Effects of the Prolyl Inhibitor S 17092 on Cognitive Deficits in Chronic Low Dose MPTP-Treated Monkeys J. S. Schneider, Ph.D., M. Giardiniere, B.S., and P. Morain, Ph.D.

A number of are affected in Parkinson’s delayed matching-to-sample, and delayed alternation tasks. disease and the endopeptidase contributes to Seven day oral administration of S 17092 followed by single the degradation of many of these neuropeptides, some of dose administration of the same dose on the day of testing which are linked to a variety of cognitive functions. In the significantly improved overall performance on these tasks. present study, the effects of the highly potent proline The most effective dose of S 17092 was 3 mg/kg. These endopeptidase inhibitor S 17092 on cognitive deficits in results indicate that S 17092 has cognition-enhancing monkeys induced by chronic low dose 1-methyl-4-phenyl- properties in this model of early parkinsonism. 1,2,3,6-tetrahydropyridine (MPTP) administration were [Neuropsychopharmacology 26:176–182, 2002] examined. Chronic low dose MPTP administration resulted © 2002 American College of Neuropsychopharmacology. in deficits in performance of variable delayed response, Published by Elsevier Science Inc.

KEY WORDS: Parkinsonism; Cognition; ; et al. 1988) and spatial working memory (Owen et al. Proline endopeptidase 1992). Parkinson’s disease patients also may have diffi- culty performing a delayed matching-to-sample short- It is generally recognized that non-demented Parkin- term visual recognition memory task, but their problems son’s disease (PD) patients exhibit a number of neuro- appear more related to attentional difficulties rather than psychological deficits, some of which are present even at to visual recognition memory problems (Lange et al. the earliest stages of the disease (Lees and Smith 1983; 1992). Levin et al. 1989; Owen et al. 1993). Many of these defi- The neurochemical deficits underlying the cognitive cits are ‘frontal-like’ in nature and consist of problems in disturbances in PD patients are not completely known. attentional set shifting (Owen et al. 1993), distractibility While most of the motor symptoms of PD can be related (Sharpe 1990) planning and ‘executive functions’ (Morris to a nigrostriatal dopaminergic defect, the relationship between the dopaminergic defect and cognitive deficits in PD is less clear. Some cognitive deficits in PD may be From the Department of Pathology, Anatomy, and Cell Biology, dopa-responsive but others are not (Cooper et al. 1992; Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA (JSS, MG), Institut de Recherches Internationales Servier, Courbe- Lange et al. 1992). Some cognitive problems in PD pa- voie, France (PM) tients are even exacerbated by dopaminergic therapy Address correspondence to: Dr. J. S. Schneider, Department of (Gotham et al. 1988). These findings suggest that the Pathology, Anatomy and Cell Biology, Thomas Jefferson University, 1020 Locust Street, Room 521 JAH, Philadelphia, PA 19107, Tel.: cognitive deficits in PD patients most likely arise from 215-503-0370, Fax: 215-923-3808, E-mail: [email protected] dysfunction of several cortical and subcortical neu- Received February 28, 2001; revised May 22, 2001; accepted June rotransmitter systems and functional circuits that can- 15, 2001. Online publication: 6/15/01 at www.acnp.org/citations/Npp not be normalized by dopamine replacement therapy 061601139. alone. This is supported by the recent finding that a

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NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 2 Effects of S 17092 on Cognition 177

sub-type specific neuronal nicotinic acetylcholine re- (Schneider and Kovelowski 1990). Prior to the start of ceptor agonist, but not levodopa, was able to improve training, all monkeys were adapted to chair restraint and cognitive functioning in dopamine lesioned monkeys the experimental set-up. Monkeys were food deprived (Schneider et al. 1999). The nicotinic receptor agonist ef- overnight prior to testing. All procedures were carried out fects on cognition were most likely related to the ability in accordance with the Guide for the Care and Use of Lab- of this compound to release dopamine from striatal, oratory Animals as adopted by the National Institutes of limbic and frontal cortical sites, norepinephrine from Health and were approved by the Thomas Jefferson Uni- hippocampal, thalamic and frontal cortical sites and versity Institutional Animal Care and Use Committee. acetylcholine from various cortical and subcortical sites (Menzaghi et al. 1996; Sacaan et al. 1997). In addition to deficits in levels of various neurotrans- Variable Delayed Response (VDR) mitters in PD and in animal models of PD, decreased The monkeys sat in a restraining chair situated in a levels of various neuropeptides may also contribute to sound-attenuating chamber with background masking parkinsonian symptomatology (Mauborgne et al. 1983). noise, behind an opaque screen that when raised, al- Several neuropeptides, particularly , have lowed access to a sliding tray. The tray contained re- been implicated in learning and memory (Huston and cessed food wells and identical sliding red Plexiglas Hasenohrl 1995) and are present endogenously in cortex covers that served as stimulus plaques that could be and striatum. Substance P levels are also depleted in the displaced by the animal to obtain rewards (raisins, striatum of monkeys made parkinsonian by exposure to dried fruit). The monkeys were trained to retrieve food the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropy- from one of the wells after observing the experimenter ridine (MPTP). Since proline-containing neuropeptides bait a well. Right and left wells were baited in a bal- such as substance P. and thyrotropin-releasing anced order. For all animals performing the VDR task, have all been implicated as potential cognition five different delay lengths were randomly distributed enhancers (Toide et al. 1995), a possible therapeutic ap- in blocks of trials over the 40 trials that made up a daily proach to the cognitive deficits associated with par- testing session. In two animals, the range of delays were kinsonism might be enhancement of endogenous neu- 2 to 30 seconds; two animals had the longest delay set at ropeptide levels. This could be accomplished through 45 seconds; one animal had the longest delay set at 60 sec- protection of neuropeptides from degradation with pep- onds. These conditions yielded approximately chance tidase inhibitors. performance at the longest delays. Proline endopeptidase is a endooligopepti- dase involved in the degradation of various neuropep- tides in vitro and in vivo (Checler 1993). S 17092 is a Delayed Matching-to-Sample Testing (DMS) highly potent, orally active, cell permeant inhibitor of On DMS trials, the monkey was shown a colored Plexi- proline endopeptidase in brain (Barelli et al. 1999; Lep- glas cover in the center of the sliding response panel agnol et al. 1996). S 17092 can at least partially reverse that served as the cue or sample for the subsequent scopolamine-induced amnesia and age-associated spa- match. Following cue presentation, a 5-sec delay was im- tial delayed alternation deficits in mice, as well as in- posed after which the monkey was given the choice of crease striatal substance P immunoreactivity (Lestage et responding to the same colored cover that was used as al. 1998). The present study aimed to assess the extent the cue or to an adjacent cover of another color. Displace- to which S 17092 might improve cognition in chronic ment of the same colored cover as used for the cue al- low dose MPTP-treated monkeys, a model of early-stage lowed access to a food reward. Each daily session con- parkinsonism previously shown to exhibit cognitive def- sisted of 30 trials and animals were trained to perform at icits similar to those detected in PD patients (Schneider approximately a 90% criterion level. and Kovelowski 1990; Schneider and Roeltgen 1993).

Delayed Alternation MATERIALS AND METHODS On each trial, monkeys were presented with two identi- cal covers over recessed food wells and were required Four adult male Macaca fascicularis monkeys (5 to 7 kg) to alternate responses between left and right wells on were trained to perform variable delayed response (VDR), successive trials separated by a 5-sec inter-trial delay. A delayed alternation (DA), delayed matching-to-sample non-correction procedure was used so that if an error (DMS) and visual discrimination tasks. One additional was made on any given trial, the reward would remain adult male M. fascicularis monkey performed only the on the same side until a correct response was made. An- VDR task. All monkeys performed tasks while seated in- imals were trained to perform at approximately a 90% side a modified Wisconsin General Test Apparatus criterion level on 30 trials per day.

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Visual Pattern Discrimination drug. Cognitive performance was assessed at the end of the washout period to insure that deficits were consis- For visual discrimination testing, monkeys were trained tent with those observed during the post-MPTP base- to discriminate between two patterns (a cross and a hor- line period prior to starting the evaluation of a new izontal bar) on otherwise identical white Plexiglas cov- drug dose. Each dose of S 17092 was assessed twice and ers. The positive stimulus (cross) appeared on a cover performance was compared to non-drug performance over the left or right food wells in a balanced order. The during washout days prior to and after drug testing. cover had to be displaced in order to retrieve reward from the recessed food well beneath the cover. A session consisted of 30 trials and the monkey was trained to a Data Analysis 90% correct criterion level. Each dose of each drug was tested twice and the data were pooled for statistical analysis. Task performance on drug was compared with matched control perfor- Drug Administration mance (non-drug). Animals served as their own con- Once animals achieved stable baseline task perfor- trols and thus statistical analyses employed repeated mea- mance, MPTP administration began. MPTP-HCl (RBI, sures designs: one way analysis of variance (ANOVA) on Natick, MA) was administered intravenously two to all drug doses with pairwise post hoc comparisons (paired three times per week while animals were seated in a re- t-test, Newman-Keuls test) of baseline (non-drug) and straining chair, as described previously (Schneider and drug performance. Kovelowski 1990). Adequate precautions were taken to protect personnel from exposure to MPTP during injec- tions and from any possible unmetabolized MPTP in RESULTS animal excreta (Schneider and Roeltgen 1993). MPTP Effects of MPTP Exposure on Cognitive was administered at a dose of 0.075 mg/kg per injec- Task Performance tion. By the time drug testing commenced, animals had received total amounts of MPTP ranging between 0.38 Prior to initiation of MPTP exposure, the animals had a and 4.8 mg over periods of 27 to 63 days. The different mean baseline performance of 81.2% correct responses total amounts of MPTP administered reflect individual (Ϯ 1.6) on the VDR task. There was a significant effect animal variability in response to the toxin. Although of delay on task performance such that all monkeys different total amounts of MPTP were administered to performed well on short delay trials but performance different animals for different periods of time, the na- deteriorated to almost chance performance at the longer ture of the cognitive deficits were the same in all the an- delays (Figure 1). In normal animals performance at imals. Pharmacological testing commenced after animals shorter duration delays (i.e., 2, 5 and 10 sec) differed sig- consistently showed at least 15% performance deficit on nificantly from performance at longer duration delays each task known to be sensitive to MPTP exposure (20, 30, 45 or 60 sec, F (6, 133) ϭ 18.2, p Ͻ .0001). Short- (Schneider and Kovelowski 1990; Schneider and Roelt- duration delay trials (2, 5 and 10 sec) were performed at gen 1993) for approximately two months. 93.3% Ϯ 2.4, 89.7% Ϯ 3.2 and 88.8% Ϯ 2.5 correct, re- S 17092 powder was mixed with 3 to 5 drops of spectively. Normal performance declined with increas- Tween 20 and added to 10 to 20 ml of fruit-flavored ingly long delay durations (20-sec delay: 71.1% Ϯ 3.5; drink. Drug was prepared immediately prior to use and 30-sec delay: 67.0% Ϯ 2.4; 45-sec delay: 59.3% Ϯ 4.3; 60- administered orally to monkeys in their home cages. S sec delay: 62.8% Ϯ 3.9. 17092 was administered for seven days prior to formal After chronic MPTP exposure, overall performance testing of drug effects on cognitive task performance. On on the VDR task deteriorated to 60.9% correct responses the day of testing, the same dose of S 17092 that was ad- (Ϯ 2.3) (t ϭ 35.7, p Ͻ .01). In contrast to the normal per- ministered during the preceding 7-day dosing period formance of this task, monkeys exhibited a delay-inde- was given to the animals and cognitive performance was pendent performance deficit after chronic exposure to assessed beginning approximately 30 min after drug ad- MPTP. That is, monkeys were now almost as likely to ministration. Because monkeys occasionally would not perform poorly on 2, 5 or 10-sec delay trials (68.6% cor- perform all of the tests in one day, task performance rect responses Ϯ 3.1, 70.9% Ϯ 3.2, and 62.7% Ϯ 3.5, re- was usually assessed over two consecutive days of ad- spectively) as on 20-sec (54.7% Ϯ 3.8), 30-sec (63.3% Ϯ ministration of the test dose of S 17092. Based on exist- 3.5), 45-sec (53.9% Ϯ 4.2) or 60-sec (53.9% Ϯ 5.2) delay ing literature (Lepagnol et al. 1996; Lestage et al. 1998), trials (Figure 1). The effect of MPTP exposure on perfor- the drug doses used were 1.0, 3.0 and 10.0 mg/kg. Dif- mance at different delays was significant (F (6, 132) ϭ ferent doses were administered in quasi-random order. 3.5, p ϭ .0029). Pairwise post hoc comparisons showed There was at least two weeks of washout prior to start- that performance at 2, 5, 10 and 20-sec delays changed ing the next 7-day dosing regimen with a new dose of significantly after MPTP exposure (t ϭ 30.2, p Ͻ .01, t ϭ

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Figure 1. Prior to MPTP exposure, all animals displayed a delay-dependent decrease in per- formance on the variable delayed response task (n ϭ 5). After MPTP exposure, trials at all delays were performed poorly. The 3.0 mg/kg dose of S 17092, after a 7-day exposure to the drug, caused a significant improvement in performance of 2, 5, and 10-sec delay trials. Graphs show means Ϯ SEM. *p Ͻ .01 vs. non-drug control trials.

17.6, p Ͻ .01, t ϭ 33.7, p Ͻ .01, t ϭ 13.3, p Ͻ .05, respec- .01) (Figure 3). Prior to receiving any MPTP, VD perfor- tively ) while performance at 30, 45 and 60-sec delays (t ϭ mance was 95.9% correct (Ϯ 1.1) and task performance 0.6, p Ͼ .05, t ϭ 0.9, p Ͼ .05, t ϭ 0.9, p Ͼ .05, respec- remained intact after chronic MPTP exposure (95.5% tively) was unaffected by the MPTP exposure. correct responses Ϯ 1.0) and was not affected by S 17092 Prior to MPTP administration, the DMS task was administration (data not shown). performed at a level of 94.4% correct responses (Ϯ 1.2). After chronic MPTP exposure, performance deterio- Effects of S 17092 on VDR, DMS, DA and rated to 62.2% correct responses (Ϯ 1.8) (t ϭ 124.0, p Ͻ VD Performance in Chronic Low Dose .01) (Figure 2). The DA task was performed at a level of MPTP-Treated Monkeys 93.5% correct responses (Ϯ 1.2) before MPTP exposure. After chronic MPTP administration, performance dete- S 17092 caused a dose-dependent improvement in per- riorated to 76.2% correct responses (Ϯ 2.6) (t ϭ 28.3, p Ͻ formance of the VDR task (Figure 1). S 17092 signifi-

Figure 2. Performance of the delayed matching-to-sample task was significantly impaired after MPTP exposure. Figure 3. Performance of the delayed alternation task was Administration of S 17092 significantly improved DMS per- significantly impaired after MPTP exposure. Administration formance at both 3.0 and 10.0 mg/kg doses, following seven of S 17092 significantly improved DA performance at the 3.0 days of drug administration. Graphs show means Ϯ SEM. mg/kg doses, after a 7-day exposure to the drug. Graphs *p Ͻ .01 vs. non-drug control trials. MPTP-1 ϭ control trials show means Ϯ SEM. *p Ͻ .01 vs. non-drug control trials. associated with testing of 1 mg/kg S 17092; MPTP-3 ϭ MPTP-1 ϭ control trials associated with testing of 1 mg/kg S control trials associated with testing 3 mg/kg S 17092; 17092; MPTP-3 ϭ control trials associated with testing of MPTP-10 ϭ control trials associated with testing of 10 mg/ 3 mg/kg S 17092; MPTP-10 ϭ control trials associated with kg S 17092. testing of 10 mg/kg S 17092.

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cantly improved VDR performance at the 3.0 mg/kg were not designed to separate out attentional from mem- dose (76.9% correct Ϯ 2.0, t ϭ 29.2, p Ͻ .01 vs. non-drug ory effects on task performance and additional work is post-MPTP performance) but not at 1.0 or 10.0 mg/kg necessary to determine if there are preferential effects doses. After administration of 3.0 mg/kg S 17092, VDR of S 17092 on attention or memory functions. performance tended to revert back to a normal delay- Chronic oral pre-treatment with S 17092 for seven dependent pattern. At the 3.0 mg/kg dose, perfor- days prior to administration of the test dose of drug mance significantly improved on shorter delay trials (2, and cognitive testing was necessary in order to observe 5, and 10 sec, t ϭ 7.2, p Ͻ .05, t ϭ 16.8, p Ͻ .01, t ϭ 24.5, cognition-enhancing effects. During the first three days p Ͻ .01, respectively) but not on longer delay trials (20, of the 7-day pre-treatment period, S 17092 did not im- 30, 45 and 60 sec). Improved performance on shorter de- prove any of the cognitive functions measured (data lay trials was not seen with either the 1.0 or 10.0 mg/kg not shown). These data are consistent with previous doses. reports that showed chronic oral administration of S Significant improvements in DMS performance were 17092 to be more effective than acute administration in also observed after S 17092 administration (F (6,109) ϭ increasing striatal substance P-like immunoreactivity 34.9, p Ͻ .0001) (Figure 2). On this task, improvements (Lestage et al. 1998). In other studies, chronic adminis- were seen with the 3.0 mg/kg dose (t ϭ 35.9, p Ͻ .01) tration of S 17092 inhibited brain post-proline cleaving as well as with the 10 mg/kg dose (t ϭ 17.2, p Ͻ .01). enzyme activity by more than 50% and improved learn- The 1.0 mg/kg dose had no effects on DMS perfor- ing and memory performances in both young scopola- mance. With the 3.0 mg/kg dose, performance went from mine-treated and aged mice (Lestage et al. 1998). Al- 59.3% Ϯ 2.6 to 79.7% Ϯ 2.7. The 10.0 mg/kg dose caused though this was not directly assessed in the current performance to improve from 60.9% Ϯ 1.3 to 72.2% Ϯ 2.8. studies, these findings suggest that cognition enhancing S 17092 administration also improved DA perfor- properties of S 17092 may be related to enhanced neu- mance, but only at the 3.0 mg/kg dose (t ϭ 12.6, p Ͻ ropeptide activities in the brain. .01) (Figure 3). Performance went from 79.0% Ϯ 2.5 to A number of neuropeptides, including substance P 90.6% Ϯ 1.6. are decreased in PD and in patients with Alzheimer’s type dementia (Husain and Nemeroff 1990). In particu- lar, tritiated substance P binding and substance P-like immunoreactivity have been reported to be signifi- DISCUSSION cantly reduced in the parietal cortex and nucleus basalis of Meynert as well as in the substantia nigra and inter- The prolyl endopeptidase inhibitor S 17092, adminis- nal globus pallidus in PD brain (Tenovuo et al. 1990). tered orally to chronic low dose MPTP-treated monkeys The neurochemical deficits underlying the cognitive with significant cognitive impairments, improved per- dysfunctions in chronic MPTP-treated monkeys and the formance of cognitive tasks (VDR, DMS, DA). The nor- status of brain neuropeptides in these animals are un- mal performance of these tasks are usually associated known. Levels of a variety of neuropeptides were unal- with the functional integrity of fronto-striatal circuits. tered in monkeys acutely administered MPTP (Zamir et The function of these circuits appear to be impaired in al. 1984). Recent pharmacological studies have shown both PD and in the chronic low dose MPTP model of that dopamine replacement therapy (using levodopa) parkinsonism. In MPTP-treated monkeys there is at was ineffective in substantially reversing the cognitive least partial improvement of these functions after ad- deficits in chronic low dose MPTP-treated monkeys ministration of S 17092. while treatment with neuronal nicotinic acetylcholine re- In the present studies, the most efficacious dose of S ceptor (nAChR) agonists (Schneider et al. 1999) or the 17092 was 3.0 mg/kg. The 1.0 mg/kg dose was ineffec- partial glycine agonist D-cyloserine (Schneider et al. tive in all tests whereas the 10.0 mg/kg dose signifi- 2000) significantly improved performance on a variety cantly improved only DMS performance. The reasons of cognitive tasks. The cognitive deficits in chronic low for this high dose effect on performance of this particu- dose MPTP-treated monkeys and in PD patients most lar task are unclear. S 17092 did not significantly im- likely arise from dysfunction of several cortical and prove performance on long duration delay trials (у20 subcortical neurotransmitter systems and functional sec) in the VDR task. Interestingly, the normal limit of circuits, such that L-dopa treatment alone cannot suffi- working memory in these monkeys was approximately ciently normalize behavior. The superior effects of 10 sec. That is, under normal conditions, task performance nAChR agonists, D-cycloserine and proline-endopepti- significantly deteriorated with delays of 20 sec or greater. dase inhibitors may be due to the ability of these drugs Thus S 17092 appeared to improve memory within its nor- to modulate release of dopamine and other neurotrans- mal limits in these animals and may also have enhanced mitters including norepinephrine and acetylcholine attentional abilities (evidenced by improved performance from various cortical and subcortical sites. It is well at short duration delays). The present studies however known that neuropeptides can modulate the activity of NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 2 Effects of S 17092 on Cognition 181

dopamine as well as other neurotransmitters such as selectively impairs cognitive performance in tests sensitive acetylcholine. In particular, cholinergic neurotransmis- to frontal lobe dysfunction. Psychopharmacol 107:394–404 sion is facilitated by substance P (Lestage et al. 1998). Lees AJ, Smith E (1983): Cognitive deficits in the early stages Proline endopeptidase inhibitors may improve cogni- of Parkinson’s disease. Brain 106:257–270 tive function in MPTP-treated monkeys by indirectly Lepagnol J, Lebrun C, Morain P, De Nateuil G, Heidet V promoting functions of a variety of neurotransmitter (1996): Cognition enhancing effects of S 17092, a potent systems and/or by direct neuropeptide effects in the inhibitor of post-proline cleaving enzyme (PPCE). Soc Neurosci Abstr 22:142 basal ganglia and other subcortical and cortical regions. These mechanisms alone or in combination may con- Lestage P, Lebrun C, Iop F, Hugot A, Rogez N, Greve P, Favale D, Gandon M-H, Raimbault O, Lepagnol J tribute to the effectiveness of S 17092 as a potential cog- (1998): S 17092, a new post-proline cleaving enzyme nition enhancing agent in PD. A similar mechanism (i.e., inhibitor: memory enhancing effects and substance P promoting functions of a variety of neurotransmitter neuromodulatory activity. Adv Behav Biol 49:653–660 systems) was previously proposed to explain the benefi- Levin BE, Llabre MM, Weiner WJ (1989) Cognitive impair- cial effects of a nicotinic acetylcholine receptor agonist ments associated with early Parkinson’s disease. Neu- as well as the lack of effect of levodopa on the same be- rology 39:557–561 haviors assessed in this study (Schneider et al. 1999). Mauborgne A, Javoy-Agid F, Legrand JC, Agid Y, Cesselin F In summary, the proline endopeptidase inhibitor S (1983): Decrease in substance P-like immunoreactivity 17092 improves cognitive task performance in chronic in the substantia nigra and pallidum in Parkinsonian low dose MPTP-treated monkeys and seems to have brains. Brain Res. 268:167–170 potential benefit as a treatment for at least some of the Menzaghi F, Sacaan AI, Reid RT, Santori EM, Correa LD, cognitive disorders associated with parkinsonism. Adams P, Whelan KT, Risbrough VB, Rao TS, Schneider JS, Lloyd GK (1996): Characterization of SIB-1508Y, the active enantiomer of a novel nicotinic acetylcholine receptor (NAChR) agonist, SIB-1765F. Soc Neurosci Abstr 22:1523 Morris RG, Downes JJ, Sahakian BJ, Evenden JL, Heald A, ACKNOWLEDGMENTS Robbins TW (1988): Planning and spatial working mem- ory in Parkinson’s disease. J Neurol Neurosurg Psychi- This research was supported by the Institut de Recherches In- atr 51:757–766 ternationales Servier. Dr. Schneider has been a paid consult- Owen AM, Beksinka M, James M, Leigh PN, Summers BA, ant of the Institut de Recherches Internationales Servier and Marsden CD, Quinn NP, Sahakian BJ, Robbins TW does not currently have a financial or other involvement with (1993): Visuo-spatial memory deficits at different stages this organization. Dr. Morain is an employee of the Institut de of Parkinson’s disease. Neuropsychologia 31:627–644 Recherches Internationales Servier. Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn NP, Lange KW, Robbins TW (1992): Fronto-stri- atal cognitive deficits at different stages of Parkinson’s REFERENCES disease. 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