Dopaminergic Function and Dopamine Transporter Binding Assessed with Positron Emission Tomography in Parkinson Disease

ORIGINAL CONTRIBUTION Dopaminergic Function and Dopamine Transporter Binding Assessed With Positron Emission Tomography in Parkinson Disease

Maria-Joao Ribeiro, MD, PhD; Marie Vidailhet, MD; Christian Loc’h, BS; Corinne Dupel, MD; Jean Paul Nguyen, MD; Michel Ponchant, BS; Fre´de´ric Dolle´, PhD; Marc Peschanski, MD, PhD; Philippe Hantraye, PhD; Pierre Cesaro, MD, PhD; Yves Samson, MD; Philippe Remy, MD, PhD

Background: Measuring progression of Parkinson dis- Results: The reduction in 76Br-FE-CBT binding to 43% ease (PD) using positron emission tomography may help of control values was more severe than the reduction in demonstrate the efficacy of neuroprotective treatments. To 18F-dopa uptake (63% of control values) in the putamen date, 18F-dopa has been the gold standard to measure pre- of patients with early PD. No significant difference was synaptic dopaminergic function in PD, but this tracer might found between either tracer’s uptake in the putamen of overestimate the rate of neuronal death in PD because its patients with advanced PD. Motor performance was highly uptake also depends on dopamine turnover rather than ex- correlated to 18F-dopa uptake, whereas correlation to 76Br- clusively on the density of dopaminergic terminals in the FE-CBT binding was weak. striatum. The latter might be assessed using newly developed ligands of the membrane dopamine transporter. Conclusions: Uptake of 18F-dopa may be up-regulated in early PD, suggesting a compensatory increase of do- Objective: To compare the striatal uptakes of 18F-dopa pamine synthesis in surviving dopaminergic terminals. and 76Br-FE-CBT, a dopamine transporter ligand, in pa- Positron emission tomography dopamine transporter tients with PD. ligands and 18F-dopa give complementary information on the presynaptic status of the nigrostriatal dopamin- Patients and Methods: The striatal uptakes of 76Br- ergic system and might be associated to investigate the FE-CBT and 18F-dopa were compared using positron emis- efficacy of neuroprotective treatments in PD. sion tomography in 10 patients with early PD and 8 with advanced PD. Correlation of uptakes with motor performance was investigated. Arch Neurol. 2002;59:580-586

VALUATING neuroprotec- paminergic synapses was partially com- tive treatments designed to pensated for by increased dopamine me- slow down the progressive tabolism in the surviving terminals (for loss of dopaminergic neu- review see Zigmond et al,9 Hornykie- rons is a crucial step for the wicz,10 and Bezard and Gross11). Thus, developmentE of therapeutic strategies in 18F-dopa uptake might overestimate the Parkinson disease (PD). A major draw- number of striatal dopaminergic nerve ter- back faced by previous neuroprotection minals in these patients.12,13 studies in PD was that the potential neu- Ligands that bind to the presynaptic roprotective effect was indistinguishable membrane dopamine transporter (DAT), from the symptomatic improvement pro- which reflect the density of striatal dopa- vided by the drug on trial.1,2 To over- minergic nerve terminals,14-16 might be more come this limitation, a biological marker suitable for assessing disease progression of disease progression could be valuable and the efficacy of neuroprotective treat- to evaluate the efficacy of neuroprotec- ments. To test this, it is necessary to com- tive drugs. Until now, positron emission pare the striatal uptakes of PET DAT li- tomography (PET) using 18F-dopa has gands and 18F-dopa at different stages of PD. been the gold standard tool for measur- In addition, the relationships between each ing disease progression in patients with tracer’s uptake in the striatum and motor PD.3-5 However, 18F-dopa uptake reflects performance remain to be investigated in the the density of striatal dopaminergic ter- same cohort of patients with PD. We com- minals6 and the conversion of 18F-dopa into pared the striatal uptake of 18F-dopa with a Author affiliations are listed at 18F-dopamine in these terminals.5,7,8 It has highly specific DAT tropane ligand in pa- the end of this article. been suggested that in PD, the loss of do- tients with early and advanced PD and

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 PATIENTS AND METHODS magnetic resonance imaging. Of these 25 controls, 7 were examined with 18F-dopa only, 8 with 76Br-FE-CBT only, and 10 with both PET tracers. All patients and controls were PATIENTS part of ongoing protocols in our center (Orsay, France) that were approved by the local ethics committee, and they gave Eighteen patients (mean±SD age, 53.7±6.0 years) fulfill- their written informed consent after the nature of the pro- ing the UK Parkinson’s Disease Brain Bank criteria for pro- cedure had been fully explained. spective diagnosis of PD17 were selected. They were di- vided into 2 groups: (1) 10 patients with early PD (mean±SD MAGNETIC RESONANCE IMAGING age, 51.7±4.4 years; mean±SD disease duration, 1.9±0.6 AND PET ACQUISITION years; Hoehn and Yahr stage I-II) without atypical signs18 who were drug naive at the time of the PET study but re- Brain magnetic resonance images were obtained using a sponded to treatment after it was initiated and (2) 8 pa- 1.5-T imager (Signa; General Electric Co, Milwaukee, Wis). tients with more advanced PD (mean±SD age, 56.1±6.6 T2-weighted images from each patient were used to reveal years; mean±SD disease duration, 12.5±6.7 years; Hoehn brain lesions and signal abnormalities in the basal ganglia. and Yahr stage ՆIII) who were all dopa responders accord- In addition, a T1-weighted SPGR (spoiled gradient acqui- ing to the criteria of the Core Assessment Program for In- sition at the steady state) acquisition with inversion recov- tracerebral Transplantations and the Core Assessment Pro- ery was performed to allow 3-dimensional reconstruction gram for Surgical Interventional Therapies (Table 1).19,20 of magnetic resonance images. All patients were assessed in the “defined off” state19,20 Positron emission tomographic examinations in pa- using the Unified Parkinson’s Disease Rating Scale 3 tients with early PD were performed using the ECAT (UPDRS-3) motor score and the Purdue Pegboard task. The EXACT HR+ tomograph (CTI-Siemens, Knoxville, Tenn), latter estimates bradykinesia and has been shown to cor- which collects 63 simultaneous 2.4-mm-thick slices with relate with striatal dopaminergic function.21 Briefly, for this an intrinsic in-plane resolution of 4.3 mm.23 Patients with task, patients were asked to put as many unmarked rods advanced PD were studied using the ECAT 953B/31 to- as possible into aligned holes using a single hand in 30 sec- mograph (CTI-Siemens), which acquires 31 simultaneous onds. The number of rods accurately placed was regis- 3.4-mm-thick slices with an intrinsic transaxial resolu- tered. tion of 6.0 mm.24 For all PET examinations, patients were Patients were scanned using 2 different PET tracers: positioned in the tomograph using 3-dimensional laser (1) 18F-dopa and (2) 76Br-FE-CBT (fluorethyl-methyl-2␤- alignment and a thermoplastic mask molded to each pa- carboxymethoxy-3␤-4-bromophenyl-tropane), a ligand of tient’s face to restrain head movements. Tissue attenua- the presynaptic plasma membrane DAT.22 This highly spe- tion was measured using 3 68Ge rod sources. cific tracer has the advantage of reaching an equilibrium For 18F-dopa studies, patients with advanced disease 30 minutes after injection. Patients with PD were com- discontinued taking antiparkinsonian medications at least pared with 25 control subjects (22 men and 3 women; 12 hours before PET examination. In all patients, 100 mg mean±SD age, 49.7±13.0 years) with no neurological his- tory, no clinical abnormality, and normal findings on brain Continued on next page

Table 1. Clinical Profile of 18 Patients With Parkinson Disease*

Patient No./ Disease UPDRS-3 Score Sex/Age, y Duration, y (No Medication) Medication: mg/d 1/M/46 0.6 17.5 . . . 2/F/48 1.5 4.0 . . . 3/F/56 1.5 14.0 . . . 4/M/55 1.5 12.0 . . . 5/M/58 2.0 18.0 . . . 6/M/56 3.0 14.5 . . . 7/M/52 1.4 17.0 . . . 8/M/50 1.8 6.0 . . . 9/M/46 1.6 12.0 . . . 10/F/50 1.5 21.0 . . . 11/F/53 11.0 36.5 L-dopa: 650; pergolide mesylate: 5 12/M/59 7.0 66.0 L-dopa: 1200 13/F/60 16.0 51.0 L-dopa: 800; bromocriptine: 30; lisuride: 0.8 14/F/52 7.0 62.0 L-dopa: 800; selegiline hydrochloride: 10 15/F/49 11.0 59.0 L-dopa: 1200; bromocriptine: 60; apomorphine hydrochloride: 10 16/M/59 10.0 74.0 L-dopa: 1000; lisuride: 3; apomorphine hydrochloride: 3; selegiline hydrochloride: 10 17/M/46 8.0 65.0 L-dopa: 1250; lisuride: 1.2 18/F/66 27.0 36.5 L-dopa: 600; lisuride: 0.6; trihexyphenidyl hydrochloride: 4

*UPDRS-3 indicates Unified Parkinson’s Disease Rating Scale 3; ellipses, not applicable.

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 of carbidopa was given 1 hour before tracer administra- calculation of the striatal binding potential (BnP) values tion, and 9 time frames were acquired for 90 minutes after of this tracer using the graphical analysis described by intravenous injection of 143.9±55.1 MBq of 18F-dopa. For Logan et al27 and using the occipital activity as a nonspe- 76Br-FE-CBT studies, we tested the effect of dopaminergic cific input function. medications in 2 patients who were studied twice: (1) af- Considering that patients were studied using 2 differ- ter 12-h drug withdrawal and (2) during administration of ent scanners, the Ki and BnP values obtained in each pa- medication. Drug withdrawal had no significant effect on tient were normalized to the mean Ki and BnP values ob- striatal tracer uptake of the 76Br-FE-CBT, confirming pre- tained in age-matched controls studied using the same vious results25 and unpublished data obtained in rats at our tomograph. Specifically, the values obtained in patients center (Orsay) (C.L. and P.H., 1996). Accordingly, all PET with early PD were normalized to values obtained using the studies with 76Br-FE-CBT were performed without drug ECAT EXACT HR+ in 7 controls (mean±SD age, 49.4±12.2 withdrawal in the 8 patients with advanced PD. For these years) for 18F-dopa uptake and 6 controls (mean±SD age, studies, 13 time frames were acquired more than 90 min- 53.3±7.2 years) for 76Br-FE-CBT, whereas the values ob- utes after intravenous injection of 34.8±9.9 MBq of 76Br- tained in patients with more advanced PD were normal- FE-CBT. ized to values in 10 controls (mean±SD age, 49.9±14.2 years) for 18F-dopa uptake and 10 controls (mean±SD age, IMAGE ANALYSIS 53.9±5.6 years) for 76Br-FE-CBT.

For both radiotracers, the time frames collected between STATISTICAL ANALYSIS 30 and 90 minutes after injection were summed to create an integrated image. This image was used to define re- The 3 groups (controls and patients with early and severe gions of interest in the striata and the occipital lobe in 4 to PD) were compared for Ki and BnP values in the caudate 6 contiguous planes where these structures could be visu- and putamen using a Kruskal-Wallis test (1-way nonpara- alized.6 Circular regions of interest 10 mm in diameter were metric analysis of variance). For that purpose, values ob- drawn, 1 on the head of the caudate nucleus and 3 on the tained in the right and left hemispheres were averaged. In putamen in each hemisphere. A 25-mm-diameter region addition, normalized Ki values were compared with nor- of interest was drawn on the occipital region using the same malized BnP values in the putamen of patients on the more image slices as those used for the striata. The mean activ- and less affected hemispheres using a Friedman test (2- ity concentration values in the region of interest for the left factor nonparametric analysis of variance). Finally, corre- and right caudate, the occipital, and the left and right pu- lations between Ki and BnP values and motor perfor- tamen were then calculated and used to obtain regional time- mance (motor score of the UPDRS-3 scale and Purdue activity curves. From these curves, the 18F-dopa uptake val- Pegboard) were analyzed using the nonparametric Spear- ues (Ki) were determined using multiple-time graphical man test. For the latter analysis between PET values and analysis, with the occipital activity as a nonspecific input Purdue Pegboard scores, right and left values were aver- function.6 The specific uptake of 76Br-FE-CBT reaches aged to avoid any statistical bias related to the lack of in- equilibrium 30 minutes after tracer injection,26 allowing dependence of the variables. Data are given as mean±SD.

investigated the correlations between these tracers’ up- Kruskal-Wallis analysis of variance comparing patients with takes and motor performances of these patients. early PD, patients with severe PD, and controls revealed significant differences among groups for Ki values (cau- RESULTS date: H=18.50; putamen: H=18.97) and BnP values (caudate: H=18.21; putamen: H=18.12) (PϽ.001 for all). 18F-DOPA AND 76BR-FE-CBT IN PATIENTS In the patient groups, we compared the normalized AND CONTROLS Ki values with the normalized BnP values in the putamen contralateral to the less and more clinically affected sides Figure 1 shows examples of images obtained in a con- (Figure 2). The Friedman analysis of variance revealed trol subject, a patient with early PD, and a patient with that Ki values were significantly higher than BnP values in advanced PD for 18F-dopa Ki and 76Br-FE-CBT BnP. Be- patients with early PD in the less affected (Ki=74%±19% cause Ki and BnP values were normalized to the mean and BnP=48%±14%) and more affected (Ki=51%±25% of control values (Table 2), they are expressed as per- and BnP=37%±20%) hemispheres (␹2=20.43; PϽ.001). In centages of the normal mean. patients with severe PD, the difference between Ki and BnP In patients with early PD, normalized Ki values av- values was not significant in the less affected (Ki=34%±12% eraged over both hemispheres were reduced to 87%±13% and BnP=27%±5%) and more affected (Ki=31%±9% and in the caudate nucleus and 63%±21% in the putamen, and BnP=27%±5%) hemispheres (␹2=3.75; P=.29). the corresponding BnP values were 70%±14% and 43%±17%. In patients with advanced disease, Ki values CORRELATIONS were 46%±11% and 33%±9% of control values in the caudate and putamen, respectively, whereas BnP values were The Ki values in the putamen averaged over both hemi- decreased to 32%±7% and 27%±5% in these regions. The spheres in patients with PD were significantly corre-

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1.0

76Br-FE-CBT

2.8

1.6

Control Subject Drug-Naive Patient With Early PD Patient With Advanced PD

Figure 1. Images of 18F-dopa and 76Br-FE-CBT uptake at the level of the striatum in a control subject, a drug-naive patient with early Parkinson disease (PD), and a patient with advanced PD. Uptake of both tracers is asymmetrically decreased in patients with PD and is less in the posterior than in the anterior striatum. In the patient with early PD, the decrease of 76Br-FE-CBT uptake is more severe than the 18F-dopa uptake reduction in the left posterior putamen and in the right putamen.

lated with motor performance, measured using the tracers is reduced in parkinsonian patients, but this re- motor score of the UPDRS-3 scale (r=−0.78; PϽ.003, duction is significantly greater with 76Br-FE-CBT than with Spearman) and the Purdue Pegboard (r=0.78; PϽ.005) 18F-dopa. Specifically, in the putamen of drug-naive pa- (Figure 3). There was a trend toward a correlation tients with early PD, 18F-dopa uptake is decreased to 63% between the corresponding BnP values and the motor of control values on average, whereas 76Br-FE-CBT BnP scores (UPDRS-3: r=−0.61; P=.01; Purdue Pegboard: is reduced to 43% of control values. For each tracer, this r=0.51; P=.05) (Figure 3), although the latter correla- value estimates the symptomatic threshold, which is the tions were not significant after Bonferroni correction. Pa- level of tracer uptake for which the clinical signs of PD tient 2 has high Ki and BnP normalized values and good appear. The symptomatic threshold found using 18F- motor performance (Figure 3) and therefore might be con- dopa is similar to that reported in previous PET stud- sidered an outlier. However, this patient has clear par- ies.12,13,28,29 Only 2 PET studies12,13 have compared 18F- kinsonian symptoms, including a rest tremor. If we make dopa and a PET DAT ligand in the same parkinsonian the correlation analysis after excluding patient 2, Ki val- patients. As in the present study, it was reported that the ues are correlated with UPDRS-3 (r=−0.73; P=.003) and binding of the DAT ligand was significantly lower than the Pegboard (r=0.74; P=.006) scores, whereas BnP values 18F-dopa uptake in the putamen of patients with early are correlated with UPDRS-3 (r=−0.54; P=.03) but not PD.12,13 Altogether, these results confirm that DAT li- Pegboard (r=0.41; P=.12) scores. gands are more sensitive than 18F-dopa to detect the early stages of PD because they reflect the loss of dopaminergic 14-16 COMMENT nerve terminals. Indeed, the mean 57% reduction in 76Br-FE-CBT in the putamen of patients with early PD is In this study, we compared the striatal binding of 2 dif- in line with the decrease in dopaminergic neurons in the ferent presynaptic dopaminergic PET tracers: 18F-dopa, substantia nigra pars compacta extrapolated from the post- which has been widely used to study striatal dopaminer- mortem analysis of brains from patients with PD.30,31 In gic function, and 76Br-FE-CBT, a recently developed highly addition, in our group of patients with advanced PD with specific ligand of the membrane DAT. The binding of both a mean disease duration of 12.1 years, the 73% loss of 76

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. Individual Positron Emission Tomography Results in 18 Patients With Parkinson Disease*

Caudate Putamen

18F-Dopa 76Br-FE-CBT 18F-Dopa 76Br-FE-CBT

Less More Less More Less More Less More Patient No. Affected Affected Affected Affected Affected Affected Affected Affected 1 0.90 0.67 0.72 0.61 0.61 0.48 0.38 0.24 2 1.17 1.15 0.93 0.89 1.12 1.12 0.88 0.81 3 0.90 0.86 0.81 0.52 0.72 0.40 0.38 0.24 4 1.08 0.60 0.68 0.48 0.73 0.47 0.38 0.31 5 0.82 0.74 0.57 0.45 0.53 0.39 0.38 0.19 6 0.84 0.76 0.70 0.76 0.57 0.36 0.50 0.38 7 0.89 0.83 0.59 0.52 0.90 0.62 0.35 0.21 8 0.88 0.79 0.72 0.69 0.58 0.26 0.51 0.36 9 0.75 0.68 0.80 0.74 0.76 0.32 0.56 0.46 10 1.18 0.82 0.94 0.91 0.89 0.67 0.56 0.42 11 0.62 0.26 0.52 0.40 0.50 0.44 0.33 0.29 12 0.17 0.35 0.33 0.34 0.17 0.22 0.34 0.32 13 0.44 0.44 0.29 0.22 0.39 0.30 0.25 0.21 14 0.45 0.27 0.26 0.20 0.29 0.17 0.19 0.21 15 0.62 0.52 0.38 0.31 0.40 0.26 0.30 0.27 16 0.56 0.42 0.31 0.31 0.38 0.16 0.28 0.24 17 0.52 0.52 0.40 0.40 0.38 0.29 0.34 0.30 18 0.70 0.46 0.25 0.28 0.43 0.39 0.23 0.21

*Less and more affected sides correspond to the hemispheres contralateral and ipsilateral, respectively, to the less and more clinically affected hemibodies. 18F-dopa uptake values (Ki) and binding potential (BnP) values have been normalized to the mean values in control subjects (see the “Image Analysis” subsection).

1.0 80 ρ ρ 18F-Dopa = –0.78 = –0.61 70 < < 0.9 76Br-FE-CBT P .003 P .05 60 0.8 50 40 0.7 30 0.6 20 10 UPDRS-3 Motor Score 0.5 0 0.4 16 0.3 14 Normalized Uptake Values 0.2 12 10 0.1 8 6 0.0 ρ ρ Less Affected More Affected Less Affected More Affected = 0.78 = 0.51 4 P < .003 P = .05 Early PD Advanced PD Purdue Pegboard Score 2 1030 50 7090 110 1030 50 70 90 18 76 Figure 2. Normalized F-dopa and Br-FE-CBT uptake in the putamen of Ki, % BnP, % patients with early and advanced Parkinson disease (PD) in the less and more affected sides. The difference between tracer uptakes is significant in Figure 3. Correlations between motor performance and each tracer’s patients with early but not advanced PD (PϽ.001, Friedman test). Error bars normalized uptake in the putamen of patients with Parkinson disease represent SD. (Spearman rank test). For the Unified Parkinson’s Disease Rating Scale 3 (UPDRS-3) motor score, increasing values indicate decreasing performances, whereas for the Purdue Pegboard, the number of digits Br-FE-CBT uptake in the putamen is comparable to the correctly placed in 30 seconds is measured. The correlations between motor 32 75% nigral cell loss observed by German et al in pa- performance and 18F-dopa uptake (Ki) are statistically significant, whereas tients with an average disease duration of 14 years. those observed using 76Br-FE-CBT binding potential (BnP) do not reach the Comparatively, 18F-dopa uptake seems to be up- PϽ.05 level after Bonferroni correction. regulated in the surviving dopaminergic terminals of patients with early PD.12,13 The striatal 18F-dopa uptake de- with a decrease in striatal DAT ligand binding,36,37 with- pends on the integrity of the nigrostriatal dopaminergic out any reduction of 18F-dopa uptake.38,39 pathway6 and on the activity of the aromatic L-amino acid This compensatory process, suggested by results ob- decarboxylase in these nerve terminals.5,8 An L-amino acid tained in patients with early PD, seems not to persist in decarboxylase overactivity is supposed to occur in the patients with advanced PD. The difference between 18F- surviving dopaminergic terminals of patients with PD to dopa uptake and 76Br-FE-CBT BnP is less and is not sig- compensate for the loss of dopaminergic neurons.9-11 This nificant in the putamen of patients with advanced dis- compensatory mechanism might be similar to that ob- ease (Figure 2). Recently, Lee et al12 found that up- served in normal aging,33,34 in which the progressive loss regulation of 18F-dopa uptake was on average 18% of of nigrostriatal dopaminergic neurons30,35 is associated control values compared with DAT ligand binding in un-

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 treated patients with early PD (20% in our data) and 12% minergic terminals, measured using 18F-dopa, than on the in patients with PD who have reached stage II to III of density of these terminals, evaluated using a DAT li- the Hoehn and Yahr scale. Our patients with advanced gand. This result, emphasizing the functional meaning PD are between stages III and V on this scale, and the of 18F-dopa uptake, is also in line with the hypothesis that apparent difference between 18F-dopa and 76Br-FE-CBT the compensatory increase of dopamine synthesis in the uptake in the putamen is only 6%. early stages of PD might be responsible for delaying mo- Thus, our results and those obtained in 2 recent PET tor symptom onset in these patients. studies12,13 suggest that compensatory mechanisms to do- Altogether, our results suggest that 18F-dopa and paminergic neuronal degeneration are present in the early 76Br-FE-CBT are complementary markers of the presyn- stages of the disease and might be less important in pa- aptic dopaminergic nigrostriatal system and thus may be tients with more advanced PD, all of which are similar to useful to assess neuroprotection therapies. However, this observations made in a rat model of PD.40 Results of pre- is based on the hypothesis that there is no down- vious studies9 suggest that the compensatory increase of regulation of 76Br-FE-CBT binding in hyperactive dopa- dopamine synthesis in PD mainly occurs at a later, al- minergic neurons or in relation to dopaminergic medi- though still presymptomatic, stage of neuronal degenera- cations. If this hypothesis is true, DAT ligands might more tion. This hypothesis is based on the widely accepted ob- accurately measure dopaminergic neuronal degenera- servation that parkinsonian symptoms appear when striatal tion than 18F-dopa and could be appropriate to evaluate dopamine is reduced to 20% to 30% of normal levels,41,42 neuroprotective strategies in PD. whereas dopaminergic neurons in the nigra are reduced to approximately 50% of normal values.30,31 However, mea- Accepted for publication November 29, 2001. surements of postmortem striatal dopamine levels should From Commissariat a`l’Energie Atomique (CEA), Ser- be cautiously interpreted considering the instability of this vice Hospitalier Fre´de´ric Joliot, Orsay, France (Drs Ribeiro, molecule.43,44 In rats given PD using the 6-OHDA toxin, Dupel, Dolle´, Samson, and Remy and Messrs Loc’h and Pon- the level of striatal dopamine measured in vivo is much chant); Service de Neurologie, Hoˆpital Saint-Antoine, Paris, higher than that found in the postmortem analysis of the France (Dr Vidailhet); Institut National de la Sante´ et de same animals.45,46 One simple explanation for this phe- la Recherche Me´dicale (INSERM) U289, Paris (Dr Vidail- nomenon is that dopamine turnover would rise in PD, lead- het); De´partement de Neurosciences, Centre Hospitalier ing to an increase in the dopamine released in the extra- Universitaire (CHU) Henri Mondor, Assistance Publique- cellular space but a decrease in the dopamine stored in the Hoˆpitaux de Paris & Universite´ Paris 12, Cre´teil, France presynaptic vesicles, which is the dopamine measured in (Drs Nguyen, Peschanski, Cesaro, and Remy); INSERM postmortem analyses. Accordingly, nearly all experimen- U421, IM3, Faculte´ de Me´decine, Cre´teil (Drs Nguyen, tal and human studies have shown that the turnover of Peschanski, and Cesaro); Unite´ de Recherche Associeé dopamine was increased in PD as demonstrated by the rise CEA–Centre National de la Recherche Scientifique 2210, in the level of dopamine metabolites in the striatum.9-11 Orsay (Drs Hantraye and Remy); and Urgences Ce´re´bro- Thus, increased synthesis of dopamine in the surviving Vasculaires, CHU Pitie´-Salpe´trie`re, Paris (Dr Samson) striatal terminals of patients with early PD would be ac- Author contributions: Study concept and design (Drs companied by an increased transformation of 18F-dopa into Vidailhet, Nguyen, Peschanski, Hantraye, Cesaro, Sam- 18F-dopamine in these terminals because of the overactiv- son, and Remy); acquisition of data (Drs Ribeiro, Dupel, ity of L-amino acid decarboxylase.9,34 The PET results fit and Dolle´ and Messrs Loc’h and Ponchant); analysis and with the latter hypothesis. Although this metabolic re- interpretation of data (Drs Ribeiro, Vidailhet, and Remy); sponse might not be the only compensatory change dur- drafting of the manuscript (Drs Ribeiro, Vidailhet, Dupel, ing neuronal degeneration in early PD,11 it likely plays a Dolle´, and Remy and Messrs Loc’h and Ponchant); criti- role in delaying the onset of symptoms during the early cal revision of the manuscript for important intellectual con- stage of disease. Conversely, the loss of such metabolic com- tent (Drs Vidailhet, Nguyen, Peschanski, Hantraye, Ce- pensations in more severely affected patients, which re- saro, Samson, and Remy); statistical expertise (Dr Remy); main to be confirmed in further studies, might play a ma- obtained funding (Drs Vidailhet, Dupel, Nguyen, Sam- jor role in the motor fluctuations observed in these son, and Remy); administrative, technical, and material sup- patients.47,48 Prospective study of the striatal uptake of both port (Mr Loc’h and Dr Dolle´); and study supervision (Drs tracers during disease progression may help confirm this. Vidailhet, Peschanski, Hantraye, Cesaro, and Remy). Finally, in all patients with PD, the relationships be- This work was supported by grant PHRC IDF-96138 from tween motor performance and putamenal tracer uptake the French Ministe`re de la Sante´, Paris; the Association France were stronger with 18F-dopa than with 76Br-FE-CBT BnP. Parkinson; grant PRAXIS XXI/BD/2657/94 from the Funda- The correlations between 18F-dopa uptake and motor per- çaõpara a Cieˆncia e Tecnologia and a grant from the ARS and formance have been emphasized in several studies.21,49,50 Universidade de Coimbra, Portugal (Dr Ribeiro); and the Fon- In addition, correlations between PD severity and stria- dation pour la Recherche Me´dicale, Paris (Dr Dupel). tal uptake of DAT ligands have been reported using ei- We thank the radiochemists and nurses at the Service ther PET or single-photon computed tomography.36,51,52 Hospitalier Fre´de´ric Joliot for their assistance and Ken Moya, However, the relationships between the 2 different PET MD, PhD, for his critical reading of the manuscript. tracers and motor performance have not been analyzed Corresponding author and reprints: Philippe Remy, MD, previously in the same patients. The present results sug- PhD, URA CEA-CNRS 2210, Service Hospitalier Fre´de´ric gest that the motor abilities of patients with PD depend Joliot, 4, place du Geńe´ral Leclerc, 91401 Orsay, CEDEX, more on the functional status of putamen dopa- France (e-mail: [email protected]).

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