A. Bjorklund and M. A. Cenci (Eds.) Progress in Brain Research, Vol. 184 ISSN: 0079-6123 Copyright � 2010 Elsevier B.V. All rights reserved.

CHAPTER 9

Imaging the nigrostriatal system to monitor disease progression and treatment-induced complications

Renju Kuriakose and A. Jon Stoessl�

Pacific Parkinson’s Research Centre, University of British Columbia and Vancouver Coastal Health, Vancouver, BC, Canada

Abstract: Radiotracer imaging (RTI) techniques such as positron emission tomography (PET) allow the in vivo assessment of nigrostriatal DA function in Parkinson’s disease and have provided valuable insights into the mechanisms of nigrostriatal degeneration and the consequent compensatory changes. Moreover, functional imaging serves as an excellent tool in the assessment of the progression of PD and the evolution of treatment-related complications. However, various studies have shown discordance between clinical progression of PD and nigrostriatal degeneration estimated by PET or SPECT, and no RTI technique can be reliably used as a biomarker for progression of PD. Presynaptic dopaminergic imaging has consistently demonstrated an anterior–posterior gradient of dopaminergic dysfunction predominantly affecting the putamen, with side-to-side asymmetry in tracer binding. Dopaminergic hypofunction in the striatum follows a negative exponential pattern with the fastest rate of decline in early disease. Evaluation of central pharmacokinetics of levodopa action by PET has demonstrated the role of increased synaptic dopamine turnover and downregulation of the dopamine transporter in the pathophysiology of levodopa­induced dyskinesias. In PD with behavioral complications such as impulse control disorders, increased levels of dopamine release have been observed in the ventral striatum during performance of a positive reward task, as well as loss of deactivation in orbitofrontal cortex in response to negative reward prediction errors. This suggests that there is a pathologically heightened “reward” response in the ventral striatum together with loss of the capacity to respond to negative outcomes. Overall, functional imaging with PET is an excellent tool for understanding the disease and its complications; however, caution must be applied in interpretation of the results.

Keywords: Positron emission tomography; dopamine turnover; dopamine transporter (DAT); fluorodopa; vesicular monoamine transporter type 2 (VMAT2); biomarker; compensation; dopamine receptors; fluctua­tions; dyskinesias; impulse control disorders

� Corresponding author. Tel.: þ1-604-822-7967; E-mail: jstoessl@interchange.ubc.ca

DOI: 10.1016/S0079-6123(10)84009-9 177

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Introduction

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, with a prevalence rate of more than 1 in 100 among affected persons above the age of 65 years (de Rijk et al., 2000). Clinically PD is characterized by symptoms of bradykinesia, resting tremor, rigidity, and postural instability (Calne et al., 1992). The pathophysiological hallmark of PD is degeneration of nigrostriatal pathway leading to dopamine (DA) deficiency (Hornykiewicz, 1998). PD symptoms appear when 80% of the striatal DA or 50% of nigral cells are lost (Bernheimer et al., 1973; Fearnley & Lees, 1991). Dopamine replace­ment therapies, which include the DA precursor levo-dopa and DA agonists, are very effective in treating motor symptoms, but can cause substantial motor and behavioral adverse events. These side-effects include motor fluctuations and levodopa-induced dyskinesia (LID) and non-motor symptoms such as mood and anxiety fluctuations, psychosis, and impulse control disorders (ICDs) (Voon et al., 2009). LIDs are defined as involuntary, purposeless, irregular but sometimes repetitive movements, which are mainly choreic, and generally coincide with the peak anti-parkinsonian effect of levodopa (Obeso et al., 2007). LIDs affect at least 90% of patients with PD after 10 years of levodopa treat­ment (Fabbrini et al., 2007) and are a major cause of disability. ICDs (i.e., pathological gambling, compulsive shopping, hypersexuality, and binge eating), punding (i.e., abnormal repetitive non-goal-oriented behaviors), or hobbyism, and compulsive medication use are associated with dopaminergic therapy and are increasingly recog­nized in PD (Avanzi et al., 2006; Grosset et al., 2006; Miyasaki et al., 2007; Pezzella et al., 2005; Voon et al., 2006; Weintraub et al., 2006). Radio­tracer imaging (RTI) techniques such as positron emission tomography (PET) and single photon emission computerized tomography (SPECT) allow the in vivo assessment of nigrostriatal DA function and have provided valuable insights into the mechanisms of nigrostriatal degeneration and the consequent compensatory changes

(Nandhagopal et al., 2008). These techniques also help to assess the progression of disease and eva­luation of treatment interventions (Au et al., 2005).

Neuroimaging of the nigrostriatal system

Biochemistry of dopamine function

A basic knowledge of biochemistry of DA meta­bolism is essential to understand the imaging of nigrostriatal DA function. The first step in DA synthesis is the conversion of tyrosine to L-3-4­dihydroxyphenylalanine (L-dopa). Exogenously administered L-dopa crosses the blood–brain bar­rier via the large neutral amino acid transporter. Striatal uptake of L-dopa requires active transport and its further conversion to DA is catalyzed by L-aromatic amino acid decarboxylase (AADC). Vesicular monoamine transporter type 2 (VMAT2) pumps both newly synthesized and recycled DA into presynaptic vesicles. Vesicular storage helps to maintain the molecular integrity of neurotransmit­ters by preventing their catabolism to potentially toxic compounds. Axonal depolarization leads to exocytotic release of DA into the extracellular space, where it interacts with pre- and post-synaptic DA receptors. The molecular effects of DA are terminated by conversion via methylation and oxi­dative deamination to homovanillic acid and also (indeed primarily) by reuptake into presynaptic terminals from the synaptic cleft. The membrane DA transporter (DAT) mediates this reuptake, following which DA is recycled into storage vesi­cles or converted to inactive metabolites.

Presynaptic imaging

There are three different strategies to assess presy­naptic dopaminergic integrity using radioligands that measure various aspects of striatal DA processing.

6-[18F]-fluoro-L-dopa (F-DOPA) is used as a marker to monitor the uptake and decarboxyla­tion of F-DOPA to fluorodopamine (FDA), and

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the subsequent storage of FDA in synaptic vesi­cles. It has been extensively characterized and is widely regarded as the “gold standard” for asses­sing the integrity of the nigrostriatal DA system. F-DOPA uptake correlates well with nigral cell counts in humans (Snow et al., 1993) and in non­human primates with MPTP-induced parkinson­ism (Pate et al., 1993). It also reflects the clinical severity of PD, and correlates well with bradyki­nesia but not with tremor (Vingerhoets et al., 1997). The standard approach is to scan for 90–120 min following tracer injection, during which time tracer uptake is unidirectional in the normal brain. Prolonged scan times of up to 4 h (during which there is tracer egress) can be used to assess effective DA turnover, which is increased in early PD (Sossi et al., 2002). Biochemically, DA turn­over is defined as the ratio between DA metabo­lites and DA. The concept of the effective dopamine turnover (EDT) that is measurable by F-DOPA PET has been developed to estimate DA turnover in vivo (Doudet et al., 1998). The blood to striatum dopa uptake rate constant Ki estimates the rate of DA synthesis and storage (Patlak et al., 1983). Ki reflects a combination of tracer uptake, decarboxylation to FDA, and sub­sequent trapping in synaptic vesicles, and has been shown to correlate well with the number of DA neurons and the levels of striatal DA (Snow et al., 1993). During the first 90 min after tracer injec­tion, F-DOPA behaves as an irreversibly bound tracer in healthy normal individuals. Ki is obtained from data acquired during this time. However, with prolonged scanning time, some degree of reversibility is observed in the data, which indi­cates neuronal release of DA and subsequent metabolism. Such reversibility is quantified with the rate constant kloss. The rate constant kloss is a measure of the frequency of depletion of the trapped tracer component, and its inverse repre­sents the mean dwell time of that component in brain tissue. The ratio kloss/Ki is a powerfully dis­criminating indicator of the turnover of the trapped F-DOPA compartment (EDT). Its inverse Ki/kloss can be interpreted as an effective distribution

volume (EDV) of the specific compartment alone with respect to the plasma tracer concentration and is a similarly discriminating measure of the ability of the trapping mechanism to store tracer. In Parkinson’s disease, the rate of F-DOPA uptake decreases and the rate of loss increases. Thus both EDT and its inverse EDV are sensitive markers of disease severity and progression. [18F]- and [11C]-labeled antagonists can be used

to determine the DAT density. DAT is a 620-amino acid protein, with 12 a-helical hydrophobic trans­membrane domains, 2–4 extracellular glycosylation sites, and up to 5 intracellular phosphorylation sites, which is found exclusively in DA axons and dendrites (Hersch et al., 1997; Nirenberg et al., 1996). DAT levels correlate with striatal DA con­centrations (Bezard et al., 2001). It is therefore a potential specific marker of DA nerve terminal density. The binding of DAT ligands correlates with the clinical severity of PD (Pirker, 2003; Seibyl et al., 1995). The reproducibility of scan results within subjects is also acceptable (Nurmi et al., 2000a; Seibyl et al., 1997; Volkow et al., 1995). [11C]dihydrotetrabenazine (DTBZ) can be used

to determine the VMAT2 density. There are two forms of VMAT expressed in human: VMAT1 is found in the adrenal glands, while VMAT2 is expressed exclusively in brain. VMAT2 is a 515-amino acid protein responsible for the uptake of intracytoplasmic monoamines into the synaptic vesicles. Although VMAT2 is not specific for DA, it is responsible for the packaging of all monoamine neurotransmitters and more than 95% of striatal monoaminergic innervation is dopaminergic. Tetrabenazine binds to VMAT2 and blocks the uptake of monoamines into the vesicles. In rats, the binding of striatal VMAT2 with [3H] methoxytetrabenazine correlated with SNc den­sity (Vander Borght et al., 1995). Since the mid­1990s, DTBZ has been used in humans to monitor the integrity of striatal monoaminergic nerve terminal density (Frey et al., 1996). The interpretation of dopaminergic scans is not

straightforward. Indeed, early PD is characterized by relative increases in F-DOPA uptake compared

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to the degree of denervation as assessed by DTBZ PET, probably reflecting compensatory upregula­tion of AADC activity (Lee et al., 2000). Hence, F-DOPA uptake may underestimate the degree of dopaminergic denervation, particularly in early disease. On the other hand, VMAT2 expression per existing DA terminal is thought to be relatively resistant to regulatory changes resulting from denervation and pharmacotherapy. DTBZ binding correlates well with presynaptic vesicle density and hence, in turn, reflects the nerve terminal density, although it is subject to competition from cytosolic DA and extensive depletion of vesicular DA may therefore lead to apparent ele­vation of VMAT2 binding (Boileau et al., 2008; Tong et al., 2008). Although DAT binding might be expected to reflect DA terminal density, the DAT is downregulated in early PD as a compen­satory change (Lee et al., 2000) and may be further influenced by pharmacotherapy and age (Parkinson Study Group, 2002; Volkow et al., 1994). Therefore, DAT binding may tend to over­estimate nigral cell loss.

Parkinson’s disease-related spatial covariance pattern (PDRP)

Functional brain imaging can provide other insights into possible mechanisms of therapy for PD and related disorders. In particular, metabolic imaging of the brain with 18F-fluorodeoxyglucose (FDG) PET has revealed useful information about disor­dered functional connectivity in neurodegenerative disease (see chapter by Eidelberg, this volume). By mapping glucose metabolism at a voxel level, this imaging approach provides a measure of regional synaptic activity and the biochemical maintenance processes that dominate the rest state. The effects of localized pathology on these cellular functions can alter functional connectivity across the entire brain in a disease-specific manner. Parkinson’s disease is associated with the expres­sion of an abnormal metabolic pattern that is characterized by increased pallidothalamic and

pontine activity, and concurrent relative metabolic reductions in the cortical motor and association regions. The PD-related spatial covariance pattern expression is highly reproducible (Ma et al., 2007) and in addition to the accurate discrimination between patients with PD and healthy volunteers, this network measure was useful in the differential diagnosis of classic PD and atypical forms of parkinsonism (Eckert et al., 2007). Substantial evidence links the PD-related spatial covariance pattern to the motor manifestations of the disease. The activity of this network is associated with standardized motor ratings (Asanuma et al., 2006) and spontaneous firing rates of neurons in the motor pallidum (Eckert and Eidelberg, 2005). Moreover, PD-related spatial covariance pattern activity can be modulated by therapeutic lesioning or deep brain stimulation of the motor pallidum and the subthalamic nucleus (Asanuma et al., 2006; Trost et al., 2006). The reduction in network activity induced by these interventions is associated with the degree of post-operative motor benefit seen.

Post-synaptic imaging

D1 and D2 receptors can be evaluated using dif­ferent radiotracers. [18F]fallypride, [11C]FLB-457 (PET ligand), and [11C]epidepride (SPECT ligand) belong to the family of ultra high-affinity DA receptor antagonist radioligands, which allows quantification and visualization of low-density DA extrastriatal D2/D3 receptors as well as striatal receptors (de Paulis, 2003). The radioligands

[123I][11C]raclopride (RAC) (for PET) and IBZM (for SPECT) are widely employed to assess striatal DA receptor availability. Since these ligands have a lower affinity for D2/D3 receptors, quantification of extrastriatal receptors is not possible (Pinborg et al., 2007). RAC competes with endogenous DA for in vivo binding to D2 receptors and changes in binding can therefore be used to infer alterations in synaptic DA con­centration. Tracer binding is also influenced by age and, to a lesser extent, the stage of PD and

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DA replacement therapy (DRT). While increased tracer binding is observed in the more affected putamen in early PD (Antonini et al., 1997; Kaasinen et al., 2000), advanced PD and chronic DRT result in normalization of binding in the putamen and decreased binding in the caudate (Antonini et al., 1997; Thobois et al., 2004). In early PD, increased D2 binding has also been demonstrated using [11C]-N-methylspiperone (Kaasinen et al., 2000). Unlike RAC, this ligand is not thought to be subject to displacement by endogenous DA and the findings therefore suggest that increased binding of D2 ligands to putaminal D2 receptors in early PD additionally reflects receptor upregulation, as opposed to increased receptor occupancy due to endogenous DA deficiency. In contrast, D1 binding as assessed by [11C]SCH23390 and PET is normal in PD (Rinne et al., 1990), but may be decreased in con­ditions characterized by loss of striatal neurons, such as multiple system atrophy (MSA).

Assessment of progression

F-DOPA uptake in early PD is most severely decreased in the dorsal part of the caudal putamen but significant decreases can be seen throughout the striatum. Even in patients with unilateral disease, the less severely affected putamen is abnormal, in keeping with subclinical loss of dopa­minergic function (Bohnen et al., 2006; Lee et al., 2000; Marek et al., 1996). An anterior–posterior gradient of dopaminergic dysfunction has been demonstrated in the putamen, with side-to-side asymmetry in tracer binding between the more and less severely affected striatum. As the disease progresses, the anterior–posterior gradient for striatal dopa influx and presynaptic reuptake of DA (DAT function) are maintained, suggesting a similar relative rate of decline throughout the putamen, while the degree of asymmetry between less and more affected putamen becomes less pro­minent (Bruck et al., 2009; Nandhagopal et al., 2009). Taken together, the findings support the

notion that while factors responsible for disease initiation may affect striatal subregions differently, disease progression could be due to non-specific mechanisms such as oxidative stress/free radical elaboration, excitotoxicity, mitochondrial damage, inflammation, etc (Muchowski, 2002; Schapira et al., 1998; Tatton et al., 2003) that might be expected to affect striatal subregions to a similar degree. This notion is supported by the observations of progres­sion of parkinsonism many years after encephalitis lethargica (Calne and Lees, 1988) or after exposure to MPTP (Langston et al., 1999; McGeer et al., 2003), associated with active inflammation. Age-related alterations in striatal DA processing, neuronal attrition, mitochondrial perturbation, and oxidative stress may also play a role in disease pro­gression (Braskie et al., 2008; Kraytsberg et al., 2006; Langston et al., 1999; McGeer et al., 2003;). Autopsy studies in PD have demonstrated a

45% decrease in nigral cell counts during the first decade of PD, 10 times greater than the loss associated with normal aging, with a tendency to approach the normal age-related linear decline in the later stages (Fearnley and Lees, 1991). This nonlinear pattern of nigral cell loss is supported by various PET studies (Bruck et al., 2009; Nandha­gopal et al., 2009). Dopaminergic hypofunction in the putamen, as demonstrated by decline in F-DOPA uptake, is faster in the beginning of the disease than in the later stages, supporting the hypothesis of negative exponential decline (Nandhagopal et al., 2009; Nurmi et al., 2003; Schulzer et al., 1994). The caudate is affected much later and to a lesser degree than the puta­men. Some studies, in which a linear decline is assumed, have estimated a slower rate of decline in the caudate compared to the putamen, but esti­mates based on exponential models of decline suggest that the rate is similar, although the inter­cept and asymptote of decline remain different. In tremor-dominant subjects, a significantly slower annual F-DOPA uptake decline has been noted in caudate than in other PD subtypes (0.6–1.3% compared with 4.3–6.5%). Estimation of preclini­cal duration in PD from F-DOPA PET studies

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varies according to the model that is used but is approximately 6 years (Hilker et al., 2005; Morrish et al., 1998) with estimated losses ranging from approximately 30% (Hilker et al., 2005; Morrish et al., 1998) to 55% (Lee et al., 2000) of normal putaminal F-DOPA uptake at the time of symp­tom onset, in broad agreement with post-mortem studies (Fearnley and Lees, 1991; Hilker et al., 2005; Morrish et al., 1998). The annual rate of decline in putamen DTBZ binding potential was 5.5% of baseline (Au et al., 2005). Given the limitations of the various PET measures, the stu­dies so far suggest that nerve terminal loss in the nigrostriatal DA system progresses at an annual rate of 5–13% in the putamen (Morrish et al., 1998; Nurmi et al., 2000b, 2001, 2003). Changes in metabolic network activity with pro­

gression of PD have been studied (Huang et al., 2007). PDRP activity has been found to increase linearly with disease progression, and is signifi­cantly elevated compared with control. The disease progression was associated with increasing metabolism in the subthalamic nucleus (STN) and internal globus pallidus (GPi), as well as in the dorsal pons and primary motor cortex. Advan­cing disease was also associated with declining metabolism in the prefrontal and inferior parietal regions. PDRP expression was elevated at base­line relative to healthy control subjects, and increased progressively over time. Changes in PDRP activity correlated with concurrent declines in striatal DAT binding and increases in motor ratings. Network analysis of metabolic imaging data showed a short preclinical period in PD, in which the dissociation of the normal relations between metabolic activity and age occurred about 5 years before the onset of symptoms.

Disparity between clinical and in vivo measures of disease progression

RTI has been used as an in vivo biomarker to assess the effect of treatment on disease progres­sion in various clinical trials. These studies include

the CALM-PD study (Parkinson Study Group, 2000) which compared the early use of L-dopa with pramipexole using b-CIT SPECT (a measure of DAT binding), the REAL-PET study (Whone et al., 2003), which compared the use of ropinirole and L-dopa in de novo PD patients using F-DOPA PET, the ELLDOPA study (Fahn, 1999), in which the effects of L-dopa on clinical progression of PD were studied, and bCIT SPECT was included, and studies on fetal nigral transplantation with F-DOPA PET as an imaging modality (Freed et al., 2001; Nakamura et al., 2001; Olanow et al., 2003; Stoessl, 2003). The effects of glial cell line-derived neuro­trophic factor (GDNF) on clinical and imaging end­points have also been reported (Gill et al., 2003). All these studies showed discordant results

between clinical progression and the estimated disease progression as determined by PET or SPECT. In the CALM-PD (Parkinson study group, 2000, 2002) and REAL-PET studies (Whone et al., 2003), imaging findings suggested a slower rate of disease progression with pramipexole and ropinirole, respectively. However, the clinical improvement, based on the Unified Parkinson’s Disease Rating Scale (UPDRS), favored the L-dopa treatment group. In the ELLDOPA study (Fahn et al., 2004), the L-dopa treatment group had a slower rate of clinical progression compared to the placebo group when clinical assessments were performed after 2 weeks of wash-out. Although this most likely reflects inadequate washout of symptomatic effects even after 2 weeks, a more rapid rate of decline in the L-dopa treatment group was noted with b-CIT imaging. In the fetal nigral transplant studies (Freed et al., 2001; Nakamura et al., 2001; Olanow et al., 2003), there was a substantial increase in striatal uptake of F-DOPA following transplantation, but clinical improvement was disappointing. A recent rando­mized controlled trial of intraputaminal GDNF infusion in PD did not confer the predetermined level of clinical benefit despite increased F-DOPA uptake (Lang et al., 2006). The phase 1 open-label trial of intraputaminal stereotactic delivery of CERE-120 (adeno-associated virus serotype

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2-neurturin) to patients with idiopathic Parkinson’s disease demonstrated potential efficacy for treatment; however, no change in striatal uptake from baseline was seen with F-DOPA PET (Marks et al., 2008). The discordance between clinical progression

and RTI markers could in part be due to the effects of the therapies on the surrogate markers rather than on the disease process. Moreover, clinical progression was measured using UPRDS, which reflects a composite of dopaminergic and non-dopaminergic dysfunctions in PD (Lang and Obeso, 2004) and the clinical sign that best reflects the severity of the nigrostriatal lesion is bradyki­nesia (Vingerhoets et al., 1997). In the case of cell-based therapies such as transplantation, grafts may survive but fail to form synaptic connections with the host striatum. Thus, assessment of the nigrostriatal DA system alone may be inadequate to assess the overall disease progression in PD. Proper study design and analysis are needed, and the PET data must be interpreted with caution and in the context of the clinical outcome.

Imaging as a biomarker

Currently there is an increasingly important need for a biomarker to monitor the course of PD, as new therapies for this disorder are developed. RTI of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in PD. Radiotracer-based imaging assessments of nigros­triatal dopaminergic function are useful to diag­nose early Parkinson’s disease and monitor the progression of the disease. However, the associa­tion between these measures and clinical change has not always been straightforward (Ravina et al., 2005). These techniques do not assess the number or density of nigral dopaminergic neurons, and do not directly measure the biologic processes under study. Non-dopaminergic symptoms such as depression, cognitive impairment, and postural instability, which are major contributors to disabil­ity in PD, are not captured by DA-related tracers (Karlsen et al., 1999; Schrag et al., 2000). These

techniques do not reliably distinguish idiopathic PD from MSA or other forms of atypical PD, although FDG PET can potentially distinguish these groups using a discriminant function analysis (Antonini et al., 1998; Eidelberg et al., 1993) The interpretation of imaging data from these clinical trials is challenging because of the potential for direct pharmacologic regulation of the targets of these ligands (Albin & Frey, 2003; Ahlskog, 2003; Clarke & Guttam, 2002). The duration of these pharmacodynamic effects is often unknown, mak­ing washout designs problematic (Albin and Frey, 2003; Ahlskog, 2003; Clarke and Guttman, 2002). Various clinical trials highlight the variable rela­tionship between RTI measure and clinical effects. Therefore, no RTI technique can be considered as a surrogate endpoint in PD for clinical trials.

Neuroimaging of treatment-related motor complications

Presynaptic mechanisms

Neuroimaging studies have provided in vivo sup­port for the importance of pulsatile stimulation of DA receptors in the emergence of LID. Altera­tion in central pharmacokinetics of DA can be assessed using PET with ligands that bind to the VMAT2, the plasmalemmal DAT (Au et al., 2005; Brooks et al., 2003) and indirectly by ligands that bind to post-synaptic DA D2 receptors. Addition­ally, the fluorinated analog of levodopa, F-DOPA can be used to assess uptake and decarboxylation of levodopa to DA, as well as storage of DA in synaptic vesicles and, when prolonged scans (4 h, rather than the usual 90–120 min) are performed, DA turnover (Sossi et al., 2001). Dyskinesias tend to occur in more advanced

PD. One might therefore anticipate a loose rela­tionship between markers of presynaptic dopami­nergic integrity and LID. With the possible exception of dyskinesias that emerge following fetal mesencephalic transplantation (see below), there is little evidence for this in the literature,

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apart from a report by Linazasoro and colleagues, who found an inverse relationship between F-DOPA uptake and dyskinesias (Linazasoro et al., 2004). Fluctuations in motor function, which commonly occur together with dyskinesias, are associated with reduced F-DOPA uptake (Fuente-Fernandez et al., 2000), but there is substantial overlap between patients with and without motor fluctuations, sug­gesting that other factors play an important role. Traditional measures of presynaptic dopaminer­

gic integrity give only a rough estimate of striatal DA nerve terminal density. The critical factor in the emergence of motor complications is the pat­tern of DA receptor stimulation. Thus, assessment of the central pharmacokinetics of levodopa action may provide greater insight. RAC labels D2/D3 receptors with relatively low affinity and its binding is subject to competition from endogen­ous DA (Breier et al., 1997; Seeman et al., 1989). Thus, interventions such as levodopa therapy that result in increased synaptic DA will result in reduced RAC binding as assessed by PET (Tedroff et al., 1996). De la Fuente-Fernandez et al. found a greater magnitude but less sustained decline in RAC binding in PD patients who had a stable response to levodopa at the time of the PET study but who went on to develop motor fluctua­tions within 3 years compared to those subjects who had stable response to medication 3 years later (Fuente-Fernandez et al., 2001). In a follow-up study, these authors found that the relative change in RAC binding 1 h after oral levodopa increases with disease duration and even after correction for this factor, is higher in subjects with LID compared to those with a stable response, while there is no difference between dyskinetic and non-dyskinetic subjects 4 h after levodopa (Fuente-Fernandez et al., 2004). This is compatible with a more pulsa­tile pattern of levodopa-induced DA release in subjects with motor complications. Similar findings have been reported by Pavese et al. (2006). Another way of assessing the kinetics of DA

release and metabolism is to estimate DA turn­over using prolonged scans with F-DOPA. While uptake measured over the standard 90–120 min

scan reflects uptake, decarboxylation to FDA, and trapping of FDA in synaptic vesicles, prolonged scans also reflect the egress and subsequent meta­bolism of this trapped radioactivity. The model used to analyze the acquired radioactivity data thus shifts from one that assumes unidirectional transport of tracer (i.e., the radioactivity is trapped) to a reversible model. The EDV that is derived from this reversible tracer model corre­lates well with the inverse of the ratio of tracer loss to tracer uptake constants (Sossi et al., 2001), which in turn correlates with classical neurochemical mea­sures of DA turnover (Doudet et al., 1998). DA turnover measured using this approach is increased early in PD (Sossi et al., 2002) and further increases occur with disease progression (Sossi et al., 2004). Even when one accounts for disease severity, the magnitude of the abnormality in DA turnover is greater in PD patients with younger disease onset than the abnormality of F-DOPA uptake (Sossi et al., 2006). This suggests that comparable degrees of denervation result in greater increases in DA turnover in younger individuals and is in keeping with the widely held view that such individuals are more prone to dyskinesias (Golbe, 1991; Grandas et al., 1999; Kumar et al., 2005; Quinn et al., 1987). The determinants of DA turnover are not fully

understood. However, it appears that in patients with PD, downregulation of the DAT results in increased turnover, again even after correcting for disease severity (Sossi et al., 2007). One would therefore predict that downregulation of DAT beyond the degree expected based on disease severity (i.e., loss of DA nerve terminals) would be an independent predictor of the development of LID and this indeed appears to be the case (Troiano et al., 2009). Thus, while downregulation of the DAT may serve a useful function in early disease in order to conserve levels of DA in the synapse (Calne and Zigmond, 1991; Lee et al., 2000), in the long run such a compensatory mechanism may prove deleterious. Dyskinesias that occur following fetal mesence­

phalic transplantation may represent a special example, as they may occur either as an

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exaggerated form of LID or in some patients, may occur off medication (Freed et al., 2001; Olanow et al., 2003). Ma and colleagues reported post­operative increases in F-DOPA uptake in the left posterodorsal putamen and left ventral striatum of patients who developed post-transplant dyskinesias (Ma et al., 2002). In contrast, using a combination of F-DOPA and RAC, Piccini et al. found no evidence for increased graft-derived DA release in subjects with dyskinesias (Piccini et al., 2005). Politis et al. (2010) have recently used PET to demonstrate increased serotonergic innervation in the grafted striatum of patients with post-transplant off-medication dyskinesias.

Post-synaptic mechanisms

There is to date no convincing evidence for a clear relationship between the densities of either DA D1 or D2 receptors and motor complications, including dyskinesias, although prolonged treatment is asso­ciated with normalization of D2 receptors in the putamen (increased in untreated patients), reduc­tion of D2 receptors in the caudate nucleus, and possibly with reduction of D1 receptors in the puta­men (Antonini et al., 1997; Turjanski et al., 1997). There is extensive evidence from animal models

of alterations downstream to striatal DA receptors following chronic dopaminergic stimulation, thought to contribute to LID. These include upre­gulation of immediate early genes and of several neuropeptides, including enkephalin and dynorphin (Cenci and Lindgren, 2007). There is very limited evidence available in the imaging literature, largely reflecting the paucity of informative tracers. Piccini and colleagues demonstrated reduced striatal bind­ing of the opioid ligand [11C]diprenorphine in PD patients with LID, presumably reflecting occupancy of striatal opioid receptors due to increased opioid levels (Piccini et al., 1997). Whone and colleagues demonstrated in a preliminary study a reduction in thalamic NK1 neurokinin receptor binding in PD patients with LID (Whone et al., 2002). Whether this represents a loss of NK1 receptors or increased

receptor occupancy reflecting increased availability of endogenous substance P is unclear.

Cerebral blood flow studies

Studies of cerebral blood flow can be used to infer changes in patterns of neuronal activity within the basal ganglia and its connections. In the rest state, tight correlations exist between regional cerebral metabolic rate and blood flow. However, because of their hemodynamic effects, dopaminergic treat­ments may cause a dissociation of these parameters. A large increase in cerebral blood flow following administration of LDOPA has been noted in thala­mus and basal ganglia in PD patients with dyskine­sia (Hershey et al., 1998; Hirano et al., 2008). Because regional cerebral blood flow is thought to predominantly reflect synaptic activity (bearing in mind the above-noted caveat), this finding may be compatible with a sensitized response to levodopa in the internal segment of the globus pallidus and while it is not easily explained by standard “box and arrow” models of the basal ganglia (Albin et al., 1989), it is very much in keeping with the reduction in LID that is consistently reported following palli­dotomy (Fine et al., 2000). Sanchez-Pernaute and colleagues have studied the hemodynamic response to a selective DA D3 receptor agonist using fMRI and found that the response was increased in rodent and non-human primate animals with LID (San­chez-Pernaute et al., 2007), in keeping with in vitro and behavioral evidence (Bezard et al., 2003; Bordet et al., 1997; van Kampen and Stoessl, 2003).

Potential future applications

With the few exceptions noted above, most studies performed to date have focused either on dopami­nergic mechanisms or on patterns of cerebral acti­vation in response to medication. Within the DA system, study of the D3 receptor may be of parti­cular interest, but investigation has been hampered by the lack of selective positron-emitting tracers.

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Other neurotransmitters of interest with respect to their role in LID include 5-hydroxytryptamine, adenosine, excitatory amino acids, and GABA, but there are very few relevant imaging studies, in part reflecting the paucity of informative radioli­gands. Studies of cell signaling pathways and of immediate early gene expression similarly await the development of better tools for in vivo imaging.

Neuroimaging of treatment-related behavioral complications

While a number of other behavioral complications such as depression and cognitive impairment repre­sent a major source of disability in PD, they pre­dominantly reflect manifestations of the underlying disease rather than its therapy and are accordingly not discussed here (but see article by Brooks in this volume). The same is true for hallucinations and other psychotic features, which while potentially induced by medication, are often seen in association with diffuse Lewy body disease. The most impor­tant treatment-induced behavioral side-effect is a group of related problems generally referred to as the impulse control disorders (ICDs). ICD affects approximately 10% of patients treated with dopa­minergic agents, particularly those treated with DA agonists (Evans et al., 2009; Voon et al., 2009) and can include pathological gambling and shopping, hypersexuality, binge eating, punding (repetitive non-goal-oriented behaviors), and compulsive med­ication use. While these behaviors may arise from an interaction between the underlying disease and its treatment, it is of interest that they have also been reported in the setting of DA agonist therapy of Restless Legs Syndrome, a condition where there is little direct evidence of meso-striatal/meso-limbic DA denervation (Tippmann-Peikert et al., 2007). Evans et al. (2006) used RAC PET to estimate levodopa-derived DA release in PD patients with compulsive medication use. In these subjects, DA release was much higher in the ventral striatum compared to PD patients without this complication. In contrast, both groups had comparable DA

release in the putamen. In keeping with other lit­erature on drugs of abuse (Leyton et al., 2002), the degree of DA release correlated with the degree of “drug wanting” rather than the degree of “drug liking”. Steeves et al. (2009) recently used a similar approach to study DA release in PD patients with pathological gambling, but in response to a gam­bling task with monetary reward, compared to a control task. The patients with pathological gam­bling had higher relative DA release in the ventral striatum during performance of the card task. Inter­estingly, however, the levels of RAC binding in the ventral striatum during performance of the control task were much lower in the gambling patients. This may suggest either a higher level of basal DA release in patients with this complication or reduced levels of DA D2/D3 receptors. Support for the latter possibility is derived from animal models of drug abuse, in which impulsive traits are associated with reduced D2/D3 receptor availability in rats (Dalley et al., 2007). In addition to this evidence for sensitized medica­

tion- and task-induced DA release, a key factor in ICD is the failure to stop, despite the conscious recognition of the deleterious effects these behaviors may have on the patient’s life. In this respect, it is relevant that DA release is thought to signal the error between predicted and actual delivery of reward (Schultz, 2001). Thus, dopaminergic therapy, while sufficient to improve the motor deficits seen in PD, cannot mimic the close temporal relationship between reward delivery (or lack thereof) and pha­sic DA release thought to underlie the temporal difference model of learning. This is particularly true for DA agonists, which produce relatively con­stant levels of dopaminergic stimulation. Using func­tional magnetic resonance imaging, van Eimeren and colleagues (Van Eimeren et al., 2009) demon­strated that use of the DA agonist pramipexole resulted in loss of deactivation in orbitofrontal cor­tex in response to negative reward prediction errors. This suggests that in addition to pathologically heightened “reward” responses in the ventral stria­tum of patients with ICD, there is likely to be loss of the capacity to respond to negative outcomes.

187

Concluding comments

Functional imaging with PET can detect DA defi­ciency in PD and correlates loosely with disease severity, particularly with bradykinesia. However, despite its overall utility in assessing disease pro­gression, caution must be used in the interpreta­tion of the results, as disparity between imaging and clinical outcomes has been the rule in most studies of putative disease-modifying therapies. Functional imaging studies may be of particular benefit in studying the pathophysiology of disease and treatment-related complications in PD, parti­cularly studies that take advantage of the dynamic capacity of PET to assess not only the functional integrity of the DA system, but also more detailed aspects of the response to pharmacological and behavioral stimuli known to modify DA release. In the future, the ability to perform analogous studies examining neurotransmitters other than DA should prove similarly fruitful.

Acknowledgments

The authors’ work is supported by the Canadian Institutes of Health Research, the Canada Research Chairs program, the Michael Smith Foundation for Health Research, the Pacific Alzheimer Research Foundation, and the Pacific Parkinsons Research Institute.

List of Abbreviations

PD Parkinson’s disease DA Dopamine LID Levodopa-induced dyskinesia ICD Impulse control disorders RTI Radio tracer imaging PET Positron Emission

Tomography SPECT Single Photon Emission

Computerized Tomography F-DOPA 6-[18F]-fluoro-L-dopa

FDA Fluoro dopamine MPTP 1-methyl-4-phenyl-1,2,3,6­

tetrahydropyridine EDT Effective dopamine turnover EDV Effective dopamine volume DAT dopamine transporter DTBZ [11C]dihydrotetrabenazine VMAT Vesicular monoamine

transporter RAC [11C]raclopride DRT Dopamine replacement

therapy PDRP Parkinson’s disease-related

spatial covariance pattern STN Subthalamic nuclei GPi Globus pallidus interna UPDRS Unified Parkinson’s disease

Rating Scale FDG 18F-fluorodeoxyglucose

References

Ahlskog, J. E. (2003). Slowing Parkinson’s disease progression: Recent dopamine agonist trials. Neurology, 60, 381–389.

Albin, R. L., & Frey, K. A. (2003). Initial agonist treatment of Parkinson disease: A critique. Neurology, 60, 390–394.

Albin, R. L., Young, A. B., & Penney, J. B. (1989). The func­tional anatomy of basal ganglia disorders. Trends in Neu­roscience, 12, 366–375.

Antonini, A., Kazumata, K., Feigin, A., Mandel, F., Dhawan, V., Margouleff, C., et al. (1998). Differential diagnosis of parkinsonism with [18F]fluorodeoxyglucose and PET. Mov­ment Disorder, 13, 268–274.

Antonini, A., Schwarz, J., Oertel, W. H., Pogarell, O., & Leen­ders, K. L. (1997). Long-term changes of striatal dopamine D2 receptors in patients with Parkinson’s disease: A study with positron emission tomography and [11C]raclopride. Movement Disorder, 12, 33–38.

Asanuma, K., Tang, C., Ma, Y., Dhawan, V., Mattis, P., Edwards, C., et al. (2006). Network modulation in the treat­ment of Parkinson’s disease. Brain, 129, 2667–2678.

Au, W. L., Adams, J. R., Troiano, A. R., & Stoessl, A. J. (2005). Parkinson’s disease: in vivo assessment of disease progression using positron emission tomography. Brain Research Molecular Brain Research, 134, 24–33.

188

Avanzi, M., Baratti, M., Cabrini, S., Uber, E., Brighetti, G., & Bonfa, F. (2006). Prevalence of pathological gambling in patients with Parkinson’s disease. Movement Disorder, 21, 2068–2072.

Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K., & Seitelberger, F. (1973). Brain dopamine and the syn­dromes of Parkinson and Huntington. Clinical, morphologi­cal and neurochemical correlations. Journal of Neurological Science, 20, 415–455.

Bezard, E., Dovero, S., Prunier, C., Ravenscroft, P., Chalon, S., Guilloteau, D., et al. (2001). Relationship between the appearance of symptoms and the level of nigrostriatal degen­eration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahy­dropyridine-lesioned macaque model of Parkinson’s disease. Journal of Neuroscience, 21, 6853–6861.

Bezard, E., Ferry, S., Mach, U., Stark, H., Leriche, L., Boraud, T., et al. (2003). Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nature Medicine, 9, 762–767.

Bohnen, N. I., Albin, R. L., Koeppe, R. A., Wernette, K. A., Kilbourn, M. R., Minoshima, S., et al. (2006). Positron emis­sion tomography of monoaminergic vesicular binding in aging and Parkinson disease. Journal of Cerebral Blood Flow and Metabolism, 26, 1198–1212.

Boileau, I., Rusjan, P., Houle, S., Wilkins, D., Tong, J., Selby, P., et al. (2008). Increased vesicular monoamine transporter binding during early abstinence in human methamphetamine users: Is VMAT2 a stable dopamine neuron biomarker? Journal of Neuroscience, 28, 9850–9856.

Bordet, R., Ridray, S., Carboni, S., Diaz, J., Sokoloff, P., & Schwartz, J. C. (1997). Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa. Proceedings of the National Academy of Sciences of the United States of America, 94, 3363–3367.

Braskie, M. N., Wilcox, C. E., Landau, S. M., O’Neil, J. P., Baker, S. L., Madison, C. M., et al. (2008). Relationship of striatal dopamine synthesis capacity to age and cognition. Journal of Neuroscience, 28, 14320–14328.

Breier, A., Su, T. P., Saunders, R., Carson, R. E., Kolachana, B. S., de Bartolomeis, A., et al. (1997). Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method. Proceedings of the National Academy of Sciences of the United States of America, 94, 2569–2574.

Brooks, D. J., Frey, K. A., Marek, K. L., Oakes, D., Paty, D., Prentice, R., et al. (2003). Assessment of neuroimaging tech­niques as biomarkers of the progression of Parkinson’s dis­ease. Experimental Neurology, 184(Suppl 1), S68–S79.

Bruck, A., Aalto, S., Rauhala, E., Bergman, J., Marttila, R., & Rinne, J. O. (2009). A follow-up study on 6-[18F]fluoro-L-dopa uptake in early Parkinson’s disease shows nonlinear progres­sion in the putamen. Movement Disorder, 24, 1009–1015.

Calne, D. B., & Lees, A. J. (1988). Late progression of post­encephalitic Parkinson’s syndrome. Canadian Journal of Neurological Sciences, 15, 135–138.

Calne, D. B., Snow, B. J., & Lee, C. (1992). Criteria for diag­nosing Parkinson’s disease. Annals of Neurology, 32(Suppl), S125–S127.

Calne, D. B., & Zigmond, M. J. (1991). Compensatory mechan­isms in degenerative neurologic diseases. Insights from par­kinsonism. Archives of Neurology, 48, 361–363.

Cenci, M. A., & Lindgren, H. S. (2007). Advances in under­standing L-DOPA-induced dyskinesia. Current Opinion in Neurobiology, 17, 665–671.

Clarke, C. E., & Guttman, M. (2002). Dopamine agonist monotherapy in Parkinson’s disease. Lancet, 360, 1767–1769.

Dalley, J. W., Fryer, T. D., Brichard, L., Robinson, E. S., Theobald, D. E., Laane, K., et al. (2007). Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinfor­cement. Science, 315, 1267–1270.

de Paulis, T. (2003). The discovery of epidepride and its ana­logs as high-affinity radioligands for imaging extrastriatal dopamine D(2) receptors in human brain. Current Pharma­ceutical Design, 9, 673–696.

de Rijk, M. C., Launer, L. J., Berger, K., Breteler, M. M., Dartigues, J. F., Baldereschi, M., et al. (2000). Prevalence of Parkinson’s disease in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology, 54, S21–S23.

Doudet, D. J., Chan, G. L., Holden, J. E., McGeer, E. G., Aigner, T. A., Wyatt, R. J., et al. (1998). 6-[18F]Fluoro-L-DOPA PET studies of the turnover of dopamine in MPTP-induced parkinsonism in monkeys. Synapse, 29, 225– 232.

Eckert, T., & Eidelberg, D. (2005). Neuroimaging and thera­peutics in movement disorders. NeuroRx, 2, 361–371.

Eckert, T., Van Laere, K., Tang, C., Lewis, D. E., Edwards, C., Santens, P., et al. (2007). Quantification of Parkinson’s disease-related network expression with ECD SPECT. European Journal of Nuclear Medicine and Molecular Ima­ging, 34, 496–501.

Eidelberg, D., Takikawa, S., Moeller, J. R., Dhawan, V., Redington, K., Chaly, T., et al. (1993). Striatal hypometabo­lism distinguishes striatonigral degeneration from Parkin­son’s disease. Annals of Neurology, 33, 518–527.

Evans, A. H., Pavese, N., Lawrence, A. D., Tai, Y. F., Appel, S., Doder, M., et al. (2006). Compulsive drug use linked to sensitized ventral striatal dopamine transmission. Annals of Neurology, 59, 852–858.

Evans, A. H., Strafella, A. P., Weintraub, D., & Stacy, M. (2009). Impulsive and compulsive behaviors in Parkinson’s disease. Movement Disorder, 24, 1561–1570.

Fabbrini, G., Brotchie, J. M., Grandas, F., Nomoto, M., & Goetz, C. G. (2007). Levodopa-induced dyskinesias. Move­ment Disorder, 22, 1379–1389.

189

Fahn, S. (1999). Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier vs later L-DOPA. Archives of Neurology, 56, 529–535.

Fahn, S., Oakes, D., Shoulson, I., Kieburtz, K., Rudolph, A., Lang, A., et al. (2004). Levodopa and the progression of Parkinson’s disease. New England Journal of Medicine, 351, 2498–2508.

Fearnley, J. M., & Lees, A. J. (1991). Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain, 114(Pt 5), 2283–2301.

Fine, J., Duff, J., Chen, R., Chir, B., Hutchison, W., Lozano, A. M., et al. (2000). Long-term follow-up of unilateral palli­dotomy in advanced Parkinson’s disease. New England Journal of Medicine, 342, 1708–1714.

Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W. Y., DuMouchel, W., Kao, R., et al. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. New England Journal of Medicine, 344, 710–719.

Frey, K. A., Koeppe, R. A., Kilbourn, M. R., Vander Borght, T. M., Albin, R. L., Gilman, S., et al. (1996). Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Annals of Neurology, 40, 873–884.

Fuente-Fernandez, R., Lu, J. Q., Sossi, V., Jivan, S., Schulzer, M., Holden, J. E., et al. (2001). Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Annals of Neurology, 49, 298–303.

Fuente-Fernandez, R., Pal, P. K., Vingerhoets, F. J., Kishore, A., Schulzer, M., Mak, E. K., et al. (2000). Evidence for impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations. Journal of Neural Transmis­sion, 107, 49–57.

Fuente-Fernandez, R., Sossi, V., Huang, Z., Furtado, S., Lu, J. Q., Calne, D. B., et al. (2004). Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: Implications for dyskinesias. Brain, 127, 2747–2754.

Gill, S. S., Patel, N. K., Hotton, G. R., O’Sullivan, K., McCar­ter, R., Bunnage, M., et al. (2003). Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson dis­ease. Nature Medicine, 9, 589–595.

Golbe, L. I. (1991). Young-onset Parkinson’s disease: A clinical review. Neurology, 41, 168–173.

Grandas, F., Galiano, M. L., & Tabernero, C. (1999). Risk factors for levodopa-induced dyskinesias in Parkinson’s dis­ease. Journal of Neurology, 246, 1127–1133.

Grosset, K. A., Macphee, G., Pal, G., Stewart, D., Watt, A., Davie, J., et al. (2006). Problematic gambling on dopamine agonists: Not such a rarity. Movement Disorder, 21, 2206–2208.

Hersch, S. M., Yi, H., Heilman, C. J., Edwards, R. H., & Levey, A. I. (1997). Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra. Journal of Comparative Neurology, 388, 211–227.

Hershey, T., Black, K. J., Stambuk, M. K., Carl, J. L., McGee-Minnich, L. A., & Perlmutter, J. S. (1998). Altered thalamic response to levodopa in Parkinson’s patients with dopa-induced dyskinesias. Proceedings of the National Academy of Sciences USA, 95, 12016–12021.

Hilker, R., Schweitzer, K., Coburger, S., Ghaemi, M., Weisen­bach, S., Jacobs, A. H., et al. (2005). Nonlinear progression of Parkinson disease as determined by serial positron emis­sion tomographic imaging of striatal fluorodopa F 18 activity. Archives of Neurology, 62, 378–382.

Hirano, S., Asanuma, K., Ma, Y., Tang, C., Feigin, A., Dhawan, V., et al. (2008). Dissociation of metabolic and neurovascular responses to levodopa in the treatment of Parkinson’s dis­ease. Journal of Neuroscience, 28, 4201–4209.

Hornykiewicz, O. (1998). Biochemical aspects of Parkinson’s disease. Neurology, 51, S2–S9.

Huang, C., Tang, C., Feigin, A., Lesser, M., Ma, Y., Pourfar, M., et al. (2007). Changes in network activity with the pro­gression of Parkinson’s disease. Brain, 130, 1834–1846.

Kaasinen, V., Ruottinen, H. M., Nagren, K., Lehikoinen, P., Oikonen, V., & Rinne, J. O. (2000). Upregulation of putam­inal dopamine D2 receptors in early Parkinson’s disease: A comparative PET study with [11C] raclopride and [11C] N-methylspiperone. Journal of Nuclear Medicine, 41, 65–70.

Karlsen, K. H., Larsen, J. P., Tandberg, E., & Maeland, J. G. (1999). Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease. Journal of Neurology, Neurosurgery and Psychiatry, 66, 431–435.

Kraytsberg, Y., Kudryavtseva, E., McKee, A. C., Geula, C., Kowall, N. W., & Khrapko, K. (2006). Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genetics, 38, 518–520.

Kumar, N., Van Gerpen, J. A., Bower, J. H., & Ahlskog, J. E. (2005). Levodopa-dyskinesia incidence by age of Parkinson’s disease onset. Movement Disorder, 20, 342–344.

Lang, A. E., Gill, S., Patel, N. K., Lozano, A., Nutt, J. G., Penn, R., et al. (2006). Randomized controlled trial of intraputa­menal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Annals of Neurology, 59, 459–466.

Lang, A. E., & Obeso, J. A. (2004). Time to move beyond nigrostriatal dopamine deficiency in Parkinson’s disease. Annals of Neurology, 55, 761–765.

Langston, J. W., Forno, L. S., Tetrud, J., Reeves, A. G., Kaplan, J. A., & Karluk, D. (1999). Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Annals of Neurology, 46, 598–605.

Lee, C. S., Samii, A., Sossi, V., Ruth, T. J., Schulzer, M., Holden, J. E., et al. (2000). in vivo positron emission tomo­graphic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Annals of Neurology, 47, 493–503.

190

Leyton, M., Boileau, I., Benkelfat, C., Diksic, M., Baker, G., & Dagher, A. (2002). Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: A PET/[11C]raclopride study in healthy men. Neuropsycho­pharmacology, 27, 1027–1035.

Linazasoro, G., Antonini, A., Maguire, R. P., & Leenders, K. L. (2004). Pharmacological and PET studies in patient’s with Parkinson’s disease and a short duration-motor response: Implications in the pathophysiology of motor com­plications. Journal of Neural Transmission, 111, 497–509.

Ma, Y., Feigin, A., Dhawan, V., Fukuda, M., Shi, Q., Greene, P., et al. (2002). Dyskinesia after fetal cell transplantation for parkinsonism: A PET study. Annals of Neurology, 52, 628–634.

Ma, Y., Tang, C., Spetsieris, P. G., Dhawan, V., & Eidelberg, D. (2007). Abnormal metabolic network activity in Parkin­son’s disease: Test–retest reproducibility. Journal of Cerebral Blood Flow and Metabolism, 27, 597–605.

Marek, K. L., Seibyl, J. P., Zoghbi, S. S., Zea-Ponce, Y., Bald­win, R. M., Fussell, B., et al. (1996). [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology, 46, 231–237.

Marks, W. J., Jr., Ostrem, J. L., Verhagen, L., Starr, P. A., Larson, P. S., Bakay, R. A., et al. (2008). Safety and toler­ability of intraputaminal delivery of CERE-120 (adeno-asso­ciated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: An open-label, phase I trial. Lancet Neurology, 7, 400–408.

McGeer, P. L., Schwab, C., Parent, A., & Doudet, D. (2003). Presence of reactive microglia in monkey substantia nigra years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. Annals of Neurology, 54, 599–604.

Miyasaki, J. M., Al Hassan, K., Lang, A. E., & Voon, V. (2007). Punding prevalence in Parkinson’s disease. Movement Dis­order, 22, 1179–1181.

Morrish, P. K., Rakshi, J. S., Bailey, D. L., Sawle, G. V., & Brooks, D. J. (1998). Measuring the rate of progression and estimating the preclinical period of Parkinson’s disease with [18F]dopa PET. Journal of Neurology, Neurosurgery and Psychiatry, 64, 314–319.

Muchowski, P. J. (2002). Protein misfolding, amyloid forma­tion, and neurodegeneration: A critical role for molecular chaperones? Neuron, 35, 9–12.

Nakamura, T., Dhawan, V., Chaly, T., Fukuda, M., Ma, Y., Breeze, R., et al. (2001). Blinded positron emission tomography study of dopamine cell implantation for Parkinson’s disease. Annals of Neurology, 50, 181–187.

Nandhagopal, R., Kuramoto, L., Schulzer, M., Mak, E., Cragg, J., Lee, C. S., et al. (2009). Longitudinal progression of sporadic Parkinson’s disease: A multi-tracer positron emis­sion tomography study. Brain, 132, 2970–2979.

Nandhagopal, R., McKeown, M. J., & Stoessl, A. J. (2008). Functional imaging in Parkinson disease. Neurology, 70, 1478–1488.

Nirenberg, M. J., Vaughan, R. A., Uhl, G. R., Kuhar, M. J., & Pickel, V. M. (1996). The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. Journal of Neuroscience, 16, 436–447.

Nurmi, E., Bergman, J., Eskola, O., Solin, O., Hinkka, S. M., Sonninen, P., et al. (2000a). Reproducibility and effect of levodopa on dopamine transporter function measurements: A [18F]CFT PET study. Journal of Cerebral Blood Flow and Metabolism, 20, 1604–1609.

Nurmi, E., Bergman, J., Eskola, O., Solin, O., Vahlberg, T., Sonninen, P., et al. (2003). Progression of dopaminergic hypofunction in striatal subregions in Parkinson’s disease using [18F]CFT PET. Synapse, 48, 109–115.

Nurmi, E., Ruottinen, H. M., Bergman, J., Haaparanta, M., Solin, O., Sonninen, P., et al. (2001). Rate of progression in Parkinson’s disease: A 6-[18F]fluoro-L-dopa PET study. Movement Disorder, 16, 608–615.

Nurmi, E., Ruottinen, H. M., Kaasinen, V., Bergman, J., Haaparanta, M., Solin, O., et al. (2000b). Progression in Parkinson’s disease: A positron emission tomography study with a dopamine transporter ligand [18F]CFT. Annals of Neurology, 47, 804–808.

Obeso, J. A., Merello, M., Rodriguez-Oroz, M. C., Marin, C., Guridi, J., & Alvarez, L. (2007). Levodopa-induced dyskine­sias in Parkinson’s disease. Handbook of Clinical Neurology, 84, 185–218.

Olanow, C. W., Goetz, C. G., Kordower, J. H., Stoessl, A. J., Sossi, V., Brin, M. F., et al. (2003). A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Annals of Neurology, 54, 403–414.

Parkinson study group (2000). A randomized controlled trial comparing pramipexole with levodopa in early Parkinson’s disease: Design and methods of the CALM-PD Study. Parkinson Study Group. Clinical Neuropharmacology, 23, 34–44.

Parkinson study group (2002). Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. Journal of the American Med­ical Association, 287, 1653–1661.

Pate, B. D., Kawamata, T., Yamada, T., McGeer, E. G., Hewitt, K. A., Snow, B. J., et al. (1993). Correlation of striatal fluorodopa uptake in the MPTP monkey with dopa­minergic indices. Annals of Neurology, 34, 331–338.

Patlak, C. S., Blasberg, R. G., & Fenstermacher, J. D. (1983). Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Journal of Cerebral Blood Flow and Metabolism, 3, 1–7.

Pavese, N., Evans, A. H., Tai, Y. F., Hotton, G., Brooks, D. J., Lees, A. J., et al. (2006). Clinical correlates of levodopa­induced dopamine release in Parkinson disease: A PET study. Neurology, 67, 1612–1617.

Pezzella, F. R., Colosimo, C., Vanacore, N., Di Rezze, S., Chianese, M., Fabbrini, G., et al. (2005). Prevalence and

191

clinical features of hedonistic homeostatic dysregulation in Parkinson’s disease. Movement Disorder, 20, 77–81.

Piccini, P., Pavese, N., Hagell, P., Reimer, J., Bjorklund, A., Oertel, W. H., et al. (2005). Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain, 128, 2977–2986.

Piccini, P., Weeks, R. A., & Brooks, D. J. (1997). Alterations in opioid receptor binding in Parkinson’s disease patients with levodopa-induced dyskinesias. Annals of Neurology, 42, 720–726.

Pinborg, L. H., Videbaek, C., Ziebell, M., Mackeprang, T., Friberg, L., Rasmussen, H., et al. (2007). [123I]epidepride binding to cerebellar dopamine D2/D3 receptors is displace-able: Implications for the use of cerebellum as a reference region. Neuroimage, 34, 1450–1453.

Pirker, W. (2003). Correlation of dopamine transporter imaging with parkinsonian motor handicap: How close is it? Movement Disorder, 18(Suppl 7), S43–S51.

Politis, M., Wu, K., Loane, C., Quinn, N. P., Brooks, D. J., Rehncrona, S., et al. (2010). Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med, 2, 38–46.

Quinn, N., Critchley, P., & Marsden, C. D. (1987). Young onset Parkinson’s disease. Movement Disorder, 2, 73–91.

Ravina, B., Eidelberg, D., Ahlskog, J. E., Albin, R. L., Brooks, D. J., Carbon, M., et al. (2005). The role of radiotracer imaging in Parkinson disease. Neurology, 64, 208–215.

Rinne, J. O., Laihinen, A., Nagren, K., Bergman, J., Solin, O., Haaparanta, M., et al. (1990). PET demonstrates different behaviour of striatal dopamine D-1 and D-2 receptors in early Parkinson’s disease. Journal of Neuroscience Research, 27, 494–499.

Sanchez-Pernaute, R., Jenkins, B. G., Choi, J. K., Iris Chen, Y. C., & Isacson, O. (2007). in vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with l-DOPA-induced dyskinesias. Neurobiology of Disease, 27, 220–227.

Schapira, A. H., Gu, M., Taanman, J. W., Tabrizi, S. J., Seaton, T., Cleeter, M., et al. (1998). Mitochondria in the etiology and pathogenesis of Parkinson’s disease. Annals of Neurology, 44, S89–S98.

Schrag, A., Jahanshahi, M., & Quinn, N. (2000). What contributes to quality of life in patients with Parkinson’s disease? Journal of Neurology, Neurosurgery and Psychiatry, 69, 308–312.

Schultz, W. (2001). Reward signaling by dopamine neurons. Neuroscientist, 7, 293–302.

Schulzer, M., Lee, C. S., Mak, E. K., Vingerhoets, F. J., & Calne, D. B. (1994). A mathematical model of pathogenesis in idiopathic parkinsonism. Brain, 117(Pt 3), 509–516.

Seeman, P., Guan, H. C., & Niznik, H. B. (1989). Endogenous dopamine lowers the dopamine D2 receptor density as mea­sured by [3H]raclopride: Implications for positron emission tomography of the human brain. Synapse, 3, 96–97.

Seibyl, J. P., Marek, K. L., Quinlan, D., Sheff, K., Zoghbi, S., Zea-Ponce, Y., et al. (1995). Decreased single-photon emis­sion computed tomographic [123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson’s disease. Annals of Neurology, 38, 589–598.

Seibyl, J. P., Marek, K., Sheff, K., Baldwin, R. M., Zoghbi, S., Zea-Ponce, Y., et al. (1997). Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopa­mine transporters in Parkinson’s patients. Journal of Nuclear Medicine, 38, 1453–1459.

Snow, B. J., Tooyama, I., McGeer, E. G., Yamada, T., Calne, D. B., Takahashi, H., et al. (1993). Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Annals of Neurology, 34, 324–330.

Sossi, V., Doudet, D. J., & Holden, J. E. (2001). A reversible tracer analysis approach to the study of effective dopamine turnover. Journal of Cerebral Blood Flow and Metabolism, 21, 469–476.

Sossi, V., Fuente-Fernandez, R., Holden, J. E., Doudet, D. J., McKenzie, J., Stoessl, A. J., et al. (2002). Increase in dopamine turnover occurs early in Parkinson’s disease: Evidence from a new modeling approach to PET 18 F-fluorodopa data. Journal of Cerebral Blood Flow and Metabolism, 22, 232–239.

Sossi, V., Fuente-Fernandez, R., Holden, J. E., Schulzer, M., Ruth, T. J., & Stoessl, J. (2004). Changes of dopamine turn­over in the progression of Parkinson’s disease as measured by positron emission tomography: Their relation to disease-compensatory mechanisms. Journal of Cerebral Blood Flow and Metabolism, 24, 869–876.

Sossi, V., Fuente-Fernandez, R., Schulzer, M., Adams, J., & Stoessl, J. (2006). Age-related differences in levodopa dynamics in Parkinson’s: Implications for motor complica­tions. Brain, 129, 1050–1058.

Sossi, V., Fuente-Fernandez, R., Schulzer, M., Troiano, A. R., Ruth, T. J., & Stoessl, A. J. (2007). Dopamine transporter relation to dopamine turnover in Parkinson’s disease: A positron emission tomography study. Annals of Neurology, 62, 468–474.

Steeves, T. D., Miyasaki, J., Zurowski, M., Lang, A. E., Pellec­chia, G., Van Eimeren, T., et al. (2009). Increased striatal dopamine release in Parkinsonian patients with pathological gambling: A [11C] raclopride PET study. Brain, 132, 1376–1385.

Stoessl, A. J. (2003). Agonizing over dopaminergic replace­ment therapy – lessons from animal models of Parkinson’s disease. Experimental Neurology, 183, 1–3.

Tatton, W. G., Chalmers-Redman, R., Brown, D., & Tatton, N. (2003). Apoptosis in Parkinson’s disease: Signals for neuro­nal degradation. Annals of Neurology, 53(Suppl 3), S61–S70.

Tedroff, J., Pedersen, M., Aquilonius, S. M., Hartvig, P., Jacobsson, G., & Langstrom, B. (1996). Levodopa-induced changes in synaptic dopamine in patients with Parkinson’s

192

disease as measured by [11C]raclopride displacement and PET. Neurology, 46, 1430–1436.

Thobois, S., Vingerhoets, F., Fraix, V., Xie-Brustolin, J., Mollion, H., Costes, N., et al. (2004). Role of dopaminergic treatment in dopamine receptor down-regulation in advanced Parkinson disease: A positron emission tomographic study. Archives of Neurology, 61, 1705–1709.

Tippmann-Peikert, M., Park, J. G., Boeve, B. F., Shepard, J. W., & Silber, M. H. (2007). Pathologic gambling in patients with restless legs syndrome treated with dopaminergic ago­nists. Neurology, 68, 301–303.

Tong, J., Wilson, A. A., Boileau, I., Houle, S., & Kish, S. J. (2008). Dopamine modulating drugs influence striatal (þ)-[11C]DTBZ binding in rats: VMAT2 binding is sensitive to changes in vesicular dopamine concentration. Synapse, 62, 873–876.

Troiano, A. R., Fuente-Fernandez, R., Sossi, V., Schulzer, M., Mak, E., Ruth, T. J., et al. (2009). PET demonstrates reduced dopamine transporter expression in PD with dyskinesias. Neurology, 72, 1211–1216.

Trost, M., Su, S., Su, P., Yen, R. F., Tseng, H. M., Barnes, A., et al. (2006). Network modulation by the subthalamic nucleus in the treatment of Parkinson’s disease. Neuroimage, 31, 301–307.

Turjanski, N., Lees, A. J., & Brooks, D. J. (1997). in vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson’s disease patients with and with­out dyskinesias. Neurology, 49, 717–723.

Van Eimeren, T., Ballanger, B., Pellecchia, G., Miyasaki, J. M., Lang, A. E., & Strafella, A. P. (2009). Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: A trigger for pathological gambling in Parkinson’s disease? Neuropsy­chopharmacology, 34, 2758–2766.

van Kampen, J. M., & Stoessl, A. J. (2003). Effects of oligonu­cleotide antisense to dopamine D3 receptor mRNA in a rodent model of behavioural sensitization to levodopa. Neuroscience, 116, 307–314.

Vander Borght, T. M., Sima, A. A., Kilbourn, M. R., Desmond, T. J., Kuhl, D. E., & Frey, K. A. (1995). [3H] methoxytetrabenazine: A high specific activity ligand for estimating monoaminergic neuronal integrity. Neuroscience, 68, 955–962.

Vingerhoets, F. J., Schulzer, M., Calne, D. B., & Snow, B. J. (1997). Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Annals of Neurology, 41, 58–64.

Volkow, N. D., Ding, Y. S., Fowler, J. S., Wang, G. J., Logan, J., Gatley, S. J., et al. (1995). A new PET ligand for the dopamine transporter: Studies in the human brain. Journal of Nuclear Medicine, 36, 2162–2168.

Volkow, N. D., Fowler, J. S., Wang, G. J., Logan, J., Schlyer, D., MacGregor, R., et al. (1994). Decreased dopamine trans­porters with age in healthy human subjects. Annals of Neu­rology, 36, 237–239.

Voon, V., Fernagut, P. O., Wickens, J., Baunez, C., Rodriguez, M., Pavon, N., et al. (2009). Chronic dopaminergic stimula­tion in Parkinson’s disease: From dyskinesias to impulse control disorders. Lancet Neurology, 8, 1140–1149.

Voon, V., Hassan, K., Zurowski, M., de Souza, M., Thomsen, T., Fox, S., et al. (2006). Prevalence of repetitive and reward-seeking behaviors in Parkinson disease. Neurology, 67, 1254–1257.

Weintraub, D., Siderowf, A. D., Potenza, M. N., Goveas, J., Morales, K. H., Duda, J. E., et al. (2006). Association of dopamine agonist use with impulse control disorders in Par­kinson disease. Archives of Neurology, 63, 969–973.

Whone, A. L., Rabiner, E. A., Arahata, Y., Luthra, S. K., Hargreaves, R., Brooks, D. J. (2002). Reduced substance P binding in Parkinson’s disease complicated by dyskinesias: An 18F-L829165 PET study [abstract]. Neurology, 58, A488–A489.

Whone, A. L., Watts, R. L., Stoessl, A. J., Davis, M., Reske, S., Nahmias, C., et al. (2003). Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Annals of Neurology, 54, 93–101.