximum in the caudal putamen. Using all three approaches, disease progression (ie, tracer uptake) is best described by an exponential function, as is seen in postmortem studies. Thus, for most purposes such as the identification of dopaminergic dysfunction for diagnosis or the assessment of disease progression, all three approaches provide similar information. However, subtle differences are found between the approaches, based on the physiological processes that they target. The VMAT2 binding is thought to be less subject to compensatory or pharmacologically mediated regulation than either DAT binding or fluorodopa (F-DOPA) uptake. In early disease, DAT binding is reduced relative to VMAT2 binding, presumably reflecting downregulation of the DAT in an effort to maintain adequate dopamine in the synapse. In contrast, F-DOPA uptake is increased relative to VMAT2 binding in early disease, possibly reflecting increased activity in L-aromatic amino acid decarboxylase, ie, increased dopamine synthesis1,2 (Fig. 2). These relatively subtle differences between radiotracer approaches are seen in early disease stages only, but they may be highly relevant in understanding the pathophysiology of treatment-related complications of Parkinson’s disease (PD). Furthermore, F-DOPA is taken up by serotonin and norepinephrine neurons and is not specific to dopamine neurons, and its uptake reflects the unidirectional transport of 18F-fluo-
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rodopamine into synaptic vesicles and not just the decarboxylation of 18F-fluorodopa to 18F-fluorodopamine. These points are critical in the interpretation of imaging studies and their relevance to understanding the complications of therapy. Finally, one of the most effective ways to study the function of the presynaptic dopamine neuron is to use a tracer that binds to postsynaptic dopamine receptors. The binding of ligands such as 11C-raclopride, which has relatively weak affinity for D2/D3 receptors, is subject to competition from endogenous dopamine. Thus, increased dopamine release will result in reduced 11C-raclopride binding, and this property can provide tremendous insights into altered central pharmacokinetics of L-dopa and the relationship to complications of therapy. Although limited in size, post-mortem studies conducted in humans who have undergone functional imaging demonstrate a good correlation between FDOPA uptake3 or DAT binding4 and nigral dopamine cell counts. Studies conducted in animal models of PD have resulted in somewhat more variable results. Although tracer uptake has been shown to correlate with striatal levels of dopamine, the relationship to nigral cell counts has been somewhat more variable,
FIG. 2. Changes in dopamine processing over the course of PD. In early disease, FD (F-DOPA) uptake (green line) is increased relative to VMAT2 binding (DTBZ; blue line), while DAT binding (MP uptake, red line) is reduced. Y-axis values are the proportion of age-expected healthy control values (i.e., 1 5 100% of normal, 0.5 5 50%, etc.). These differences converge over time. Reproduced from Nandhagopal et al.2
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possibly reflecting the relatively limited loss of nigral neurons in some protocols using 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP).5 The differential involvement of VMAT2 binding, F-DOPA uptake, and DAT binding has also been called into question based on a study conducted in MPTP-treated nonhuman primates.6 However, the MPTP model results in relatively acute toxicity as opposed to PD, in which progression is much more indolent, thereby affording a much greater opportunity for compensatory changes.
Assessment of Dopamine Release As noted, changes in 11C-raclopride binding after an intervention can be used to surmise the effects of that intervention on dopamine release. At usual doses, amphetamine results in dopamine release by reversal of the DAT. Thus, dopamine release (estimated by percent decrease in 11C-raclopride binding after amphetamine) is directly correlated with the number of surviving dopamine neurons as estimated by F-DOPA uptake.7 The situation with L-dopa is somewhat more complex. Changes in 11C-raclopride binding can be demonstrated after oral8 or intravenous9 L-dopa, but, in contrast to amphetamine, the magnitude of dopamine release after L-dopa administration increases with increased duration and severity of disease (Fig. 3). Although this may seem paradoxical, it is actually very much in keeping with the findings reported using microdialysis in rats with partial 6hydroxydopamine lesions, whereas substantial dopamine release is seen only when the lesion is greater than 80%.10 Interestingly, imaging studies have demonstrated evidence for a prolonged effect of L-dopa therapy on 11Craclopride binding. Thobois et al.11 studied patients with advanced PD who had undergone subthalamic nucleus deep brain stimulation surgery. Although all subjects were imaged after 12-hour medication withdrawal, those patients in whom DBS afforded longterm withdrawal of dopaminergic medication demonstrated increased D2 binding in the putamen, as is seen in early, untreated PD. In patients who required ongoing medication, D2 binding in the putamen was comparable to healthy control levels, whereas binding in these subjects was reduced to slightly subnormal levels in the caudate nucleus. Similar findings have been reported in patients with PD caused by parkin mutation. Early reports suggested reductions in 11Craclopride binding,12 with scans again conducted after 12 hours of medication withdrawal. A follow-up study conducted in treatment-na€ıve parkin mutants revealed increased binding.13 Increased 11C-raclopride binding in treatment-na€ıve subjects probably represents a combination of receptor upregulation and reduced occupancy by endogenous dopamine.14 Whereas acute
FIG. 3. Dopamine release (% change in RAC BP 5 raclopride binding potential) increases with disease duration in both the caudate (upper) and putamen (lower). Reproduced from de la Fuente-Fernandez et al.19
reductions in 11C-raclopride binding can readily be explained by increases in synaptic dopamine,15,16 longer-term reductions might reflect receptor downregulation. Internalized D2 receptors appear to bind 11Craclopride to a degree similar to receptors localized on the cell surface, but sustained dopaminergic stimulation might presumably result in long-term reductions in total receptor number.
Dopamine Release After L-Dopa A number of classical studies examining the relationship between plasma L-dopa levels and motor response duration in PD have demonstrated that peripheral pharmacokinetic factors are unlikely to explain motor fluctuations in most patients.17,18 Using 11 C-raclopride PET, de la Fuente-Fernandez et al.8 showed that central pharmacokinetics of L-dopa– derived dopamine are indeed altered. In fact, an abnormal pattern of dopamine release was seen in those patients with a stable response to L-dopa who later went on to develop motor fluctuations8 (Fig. 4). Patients who had a modest reduction in 11C-raclopride binding that was sustained for at least 4 hours after oral administration of L-dopa maintained a stable clinical response for at least 3 years after they were studied. In contrast, those patients who showed an early large increase in dopamine release that was poorly sustained went on to develop motor response fluctuations within 3 years of study. This supports a model
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FIG. 4. Changes in the pattern of DA release in response to L-dopa anticipate the future development of motor fluctuations. The left panel demonstrates raclopride binding in eight PD patients, all of whom had a stable response at the time of study. Note that in in four patients (Nos. 1, 2, 4, 8), there is a small reduction in raclopride binding 1 hour after levodopa, which is sustained or of greater magnitude 4 hours later. In the other patients, there is a larger but more transient decline in raclopride binding. The latter pattern is associated with the future development of motor fluctuations 3 years later (right panel). Modified from de la Fuente-Fernandez et al.8
in which altered central pharmacokinetics of L-dopa characterized by short-duration release of substantial amounts of dopamine and thereby pulsatile stimulation of dopamine receptors are the necessary underpinning for future complications that also may reflect changes downstream to dopamine receptors. In contrast to dopamine release after amphetamine, dopamine release after L-dopa increases with disease duration19 (Fig. 3). This may reflect a number of factors, including impaired vesicular storage of dopamine as disease progresses, reduced reuptake of dopamine because of loss of DAT sites on surviving dopamine nerve terminals, and synthesis of dopamine by nondopaminergic neurons. Regardless of mechanism, this means that advanced disease is associated with a higher magnitude of dopamine release after L-dopa that is, however, of reduced duration. This pattern is associated with dyskinesias19 (Fig. 5), as well as the degree of clinical improvement after medication.20 Patients with younger onset of PD are more prone to fluctuations in motor function and dyskinesias in response to L-dopa. In fact, we have found that the degree of dopamine denervation at disease onset is more severe in those with younger age of onset, even though disease progresses more slowly in these individuals.21 This presumably reflects stronger compensatory mechanisms in those with young disease onset. Although some of this compensation may be attributable to engagement of nondopaminergic networks, increased dopamine turnover is another potential mechanism. Dopamine turnover can be estimated using PET by performing 18F-DOPA scans for longer times. During a traditional 90-minute F-DOPA scan, tracer uptake is unidirectional in healthy individuals, reflecting tracer conversion to 18F-fluorodopamine and its storage in synaptic vesicles. This unidirectional
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transport is reflected in the determination of the influx constant (Ki or Kocc) based on multiple time graphical analysis. However, even in healthy individuals, more prolonged scan times of 4 hours will be associated with egress of 18F-fluorodopamine from synaptic vesicles and loss of unidirectional tracer kinetics.
FIG. 5. In a subject with L-dopa–induced dyskinesias, L-dopa induces a marked reduction in raclopride binding from baseline (left) to 1 hour later (right) (upper panel). In patients with L-dopa–induced dyskinesias, the reduction in raclopride binding, corresponding to increased DA release, is of much greater magnitude but shorter duration compared with those with a stable response to medication. Modified from de la Fuente-Fernandez et al.19
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FIG. 6. Model of aberrant release proposed by Carta et al.28 In the intact striatum, DA levels are regulated by reuptake via the DAT and D2 autoreceptors on DA nerve terminals (A). In PD, L-dopa is converted to DA in serotonergic nerve terminals, but the lack of D2 autoreceptors and of reuptake via the DAT lead to high but poorly sustained levels of DA in the synapse (B). Aberrantly high DA release can be dampened by using drugs that stimulate 5HT1A and 5HT1B autoreceptors (C). Reproduced from Carta et al.28
The rate of loss can be estimated by kinetic modeling.22,23 A simpler and essentially equivalent approach is to determine tracer distribution volume using an alternate graphical method that assumes that a state of equilibrium is achieved over the time of the scan (i.e., that tracer uptake is not unidirectional).24 The tracer distribution volume is inversely related to dopamine turnover. Using this approach, for a given degree of dopamine denervation, dopamine turnover is higher in younger PD patients.25 This would contribute to increased oscillations in dopamine release and more pulsatile stimulation of dopamine receptors. By using multi-tracer PET, it also can be shown that dopamine turnover is inversely proportional to the degree to which the DAT is downregulated.26 The logical extension of this is that while downregulation of the dopamine transporter might serve to preserve synaptic dopamine levels in the short-term, this may lead to increased dopamine turnover in the longer term, with subsequent increase in dyskinesias. This is indeed what we found. When correcting for the degree of dopamine denervation based on VMAT2 binding, dyskinetic patients had lower levels of DAT binding.27
Indeed, the effects of dopamine denervation on Ldopa–induced dopamine release are similar to those of DAT blockade.10 Whether the use of DAT blocking agents in PD is associated with a higher risk of longterm complications is not clear.
The Role of Serotonergic Neurons In recent years, increased evidence has appeared in support of the view that in PD, L-dopa–derived dopamine is produced in serotonergic neurons. These neurons express L-aromatic amino acid decarboxylase and have the capacity to store dopamine in synaptic vesicles, but they do not express either DAT or dopamine autoreceptors; hence, synthesis and release of dopamine are not regulated. Lack of DAT means that released dopamine cannot be taken back up for subsequent re-use. This model, proposed by Carta et al.28 (Fig. 6), is entirely compatible with the findings we have reported using 11C-raclopride PET. In support of their model, Carta et al. showed that in animals with 6-hydroxydopamine lesions, L-dopa–induced
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dyskinesia was suppressed either by concurrent lesions of serotonin neurons (induced by the selective neurotoxin 5,7-dihydroxytryptamine) or by treatment with serotonergic somatodendritic (5HT1A) or terminal (5HT1B) autoreceptor agonists. The hypothesis gained further support from the demonstration that in PD patients with dyskinesias after neural transplantation, the grafts expressed much higher levels of the serotonin transporter than is seen in either healthy control or typical PD striatum.29 More recently, the same authors have demonstrated that dyskinetic PD subjects have a greater decline in 11C-raclopride binding after L-dopa than do nondyskinetic patients and furthermore, that Ldopa–induced dopamine release is suppressed by the 5HT1A agonist buspirone.30 The degree to which buspirone suppressed L-dopa–induced dopamine release in these patients was directly correlated with the density of serotonin innervation, as determined by PET with the 5HT transporter ligand 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile (11C-DASB). However, although PD subjects all had reduced striatal 11 C-DASB binding compared with healthy controls, no clear relationship was found between 5HT transporter binding and the presence or severity of L-dopa–induced dyskinesias. This negative finding was unexpected and at first glance appears to run counter to the model proposed by Carta and colleagues. As noted, however, altered central pharmacokinetics of L-dopa set the stage for future trouble by contributing to pulsatile stimulation of dopamine receptors and subsequent downstream effects. Thus, the critical question is not so much the difference in 5HT transporter binding between those who currently have dyskinesia and those who do not, but rather, whether 5HT transporter binding can predict the future development of dyskinesias.
Non-motor Complications Finally, the present article has focused on the relationship between altered central pharmacokinetics of L-dopa and the emergence of motor complications. However, similar considerations may apply to the development of behavioral complications. In patients with dopamine dysregulation syndrome, L-dopa– derived dopamine release is increased in the ventral striatum compared with those without this complication.31 Gambling or even exposure to visual cues results in increased ventral striatal dopamine release in PD patients prone to impulse control disorders.32,33 This increase in dopamine release is in keeping with the reductions in DAT binding that have been reported in association with these disorders.
Concluding Comments Dopamine release is of greater magnitude but shorter duration in patients with advanced PD. This
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undoubtedly contributes to pulsatile stimulation of dopamine receptors and the emergence of motor and, quite likely, non-motor complications. Radiotracer imaging has been particularly helpful for identifying and quantifying changes in the pattern of dopamine release and dopamine turnover and more recently have provided support for the view that these arise at least in part from conversion of L-dopa to dopamine in serotonergic neurons as dopaminergic neurons are lost. Although not the focus of the current article, future studies may address changes that occur downstream to dopamine receptors34 and their potential role in these complications. Additionally, developments in hybrid PET–magnetic resonance imaging imaging may allow the concurrent determination of changes in neurotransmitter function and alterations in blood flow and brain network activation.35 Acknowledgements: We thank our many colleagues who have contributed to this work, especially Drs. Raul de la Fuente-Fernandez, Vesna Sossi, Ramchandiran Nandhagopal, and Andre Troiano, Dr. Thomas Ruth and the UBC-TRIUMF PET program, and Jessamyn McKenzie.
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