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Monitoring therapeutic effects in Parkinson's disease by serial imaging of the nigrostriatal dopaminergic pathway
Journal of the Neurological Sciences 310 (2011) 40–43
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Monitoring therapeutic effects in Parkinson's disease by serial imaging of the nigrostriatal dopaminergic pathway Jan Booij a,⁎, Henk W. Berendse b a b
Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, The Netherlands Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 14 March 2011 Received in revised form 3 June 2011 Accepted 19 July 2011 Available online 15 August 2011 Keywords: Parkinson's disease Dopamine PET SPECT Progression
a b s t r a c t PET and SPECT are very sensitive techniques to detect in-vivo nigrostriatal degeneration in Parkinson's disease, even in the pre-motor phase of the disease. Furthermore, these techniques are able to measure disease progression. However, caution must be used in the interpretation of studies in which therapeutic effects in Parkinson's disease were also monitored by serial imaging of nigrostriatal neurons, as disparity between imaging and clinical outcomes has been reported in several clinical studies. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Parkinson's disease (PD) is characterized by severe loss of dopaminergic nigrostriatal neurons. The scintigraphic tools positron emission tomography (PET) and single photon emission tomography (SPECT) offer unique means to assess the in-vivo integrity of the nigrostriatal pathway. At present, different molecular aspects of this pathway have been imaged successfully in PD patients. Firstly, the PET 18 tracer DOPA (DOPA is commonly labeled with [ F] but in some clinical 11 studies with [ C]), provides a measure of the structural and biochemical integrity of presynaptic dopaminergic neurons (for a review see Ref. [1]). After the radiotracer has been taken up in dopaminergic neurons it is decarboxylated (by L-amino acid decarboxylase; AADC) to fluorodopamine and then temporarily stored in vesicles within the nerve terminals. Therefore, DOPA uptake reflects a regulated aspect of presynaptic dopamine synthesis. Secondly, the 18 radiotracer [ F]fluoro-L-m-tyrosine (FMT) has been developed successfully. This radiotracer is similar to DOPA in that both radioligands are substrates of AADC. However, unlike DOPA, FMT is not a substrate for the enzyme catechol-O-methyl-transferase (COMT) which plays a crucial role in the breakdown of dopamine. Therefore, there are no metabolites to contribute to radioactive metabolites that may cause non-specific uptake, which improves contrast and simplifies kinetic modeling [2]. Thirdly, radiotracers (radiolabeled tetrabenazine de⁎ Corresponding author at: Department of Nuclear Medicine, F2N, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: + 31 20 5662397; fax: + 31 20 5669092. E-mail address: [email protected] (J. Booij). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.029
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rivatives like [ C]DTBZ or [ F]AV-133; [3,4]) have been developed for PET imaging to assess the expression of vesicular monoamine transporters (VMAT-2; the VMAT-2 is expressed exclusively in brain), which are located on the membrane of vesicles (for a review see Ref. [1]). Finally, PET as well as SPECT tracers (particularly 11 123 radiolabeled cocaine derivatives like [ C]PE2I or [ I]FP-CIT; [5,6]) have been developed successfully to image the dopamine transporter (DAT) (for a review see Ref. [1]). Since the DAT is expressed exclusively in the terminals of dopaminergic neurons, it is considered as a marker of terminals of dopaminergic nigrostriatal neurons. In agreement with necropsy data, DOPA PET, FMT PET, VMAT-2 PET as well as DAT imaging studies (PET and SPECT) consistently showed an anterior–posterior gradient of loss of uptake in the striatum in sporadic PD patients, with side-to-side asymmetry in striatal uptake [3,5,7,8]. Moreover, DOPA PET and DAT SPECT are sensitive enough to detect a loss of nigrostriatal neurons in-vivo even in preclinical phases of sporadic PD [9–12]. 2. Monitoring disease progression in PD Clinicopathological observations suggest that the relationship between PD disease duration and the loss of nigral neurons is not linear [13]. Indeed, also imaging studies suggested that progression of putaminal dopaminergic hypofunction in early PD follows a nonlinear pattern [4]. Longitudinal imaging studies have shown greater loss of nigrostriatal neurons than the loss associated with natural 18 aging. In addition, the mean annual rate of decline in striatal [ F]DOPA uptake, or the rate of loss of striatal DATs in PD patients is larger in the putamen than in the caudate nucleus [14–19]. Finally, the rate of
J. Booij, H.W. Berendse / Journal of the Neurological Sciences 310 (2011) 40–43
progression may be faster in atypical parkinsonian syndromes than in sporadic PD [18]. The reliability of PET and SPECT in assessing progression of dopamine neuron loss in sporadic PD has been questioned. In early 18 stages of PD, [ F]DOPA uptake might underestimate the severity of the nigrostriatal degeneration, as compensatory mechanisms, such as an upregulation of decarboxylase activity, may occur in the remaining terminals. Alternatively, the expression of DAT might be upregulated, also as a compensatory mechanism, while VMAT-2 expression might not be affected to the same extent by such compensatory mechanisms [3,19,20]. Furthermore, although test–retest studies show relatively good reproducibility scores for both DOPA uptake and DAT binding, one has to take into account that such studies typically evaluate the reproducibility by repeated measurements in the same PD subjects within a small time-frame (typically test/retest scans in the same subject will be acquired within a time-frame of several weeks [21,22]). However, repeated scans in progression studies are generally not acquired within such short time-frames. Consequently, this may increase the likelihood that factors that can influence the expression of molecular markers of the nigrostriatal pathway have changed. Of note, also non-dopaminergic drugs may influence the quantification of e.g., DAT imaging studies (for a review see Ref. [23]). Furthermore, DOPA uptake may be affected by seasonal variation. More specifically, a recent study performed in healthy volunteers reported significantly 18 greater [ F]FDOPA uptake in the putamen in the fall/winter period relative to the spring/summer period [24]. Consequently, to improve the accuracy of measuring progression of dopamine neuron loss in sporadic PD, attention should be paid to potential medication effects (also of non-dopaminergic drugs) and repeat scans should always be acquired in the same season. 2.1. Serial imaging of the nigrostriatal pathway to assess the effects of pharmacological treatment with dopaminomimetics on disease progression There is a need for a biomarker to monitor disease progression in PD, as novel neuroprotective therapies are being developed. In several studies imaging of the nigrostriatal pathway has been used as an in-vivo marker. However, some of these studies showed discordant results between clinical progression data and disease progression as assessed with imaging. The so-called ELLDOPA study assessed the effect of L-DOPA treatment in PD [25]. Early stage PD patients were randomized to either placebo or L-DOPA for 40 weeks. The change in clinical severity, as measured using UPDRS motor scores, was assessed from baseline to week 42 (40 weeks of treatment with L-DOPA/placebo and 2 weeks of washout). A subset of patients underwent DAT SPECT to assess the percentage change in striatal DAT binding between baseline and week 40 (while on treatment). Unfortunately, clinical and imaging outcomes were contradictory; while L-DOPA treatment improved the clinical scores, the percentage decrease in striatal DAT binding was significantly greater with L-DOPA than with placebo. A variety of factors may explain this disparity between imaging and clinical outcomes. However, considering that the symptomatic effect of L-DOPA is long-lasting, it is most likely that the washout period in this study was too short, causing the apparent effect on the clinical outcomes [26]. Regarding the decrease in DAT binding, the authors stated that they could not exclude the possibility that L-DOPA simply down-regulates the DAT [25]. Contrary, the majority of experimental studies did not find a significant pharmacological effect of L-DOPA treatment on DAT binding (for a review see Ref. [23]). The presumed neuroprotective properties of dopamine receptor agonists in PD have been investigated in a number of clinical trials. In the so-called CALM-PD study, early PD patients were randomized to the dopamine agonist pramipexole or L-DOPA [27]. Repeated DAT SPECT imaging was performed at baseline and again up to 46 months later. At follow-up, patients initially treated with pramipexole had a
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significantly smaller decrease in striatal DAT binding than those treated with L-DOPA. Also, the percentage reduction in striatal DAT binding did not correlate significantly with changes in clinical scores (UPDRS measured 12 h off PD medications). In the so-called REAL-PET study, early PD patients were randomized to the agonist ropinirole or L-DOPA and assessed over a period of 2 years [28]. The rate of decline 18 of putaminal [ F]DOPA uptake was significantly lower with ropinirole than with L-DOPA. Clinical improvement, however, based on UPDRS (measured while on treatment), favored the L-DOPA group. Since the symptomatic effects of L-DOPA are greater than that of ropinirole, this may have caused the disparity between imaging and clinical outcomes. Furthermore, in both studies the authors stated that they could not exclude that the agonists and L-DOPA may directly and differentially affect DAT binding/DOPA uptake, but again the majority of experimental data do not support this statement (for a review see Ref. [23] and Refs. [27,28]). Finally, in the so-called PELMOPET trial, the dopamine receptor agonist pergolide was evaluated versus L-DOPA in early PD patients 18 over 3 years [29]. Similar decreases in mean putaminal [ F]DOPA uptake were observed in the two groups under study, with a trend in favor of pergolide. The interpretation of the findings is hard because of the lack of a placebo-treated group, and because a neurotoxic effect of L-DOPA could not be excluded. 2.2. Serial imaging of the nigrostriatal pathway and the effects of deep brain stimulation It has been suggested that glutamate-mediated excitotoxicity of the subthalamic nucleus (STN) may contribute to nigral degeneration in PD (see Ref. [30]). Deep brain stimulation of the STN (STN DBS) may inhibit STN hyperactivity and therefore decrease progression of PD. A clinical trial revealed, however, a continuous decline of dopaminergic 18 neurons (as assessed with [ F]DOPA PET) in patients with advanced PD under clinically effective bilateral STN stimulation. The authors argued that the rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD, and that, consequently, this study did not confirm the neuroprotective properties of DBS in the STN [30]. The results of another DAT SPECT imaging study also argued against a neuroprotective effect of STN stimulation in PD [31]. 2.3. Serial imaging to assess the effects of neurotrophic factors, gene therapy and transplantation on disease progression in PD Administration of neurotrophic factors is another approach that is being used to try to prevent disease progression in PD. Glial cell linederived neurotrophic factor (GDNF) is a neurotrophic factor that stimulates embryonic stem cells to differentiate into dopaminergic cells. In a small open-label trial, bilateral putaminal infusion of GDNF was continuously administered to five patients with PD. After 1 year of treatment, the patients showed a significant improvement of UPDRS score, and PET studies revealed a significant postoperative 18 increase in putaminal [ F]DOPA uptake [32]. However, a more recent randomized placebo-controlled study in a larger number of patients failed to show any significant clinical benefit of this procedure [33]. In 18 spite of the lack of a clinical effect, there was an increase in [ F]DOPA uptake in the putamen. Possibly, GDNF induces terminal sprouting of dopaminergic cells in PD putamen, but without restoring synaptic functioning. Gene transfer is yet another emerging therapy for PD. Gene therapy by intraputaminal stereotactic delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) has recently been evaluated in a phase I open-label trial in 12 advanced-stage PD patients [34]. Neurturin is a naturally occurring structural and functional analog of GDNF. While several measures of motor function showed improvement 1 year after 18 treatment onset, no significant changes from baseline in striatal [ F]
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DOPA PET uptake were observed [34]. A larger double-blind, phase II randomized trial in 58 PD patients failed to confirm that intraputaminal delivery of neurturin is superior to sham surgery when assessed using the UPDRS motor score at 12 months [35]. The effect of gene transfer of dopamine-synthesizing enzymes into the striatum has also been evaluated as therapy for PD [8,36]. Recently, the safety, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of AADC into the putamen of PD patients was reported. Small groups of PD patients were evaluated at baseline as 18 well as 6 months later, including clinical outcomes (UPDRS) and [ F] FMT PET. Six months after surgery, motor function was improved and PET revealed a significant increase in FMT uptake [8,36], which may persist up to 96 weeks from baseline [8]. Preliminary analysis of these data suggests both a clinical and imaging improvement, but absence of a control condition makes interpretation difficult [36]. Transplantation of human embryonic dopaminergic neurons bilaterally into the putamen of advanced PD patients has been evaluated in controlled clinical trials. The transplants survived, as indicated by an 18 increase in [ F]DOPA uptake or postmortem examination, and resulted in some clinical benefit in younger but not in older patients [37]. Unfortunately, after an initial improvement in the first year, dystonia and dyskinesias recurred in a substantial subgroup of patients who received transplants. A recent study [38], reported on the long-term clinical and PET outcomes from many of the original trial participants who were followed for 2 years after transplantation. Approximately half of the participants were even followed for 2 additional years. The results suggest that clinical benefit and graft viability are sustained up to 4 years after transplantation. Moreover, the imaging changes reliably correlated with clinical outcome over the entire posttransplantation time course. In 18 another imaging study, striatal [ F]DOPA uptake was directly compared with DAT PET in 6 patients with PD grafted with fetal mesencephalic cells [39]. There was no significant change in DAT ligand binding in the 18 grafted putamen despite a significant increase of [ F]DOPA uptake. This finding suggests that the clinical benefit induced by the graft is more related to increased dopaminergic activity (within dopaminergic terminals?) (measured with DOPA PET) than to improved dopaminergic innervation (measured with DAT imaging). In contrast to these findings, a DAT SPECT study performed in two PD patients who had undergone bilateral intrastriatal transplantation of human embryonic mesencephalic tissue showed increases of DAT striatal binding up to 3 years after implantation in one patient and up to 8 years after transplantation in the other [40]. Clinically, both patients experienced a moderate improvement in motor performance, but also developed moderate to severe offmedication dyskinesias.
3. Concluding remarks Taken together, imaging of the nigrostriatal pathway with PET or SPECT is a sensitive technique to detect and monitor nigrostriatal degeneration in PD. However, in spite of this, caution must be used in the interpretation of results, as disparities between imaging data and clinical outcomes have been reported frequently in clinical trials. In some studies, this disparity could be explained because clinical motor performance was assessed while the patients were on a drug with symptomatic properties [28] or because the wash-out period of the drug was probably too short [27]. The disparity between clinical and imaging data in studies focusing on GDNF or transplantation might be explained by induction of sprouting of dopaminergic cells without restoring synaptic functioning [41]. Furthermore, in vivo markers of the dopaminergic nigrostriatal system not necessarily reflect density of nigrostriatal cells, whereas clinical measures (such as UPDRS) may reflect dopaminergic as well as non-dopaminergic dysfunctions. Therefore, the results of progression studies in PD, in which imaging of the dopaminergic system is used in parallel with clinical assessments, should be interpreted with caution, taking into account
the potential drawbacks of both the clinical as well as the imaging outcomes.
Conflict of interest J.B. is consultant at GE Healthcare. H.W.B. reported no conflict of interest.
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Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Monitoring therapeutic effects in Parkinson's disease by serial imaging of the nigrostriatal dopaminergic pathway Jan Booij a,⁎, Henk W. Berendse b a b
Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, The Netherlands Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 14 March 2011 Received in revised form 3 June 2011 Accepted 19 July 2011 Available online 15 August 2011 Keywords: Parkinson's disease Dopamine PET SPECT Progression
a b s t r a c t PET and SPECT are very sensitive techniques to detect in-vivo nigrostriatal degeneration in Parkinson's disease, even in the pre-motor phase of the disease. Furthermore, these techniques are able to measure disease progression. However, caution must be used in the interpretation of studies in which therapeutic effects in Parkinson's disease were also monitored by serial imaging of nigrostriatal neurons, as disparity between imaging and clinical outcomes has been reported in several clinical studies. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Parkinson's disease (PD) is characterized by severe loss of dopaminergic nigrostriatal neurons. The scintigraphic tools positron emission tomography (PET) and single photon emission tomography (SPECT) offer unique means to assess the in-vivo integrity of the nigrostriatal pathway. At present, different molecular aspects of this pathway have been imaged successfully in PD patients. Firstly, the PET 18 tracer DOPA (DOPA is commonly labeled with [ F] but in some clinical 11 studies with [ C]), provides a measure of the structural and biochemical integrity of presynaptic dopaminergic neurons (for a review see Ref. [1]). After the radiotracer has been taken up in dopaminergic neurons it is decarboxylated (by L-amino acid decarboxylase; AADC) to fluorodopamine and then temporarily stored in vesicles within the nerve terminals. Therefore, DOPA uptake reflects a regulated aspect of presynaptic dopamine synthesis. Secondly, the 18 radiotracer [ F]fluoro-L-m-tyrosine (FMT) has been developed successfully. This radiotracer is similar to DOPA in that both radioligands are substrates of AADC. However, unlike DOPA, FMT is not a substrate for the enzyme catechol-O-methyl-transferase (COMT) which plays a crucial role in the breakdown of dopamine. Therefore, there are no metabolites to contribute to radioactive metabolites that may cause non-specific uptake, which improves contrast and simplifies kinetic modeling [2]. Thirdly, radiotracers (radiolabeled tetrabenazine de⁎ Corresponding author at: Department of Nuclear Medicine, F2N, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: + 31 20 5662397; fax: + 31 20 5669092. E-mail address: [email protected] (J. Booij). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.07.029
11
18
rivatives like [ C]DTBZ or [ F]AV-133; [3,4]) have been developed for PET imaging to assess the expression of vesicular monoamine transporters (VMAT-2; the VMAT-2 is expressed exclusively in brain), which are located on the membrane of vesicles (for a review see Ref. [1]). Finally, PET as well as SPECT tracers (particularly 11 123 radiolabeled cocaine derivatives like [ C]PE2I or [ I]FP-CIT; [5,6]) have been developed successfully to image the dopamine transporter (DAT) (for a review see Ref. [1]). Since the DAT is expressed exclusively in the terminals of dopaminergic neurons, it is considered as a marker of terminals of dopaminergic nigrostriatal neurons. In agreement with necropsy data, DOPA PET, FMT PET, VMAT-2 PET as well as DAT imaging studies (PET and SPECT) consistently showed an anterior–posterior gradient of loss of uptake in the striatum in sporadic PD patients, with side-to-side asymmetry in striatal uptake [3,5,7,8]. Moreover, DOPA PET and DAT SPECT are sensitive enough to detect a loss of nigrostriatal neurons in-vivo even in preclinical phases of sporadic PD [9–12]. 2. Monitoring disease progression in PD Clinicopathological observations suggest that the relationship between PD disease duration and the loss of nigral neurons is not linear [13]. Indeed, also imaging studies suggested that progression of putaminal dopaminergic hypofunction in early PD follows a nonlinear pattern [4]. Longitudinal imaging studies have shown greater loss of nigrostriatal neurons than the loss associated with natural 18 aging. In addition, the mean annual rate of decline in striatal [ F]DOPA uptake, or the rate of loss of striatal DATs in PD patients is larger in the putamen than in the caudate nucleus [14–19]. Finally, the rate of
J. Booij, H.W. Berendse / Journal of the Neurological Sciences 310 (2011) 40–43
progression may be faster in atypical parkinsonian syndromes than in sporadic PD [18]. The reliability of PET and SPECT in assessing progression of dopamine neuron loss in sporadic PD has been questioned. In early 18 stages of PD, [ F]DOPA uptake might underestimate the severity of the nigrostriatal degeneration, as compensatory mechanisms, such as an upregulation of decarboxylase activity, may occur in the remaining terminals. Alternatively, the expression of DAT might be upregulated, also as a compensatory mechanism, while VMAT-2 expression might not be affected to the same extent by such compensatory mechanisms [3,19,20]. Furthermore, although test–retest studies show relatively good reproducibility scores for both DOPA uptake and DAT binding, one has to take into account that such studies typically evaluate the reproducibility by repeated measurements in the same PD subjects within a small time-frame (typically test/retest scans in the same subject will be acquired within a time-frame of several weeks [21,22]). However, repeated scans in progression studies are generally not acquired within such short time-frames. Consequently, this may increase the likelihood that factors that can influence the expression of molecular markers of the nigrostriatal pathway have changed. Of note, also non-dopaminergic drugs may influence the quantification of e.g., DAT imaging studies (for a review see Ref. [23]). Furthermore, DOPA uptake may be affected by seasonal variation. More specifically, a recent study performed in healthy volunteers reported significantly 18 greater [ F]FDOPA uptake in the putamen in the fall/winter period relative to the spring/summer period [24]. Consequently, to improve the accuracy of measuring progression of dopamine neuron loss in sporadic PD, attention should be paid to potential medication effects (also of non-dopaminergic drugs) and repeat scans should always be acquired in the same season. 2.1. Serial imaging of the nigrostriatal pathway to assess the effects of pharmacological treatment with dopaminomimetics on disease progression There is a need for a biomarker to monitor disease progression in PD, as novel neuroprotective therapies are being developed. In several studies imaging of the nigrostriatal pathway has been used as an in-vivo marker. However, some of these studies showed discordant results between clinical progression data and disease progression as assessed with imaging. The so-called ELLDOPA study assessed the effect of L-DOPA treatment in PD [25]. Early stage PD patients were randomized to either placebo or L-DOPA for 40 weeks. The change in clinical severity, as measured using UPDRS motor scores, was assessed from baseline to week 42 (40 weeks of treatment with L-DOPA/placebo and 2 weeks of washout). A subset of patients underwent DAT SPECT to assess the percentage change in striatal DAT binding between baseline and week 40 (while on treatment). Unfortunately, clinical and imaging outcomes were contradictory; while L-DOPA treatment improved the clinical scores, the percentage decrease in striatal DAT binding was significantly greater with L-DOPA than with placebo. A variety of factors may explain this disparity between imaging and clinical outcomes. However, considering that the symptomatic effect of L-DOPA is long-lasting, it is most likely that the washout period in this study was too short, causing the apparent effect on the clinical outcomes [26]. Regarding the decrease in DAT binding, the authors stated that they could not exclude the possibility that L-DOPA simply down-regulates the DAT [25]. Contrary, the majority of experimental studies did not find a significant pharmacological effect of L-DOPA treatment on DAT binding (for a review see Ref. [23]). The presumed neuroprotective properties of dopamine receptor agonists in PD have been investigated in a number of clinical trials. In the so-called CALM-PD study, early PD patients were randomized to the dopamine agonist pramipexole or L-DOPA [27]. Repeated DAT SPECT imaging was performed at baseline and again up to 46 months later. At follow-up, patients initially treated with pramipexole had a
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significantly smaller decrease in striatal DAT binding than those treated with L-DOPA. Also, the percentage reduction in striatal DAT binding did not correlate significantly with changes in clinical scores (UPDRS measured 12 h off PD medications). In the so-called REAL-PET study, early PD patients were randomized to the agonist ropinirole or L-DOPA and assessed over a period of 2 years [28]. The rate of decline 18 of putaminal [ F]DOPA uptake was significantly lower with ropinirole than with L-DOPA. Clinical improvement, however, based on UPDRS (measured while on treatment), favored the L-DOPA group. Since the symptomatic effects of L-DOPA are greater than that of ropinirole, this may have caused the disparity between imaging and clinical outcomes. Furthermore, in both studies the authors stated that they could not exclude that the agonists and L-DOPA may directly and differentially affect DAT binding/DOPA uptake, but again the majority of experimental data do not support this statement (for a review see Ref. [23] and Refs. [27,28]). Finally, in the so-called PELMOPET trial, the dopamine receptor agonist pergolide was evaluated versus L-DOPA in early PD patients 18 over 3 years [29]. Similar decreases in mean putaminal [ F]DOPA uptake were observed in the two groups under study, with a trend in favor of pergolide. The interpretation of the findings is hard because of the lack of a placebo-treated group, and because a neurotoxic effect of L-DOPA could not be excluded. 2.2. Serial imaging of the nigrostriatal pathway and the effects of deep brain stimulation It has been suggested that glutamate-mediated excitotoxicity of the subthalamic nucleus (STN) may contribute to nigral degeneration in PD (see Ref. [30]). Deep brain stimulation of the STN (STN DBS) may inhibit STN hyperactivity and therefore decrease progression of PD. A clinical trial revealed, however, a continuous decline of dopaminergic 18 neurons (as assessed with [ F]DOPA PET) in patients with advanced PD under clinically effective bilateral STN stimulation. The authors argued that the rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD, and that, consequently, this study did not confirm the neuroprotective properties of DBS in the STN [30]. The results of another DAT SPECT imaging study also argued against a neuroprotective effect of STN stimulation in PD [31]. 2.3. Serial imaging to assess the effects of neurotrophic factors, gene therapy and transplantation on disease progression in PD Administration of neurotrophic factors is another approach that is being used to try to prevent disease progression in PD. Glial cell linederived neurotrophic factor (GDNF) is a neurotrophic factor that stimulates embryonic stem cells to differentiate into dopaminergic cells. In a small open-label trial, bilateral putaminal infusion of GDNF was continuously administered to five patients with PD. After 1 year of treatment, the patients showed a significant improvement of UPDRS score, and PET studies revealed a significant postoperative 18 increase in putaminal [ F]DOPA uptake [32]. However, a more recent randomized placebo-controlled study in a larger number of patients failed to show any significant clinical benefit of this procedure [33]. In 18 spite of the lack of a clinical effect, there was an increase in [ F]DOPA uptake in the putamen. Possibly, GDNF induces terminal sprouting of dopaminergic cells in PD putamen, but without restoring synaptic functioning. Gene transfer is yet another emerging therapy for PD. Gene therapy by intraputaminal stereotactic delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) has recently been evaluated in a phase I open-label trial in 12 advanced-stage PD patients [34]. Neurturin is a naturally occurring structural and functional analog of GDNF. While several measures of motor function showed improvement 1 year after 18 treatment onset, no significant changes from baseline in striatal [ F]
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DOPA PET uptake were observed [34]. A larger double-blind, phase II randomized trial in 58 PD patients failed to confirm that intraputaminal delivery of neurturin is superior to sham surgery when assessed using the UPDRS motor score at 12 months [35]. The effect of gene transfer of dopamine-synthesizing enzymes into the striatum has also been evaluated as therapy for PD [8,36]. Recently, the safety, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of AADC into the putamen of PD patients was reported. Small groups of PD patients were evaluated at baseline as 18 well as 6 months later, including clinical outcomes (UPDRS) and [ F] FMT PET. Six months after surgery, motor function was improved and PET revealed a significant increase in FMT uptake [8,36], which may persist up to 96 weeks from baseline [8]. Preliminary analysis of these data suggests both a clinical and imaging improvement, but absence of a control condition makes interpretation difficult [36]. Transplantation of human embryonic dopaminergic neurons bilaterally into the putamen of advanced PD patients has been evaluated in controlled clinical trials. The transplants survived, as indicated by an 18 increase in [ F]DOPA uptake or postmortem examination, and resulted in some clinical benefit in younger but not in older patients [37]. Unfortunately, after an initial improvement in the first year, dystonia and dyskinesias recurred in a substantial subgroup of patients who received transplants. A recent study [38], reported on the long-term clinical and PET outcomes from many of the original trial participants who were followed for 2 years after transplantation. Approximately half of the participants were even followed for 2 additional years. The results suggest that clinical benefit and graft viability are sustained up to 4 years after transplantation. Moreover, the imaging changes reliably correlated with clinical outcome over the entire posttransplantation time course. In 18 another imaging study, striatal [ F]DOPA uptake was directly compared with DAT PET in 6 patients with PD grafted with fetal mesencephalic cells [39]. There was no significant change in DAT ligand binding in the 18 grafted putamen despite a significant increase of [ F]DOPA uptake. This finding suggests that the clinical benefit induced by the graft is more related to increased dopaminergic activity (within dopaminergic terminals?) (measured with DOPA PET) than to improved dopaminergic innervation (measured with DAT imaging). In contrast to these findings, a DAT SPECT study performed in two PD patients who had undergone bilateral intrastriatal transplantation of human embryonic mesencephalic tissue showed increases of DAT striatal binding up to 3 years after implantation in one patient and up to 8 years after transplantation in the other [40]. Clinically, both patients experienced a moderate improvement in motor performance, but also developed moderate to severe offmedication dyskinesias.
3. Concluding remarks Taken together, imaging of the nigrostriatal pathway with PET or SPECT is a sensitive technique to detect and monitor nigrostriatal degeneration in PD. However, in spite of this, caution must be used in the interpretation of results, as disparities between imaging data and clinical outcomes have been reported frequently in clinical trials. In some studies, this disparity could be explained because clinical motor performance was assessed while the patients were on a drug with symptomatic properties [28] or because the wash-out period of the drug was probably too short [27]. The disparity between clinical and imaging data in studies focusing on GDNF or transplantation might be explained by induction of sprouting of dopaminergic cells without restoring synaptic functioning [41]. Furthermore, in vivo markers of the dopaminergic nigrostriatal system not necessarily reflect density of nigrostriatal cells, whereas clinical measures (such as UPDRS) may reflect dopaminergic as well as non-dopaminergic dysfunctions. Therefore, the results of progression studies in PD, in which imaging of the dopaminergic system is used in parallel with clinical assessments, should be interpreted with caution, taking into account
the potential drawbacks of both the clinical as well as the imaging outcomes.
Conflict of interest J.B. is consultant at GE Healthcare. H.W.B. reported no conflict of interest.
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