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tasks used in clinical practice and experimental protocols. This task lobe processes such as strategic search processes, cognitive flexi-

2001) has shown a deleterious effect of age on phonemic fluency.Thus, when consideringmerely the dissociation between semanticand phonemic fluency and the overall performance (number ofwords generated in a limited amount of time) it remains unclear

Progress in Neuro-Psychopharmacology & Biolog

Abbreviations: DA, Dopaminergic agonist; DRS, Mattis Dementia RatingScale; DSST, Wechsler Adult Intelligence Scale-Revised Digit Symbol

Substitution Test; MMSE, Mini-Mental State Examination; PET, PositronEmission Tomography; PFTCN, prefrontal temporal cortical network.requires subjects to generate as many words as possible in a limitedamount of time for a given letter (phonemic fluency) or a givencategory (semantic fluency). Although measures of verbal fluencyprimarily tap language functions and depend on lexico-semanticstore integrity, it is now well established that they also involveexecutive processes. According to Dursun et al. (2002) verbalfluency tasks are likely to involve an important part of a widelydistributed neural network, namely the prefrontal temporal corticalnetwork (PFTCN). Other studies have also suggested a multiple

bility, and shifting (Troyer et al., 1997). In normal aging, a specificpattern of performances has been demonstrated. Several studiesshowed a reduction in the total number of words produced insemantic fluency tasks (Kempler et al., 1998;Kozora andCullum,1995; Tombaugh et al., 1999; Tomer and Levin, 1993), whereasphonemic fluency performance has been found to be spared(Bolla et al., 1990; Lamar and Resnik, 2004; Ruff et al., 1996;Tomer and Levin, 1993). However, this pattern has not alwaysbeen observed (Dursun et al., 2002; Kozora and Cullum, 1995;Tombaugh et al., 1999) and a meta-analysis (Loonstra et al.,phonemic categories, depending on the integrity of temporal lobe), and switching (i.e. the ability to shift between clusters, depending on frontallobe functioning). Results revealed no significant main effect of the DA treatment on either verbal fluency variables but showed a significantinteraction with working memory capacities, with high-capacity span subjects improving phonemic switching on DA whereas low-capacity spansubjects performed more poorly on the drug than off. These data are consistent with the literature and confirm the crucial link between workingmemory capacities and dopamine agonist effects. The present study also provides evidence that pharmacological remediation of age-relatedcognitive decline has to be taken into consideration. 2006 Elsevier Inc. All rights reserved.

Keywords: Agonist; Clustering; Dopamine; Piribedil; Switching; Verbal fluency

1. Introduction

Verbal fluency is one of themost commonly neuropsychological

brain region involvement of the tasks, with semantic fluency tasksrelying upon temporal-lobe processes such as verbal memory andword storage, whereas phonemic fluency tasks rely upon frontal-50 mg/day) in a double-blind crossover design. Protocols were scorNormal aging has been associated with impaired performance in verbal fluency suggesting a prefrontal temporal cortical network (PFTCN)deficiency. In this study, we investigated the effects of a 2-month treatment period with a dopaminergic agonist (DA) on PFTCN function. Fortyhealthy, elderly volunteers were assessed on semantic and phonemic verbal fluency after two months of a placebo or a DA treatment (i.e. piribedil

ed considering clustering, (i.e. production of words within semantic orEffects of the dopamine agonist pirnetwork function in normal agi

Fabien Gierski a,b,, Charles-Siega Service de Psychiatrie des Adultes, Hpital Robert Debr, Cen

b Laboratoire de Psychopathologie et de Neuropsychologie Cliniques, Institut

Available onli

Abstract Corresponding author. Service de Psychiatrie des Adultes, Hpital RobertDebr, Centre Hospitalier Universitaire de Reims, 51092 Reims Cedex, France.Tel.: +33 326 787 045; fax: +33 326 788 319.

E-mail address: fgierski@chu-reims.fr (F. Gierski).

0278-5846/$ - see front matter 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.pnpbp.2006.06.017edil on prefrontal temporal corticalas assessed by verbal fluency

ed Peretti a, Anne-Marie Ergis b

ospitalier Universitaire de Reims, 51092 Reims Cedex, Francesychologie, Universit Ren Descartes, 92100 Boulogne-Billancourt, France

28 July 2006

ical Psychiatry 31 (2007) 262268www.elsevier.com/locate/pnpbpwhether verbal decline occurring in normal aging originates froma reduction of the lexico-semantic store integrity or from impairedstrategic retrieval search processes.

acoConsistent with the idea that verbal fluency is a multifactorialtask and that a simple dissociation between semantic and pho-nemic fluency is unlikely to capture the real complexity of theunderlying processes, Troyer et al. (1997) proposed a qualitativeanalysis method for analysing verbal fluency protocols. Theysuggested that optimal performance on fluency tasks, reflected asthe total number of words generated, relies on the use of a com-bination of two main processes: (1) clustering corresponds to theproduction of words within semantic or phonemic categories, anddepends on the integrity of temporal lobe; (2) switching reflects theability to shift to a new category, and relies on frontal lobefunctioning. According to these authors, an optimal fluencyperformance requires the production of clusters of semantically orphonemically related words, and once a subcategory is exhausted,switching to another. By applying methods for measuring switch-ing and clustering, converging evidence for the hypothesis, ac-cording to which switching processes are related to frontal lobefunctioning and clustering processes to the temporal lobe, has beenobtained. Thus, clustering and switching have been found to bedifferentially impaired in patients with neuropsychologicaldisorders. Clustering processes appear to be mostly impaired intemporal brain damage patients (Troyer et al., 1998a), partialtemporal seizure patients (N'Kaoua et al., 2001) and Alzheimerdisease patients (Beatty et al., 2000; Beatty et al., 2002; Trsteret al., 1998; Troyer et al., 1998b). Conversely, switching processesappear to be impaired in patients with frontal brain damage(Troyer et al., 1998a), as well as in Parkinson disease (Raskin etal., 1992; Trster et al., 1998; Troyer et al., 1998b), Huntingtondisease (Ergis et al., 1998; Ho et al., 2002; Rich et al., 1999;Trster et al., 1998), schizophrenia (Robert et al., 1998; Zak-zanis et al., 2000) or depression (Fossati et al., 2003).

Few studies have been carried out concerning the qualitativeanalysis in verbal fluency performance in older adults. Resultsshowed an age-invariance or a small increase of clustering inphonemic fluency tasks and a decrease in the number of switches insemantic tasks (Troyer, 2000; Troyer et al., 1997) suggesting thatage differences in semantic fluency arise specifically from aswitching deficiency, whereas semantic memory components, asassessed by clustering, appear relatively age-insensitive. Accord-ingly, these results are in agreement with the frontal-lobe theory ofcognitive aging (West, 1996; 2000). Furthermore, many neurop-sychopharmacological studies support this view by showing adecline of the prefrontal dopaminergic transmission with age(Ichise et al., 1998; Inoue et al., 2001; Kaasinen and Rinne, 2002;Rinne et al., 1993; Volkow et al., 1996; Wang et al., 1998; Wonget al., 1997).

The effects of dopamine depletion on cognitive functions havebeen largely documented through Parkinson's disease (Kaasinenand Rinne, 2002; Zgaljardic et al., 2003). For instance, Lewiset al. (2005) recently showed that working memory deficits especially manipulationwere related to dopamine depletion inParkinson's disease. However, very little is known about theeffects of the natural course of dopamine depletion in normalaging.Volkow et al. (1998), using PositronEmission Tomography

F. Gierski et al. / Progress in Neuro-Psychopharm(PET) scanning and the competitive dopamine receptor antagonist[11C]-raclopride in healthy volunteers, demonstrated an associa-tion between striatal dopamineD2 receptor density and behavioralmeasures of frontal lobe functioning. These authors found a strongcorrelation between D2 receptor binding and tests of executivefunctioning that require abstraction and mental flexibility(Wisconsin Card Sorting Test), or selective attention and responseinhibition (Stroop ColorWord Test). Comparable results wereobtained by Bckman et al. (2000) who showed an associationbetween striatal dopamine D2 receptor binding and performancein two tests measuring attention and speed of processing.

Consequently, we could assume that enhancing dopaminer-gic activity may improve frontal lobe functioning. Thus, severalstudies have investigated the effects of various dopaminergicagonists (DAs) on the cognitive functions of young subjects.For instance, piribedil, a D2/D3 receptor agonist, was shown toimprove reaction time, immediate and delayed free recall anddual coding tasks performance in young healthy volunteers(Schuck et al., 2002). Bromocriptine, a selective D2 receptoragonist, was shown to facilitate working memory processes(Kimberg et al., 1997; Luciana and Collins, 1997; Luciana et al.,1998). Finally, Kimberg and D'Esposito (2003) showed adeleterious effect of pergolide, a D1/D2 receptor agonist, onphonemic verbal fluency and a beneficial effect on delayed-recall tasks for subjects with greater verbal working memorycapacities. Interestingly, these authors found that high-spanhealthy adults improved their delayed-memory performance onpergolide, while low-span healthy adults performed better onplacebo; they suggest that the effects of DAs could differdepending on verbal working memory capacity of the subjects.

Surprisingly, very few studies explored the effects of DAs inolder adults. In 1975, Scholing and Clausen compared theeffects of piribedil and a placebo in a 14-week open-labeldouble-blind trial; they found a beneficial effect of piribedil onmemory, attention and speed of information processing.Nagaraja and Jayashree (2001) showed that piribedil improvedMini-Mental State Examination scores in older adults with mildcognitive impairment. Finally, in a recent study, Peretti et al.(2004) found that a 2-month treatment period with piribedil waslikely to enhance components of cognitive skill learning (i.e.learning to solve and acquiring a problem solving routine) asassessed by repeated testing on the tower of Toronto task.

The aim of the present studywas to investigate the effects of thedopamine receptor agonist piribedil on verbal fluency in healthyelderly volunteers. Since the age-related decline of brain dopaminelevels has been clearly linked to measures of frontal lobefunctioning, we assumed that it is responsible for the switchingprocessing deficit observed in older adults. Therefore we hypo-thesized that enhancing dopaminergic activity in older adultswould improve their verbal fluency performance by increasingswitching capacities, whereas it would have no effect on clusteringprocesses which are dependant upon temporal structures.

2. Methods

2.1. Subjects

263logy & Biological Psychiatry 31 (2007) 262268Fifty-four native-French-speaking older adults were recruitedby advertisements in order to take part in a larger research pro-tocol. All of them underwent a comprehensive medical

acoexamination for past or current health problems and a neu-ropsychological screening battery. Seven subjects were excludedfrom participation because of the presence of neurological disease(mainly Alzheimer's disease) or medication with psychoactivedrugs. During the study, 3 subjects (6.38%) withdrew because ofadverse events of the treatment (mainly nausea or gastrointestinalsymptoms) and were not included in the analyses below. Another4 subjects discontinued testing for personal reasons, leaving atotal number of 40 subjects.

Age of the included subjects ranged from 65 to 82 years with amean of 72.65 years (S.D.=4.78). The proportion of femalesubjects was 60% and themean level of education was 10.50 years(S.D.=2.44). The Mini-Mental State Examination (MMSE;Folstein et al., 1974) and the Mattis Dementia Rating Scale(DRS; Mattis, 1976) were used as screening measures for ab-normal cognitive decline. Mean MMSE was 28.25 (S.D.=1.29)and mean DRS total score was 140.15 (S.D.=2.87). All subjectsscored above standard cutoffs [24, 129, respectively (Folsteinet al., 1974; Monsch et al., 1995)].

The protocol was approved by the local ethics committee(CPP of Champagne-Ardenne). After complete description ofthe study to the subjects, written informed consent was obtained.

2.2. Study design and assessment instruments

The study design was placebo-controlled and double-blindwith piribedil and placebo treatment. Subjects were randomlyassigned into two parallel sub-groups. Each sub-group receivedone of the following substances orally: piribedil 50 mg extended-release or a placebo (one capsule per day for two months). Be-cause piribedil is an agonist mostly for D2-like family receptors, itappears well positioned to improve frontal lobe functioning. Thechoice of this drug and dosage was also made according toprevious studies (Nagaraja and Jayashree, 2001; Peretti et al.,2004) and with the view that it was likely to give less adversereactions and to be associated with a sustained blood-level overdays of treatment.

Subjects were tested on three occasions: once at baseline,once after two months of the first treatment, and once after twomonths of the second treatment according to a crossover pro-cedure. The cognitive performance of all subjects was assessedduring the baseline period before assignment to double-blindtreatment. The cognitive assessment was performed in thefollowing order, and included: (a) the Mini-Mental State Ex-amination (Folstein et al., 1974); (b) The Mattis DementiaRating Scale (Mattis, 1976); (c) a test of episodic memory(Ergis et al., 1994) adapted from the Grober and Buschke'sprocedure (Grober and Buschke, 1987). This test consisted in a16 to-be-learned items with an immediate free recall in order tocontrol encoding, three free recalls, each immediately followedby cued recall for items not retrieved at free recall. Total recallsare defined as the sum of free and cued recalls; (d) a workingmemory span, assessed using WAIS-R digit span subtest(Wechsler, 1981). This test requires listening to increasingly

264 F. Gierski et al. / Progress in Neuro-Psychopharmlonger lists of digits presented for immediate recall in either theexact order presented (forward span) or in the reverse order(backward span). Scores represent the maximum number ofdigits that can be retained for each condition; (e) the WechslerAdult Intelligence Scale-Revised Digit Symbol Subtest (DSST)(Wechsler, 1981), a test of psychomotor speed and attentionrequiring subjects to rapidly code a series of nonsense symbolsmatching with numbers in 90 s; and (f ) verbal fluency tasks(Cardebat et al., 1990), which are described below.

Because of the pharmacokinetic property of the chosen formof the DA (i.e. piribedil extended-release), time betweencognitive testing and drug administration or time of day werenot controlled. Nevertheless, subjective feelings of alertness andcalmness were assessed at the beginning of each testing sessionusing visual analogue scales derived from Bond and Lader(1974). Compliance with medication during the 2-month treat-ment period was also recorded.

2.3. Verbal fluency tasks

Both semantic and phonemic verbal fluency tasks wereadministered. In the semantic task, subjects were instructed togenerate in 2 min as many different names of animals as possible.In the phonemic task, subjects were required to generate as manywords as possible beginning with the letter P in 2 min, excludingproper name and variants of the same word (e.g. conjugation of asame verb). The order of presentation of the taskswas the same forall subjects, with the phonemic task administered first.

Four scores were obtained for each fluency task: (1) the totalnumber of words generated excluding perseverative errors andintrusive errors; (2) the mean cluster size; (3) the number ofswitches; and (4), according to Trster et al. (1998), the number ofswitches divided by the number of words generated was alsocalculated to take into account the overall performance. Thescoring procedure for switching and clustering was similar to theone used by Troyer et al. (1997). In brief, phonemic clustersconsisted of successively generated words including perse-verations and intrusions beginning with at least the same firsttwo letters (e.g. foot, food), differing only by a vowel sound (e.g.foot, fat), rhyming (flight, fight) or homonymous. In the semantictask, clusters consisted of generated words belonging to the samesemantic subcategory, such as farm animals, insects, pets.Cluster size was counted beginning with the second word in eachcluster and mean cluster size was calculated for the phonemic andthe semantic tests. Phonemic and semantic switches werecalculated as the number of transitions between clusters, includingsingle words. Detailed rules for scoring switching and clusteringcan be found elsewhere (Gierski and Ergis, 2004; Troyer, 2000;Troyer et al., 1997).

All protocols were scored by the same experimenter (i.e. firstauthor), blind for treatment.

2.4. Data analysis

Socio-demographic characteristics, cognitive functioning andverbal fluency performance of groups at baseline were comparedusing the appropriate cross-sectional statistics (independent

2

logy & Biological Psychiatry 31 (2007) 262268sample t test or ). To test for a main effect of piribedil, a seriesof repeated measure analysis of variance (ANOVAs) wereconducted with treatment order (piribedil first or second) as the

Statistical package for windows (SPSS version 10.0.7). Signif-icance level was set at p

treatment periods among groups (F(1,38)=0.27, p=0.61;piribedil first mean compliance: 95.59%6.16; piribedil secondmean compliance: 94.63%5.46).

3.2. Interaction with working memory capacities

According to Kimberg and D'Esposito (2003) we examinedinteractions with subjects' verbal working memory capacities.The forty initial older adults group was then divided into sub-groups bymedian split with the span level, resulting in a subgroupof 22 low-span subjects (0.05). However, the same comparisonson the number of switches revealed a significant differencebetween piribedil (19.445.31) and placebo (17.005.87) forthe high-span group (p=0.01) but not for the low-span group(mean piribedil: 16.325.71, mean placebo: 18.006.52;p=0.11; Fig. 1). This beneficial effect of piribedil was not due todifferences in alertness (span leveldrug interaction: p=0.20),calmness (span leveldrug interaction: p=0.79) or speed ofinformation processing (DSST: span leveldrug: p=0.93).

Fig. 1. Drugs interactions with older adults span-level's on mean number ofswitches of phonemic fluency (meansS.E.M.), p

acoContrastingwith the results ofKimberg andD'Esposito (2003)study showing a deleterious effect of pergolide on phonemicfluency in young healthy subjects, we showed that piribedil wasable to improve phonemic verbal fluency in high span older adultsby an action on switching processes. We thought that this dis-crepancy can originate from multiple interacting factors. Firstly,the DAs employed (i.e. pergolide and piribedil) have severaldifferent pharmacological properties: pergolide is an agonist forD1-like family and D2-like family receptors while piribedil is anagonist mostly for D2-like family receptors (D2 and D3)(Cagnotto et al., 1996). Moreover, drugs doses and administra-tionswere different: acute administration of 0.1mg of pergolide inthe study of Kimberg and D'Esposito versus a 2-month treatmentperiod with 50 mg of extended-release piribedil in our study.Secondly, we also suppose that this discrepancy comes from thestudied population: young healthy adults in Kimberg andD'Esposito study versus older healthy adults in our study. Thus,it is interesting to note that adverse events were quite low in oursample (6.38%) and were higher in Kimberg and D'Espositostudy (39%). As previously seen, this difference can be due eitherto drugs or their administration. Yet, we assumed that DAs givento young healthy adults would have caused hyperdopaminergiaand an important rate of side effects whereas in older adultsknown to have dopaminergic transmission disturbances and asome degree of hypodopaminergia, it would have led to a close tonormal level and to enhanced switching capacities. As a supportfor this assumption, it should be stressed that DAs in monkeyshave been shown to have an inverted U-shape effect with smalldoses improving performance and larger doses having a delete-rious effect (Arnsten et al., 1995).

Another important finding concerns the major role thatworking memory capacities seem to play in the relation betweendopamine and cognitive functions. This has also been demon-strated in studies using different DAs in normal subjects (for areview, see Kimberg and D'Esposito, 2003). However, the com-parison made in our study between the cognitive performances ofthe two groups at baseline enables us to say that besides theirworking memory capacities the subjects were also characterizedby different overall cognitive capacities, low-span subjects per-formingmore poorly on theMMSE and theDRS. Thus,DAs suchas piribedil might be effective at this dose only for older adultshaving high overall cognitive capacities. In a brain imaging study,Volkow et al. (1998) demonstrated a linear relation between age,decrease in the number of striatal dopamine D2 receptors, andneuropsychological performance. Nevertheless the authors alsoemphasized that the correlations with neuropsychologicalperformance remained significant after the partialing out of ageeffects, suggesting that dopamine activity would influence cog-nitive performance regardless of age. Moreover, in a subsequentstudy, Volkow et al. (2000) showed a relationship between mea-sures of brain dopamine D2 receptors and regional brain glucosemetabolism in healthy individuals by the use of positron emissiontomography scans after injection of [11C]-raclopride, to assessdopamine D2 receptors, and [18F]-fluorodeoxyglucose, to assess

F. Gierski et al. / Progress in Neuro-Psychopharmregional brain glucose metabolism. They found that D2 receptors,as well as frontal and cingulatemetabolism, declinedwith age andthat significant correlations between metabolism and D2 re-ceptors in the frontal cortex, the anterior cingulate gyrus, thetemporal cortex, and caudate decrease regardless of age. Quitepossibly, the influence of working memory capacities may be amere consequence of a more general difference in the basal dopa-minergic tone and overall cognitive functioning of the subjects.

5. Conclusion

The results of the present study are consistent with the hypo-thesis that dopaminergic networks are involved in mental flexi-bility and switching processes, and with the important role ofdopaminergic depletion with age and alterations of cognitivefunctions. Although the study is limited by the very small sample,results suggest that piribedil is likely to enhance switching pro-cesses of older healthy adults and support the idea that pharma-cological remediation of cognitive impairment of the elderly hasto be challenged. Future studies with a larger sample shouldattempt to replicate these findings and investigate more speci-fically doseresponse effects and the implication of overall cog-nitive capacities.

Acknowledgements

This research was supported by a grant from the ARSPGassociation. The authors wish to thank S. Harrois, A. Fay, andM. Leroy for their assistance with data collection and R. Niveletfor the medical examination of subjects.

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Effects of the dopamine agonist piribedil on prefrontal temporal cortical network function in n.....IntroductionMethodsSubjectsStudy design and assessment instrumentsVerbal fluency tasksData analysis

ResultsMain effect of piribedilInteraction with working memory capacities

DiscussionConclusionAcknowledgementsReferences