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

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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 devel- oped 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 perfor- mance 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, Edevelopment 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 (REPRINTED) ARCH NEUROL / VOL 59, APR 2002 WWW.ARCHNEUROL.COM 580 ©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. (REPRINTED) ARCH NEUROL / VOL 59, APR 2002 WWW.ARCHNEUROL.COM 581 ©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.
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    Indi an Journal of Experiment al Biology Vol. 37, March 1999, pp. 23 4-237 Involvement of dopamine D2 and 5-HT IA receptors in roxindole-induced antinociception Ipe Ninan & S K Kulkarni* Ph armaco logy Di vision, Universit y In stitute of Pharmaceutical Sciences, Panj ab Uni versity, Chand igarh )60014, Indi a Received 23 March 1998; revi sed 27 November 1998 Rox i Il dole. a DA O2 receptor ago ni st (2-1 6 mglkg) produ ced dose-dependent i ncrease in percent age <I ntinociceptio nT he effect whi ch was bl ocked by DA O2 antago ni st (-)s ulpiride (50 mglkg) and 5-HTIAr eceptor antagoni st (-) pin do lol (5 mg/kgl. Rox in do le (4 and 8 mglkg) reversed both nalo xo ne (20 mglkg)-induced hyperalgesia and reserpine (2 mg/kg)-i nduced hyperalgesia. Th is reversal was sensiti ve to blockade by both (-)su lpiri cte (50 mglkg) and (-) pindolol (5 mg/kg). The presen t stud y s~ges t s th at ro xindol e-induced ant inocicepti on is mediated by postsynaptic DA D2 and 5-HTIA rece pt ors. Rox indole (EMD 49980) is a representati ve of a new severe pain associated with various states of di sease class of dopaminergic drugs, I. e., the indolyl affecting the nervous system, such as. the thalamic butylamines. whi ch lac k structural similarities with syndrome, herpes zoster and Parkinson's either ri gid dopamine (DA ) analogs or ergot di sease' 1.l 2.'J.'4. and a recent study showed that 8-0H deri vatives '.