European Journal of Neurology 2005, 12: 9–15

Cognitive performance in people with Parkinson’s disease and mild or

moderate depression: effects of dopamine agonists in an add-on to L-dopa
therapy
I. Rektorováa, I. Rektora, M. Bareša, V. Dostálb, E. Ehlerb, Z. Fanfrdlováa, J. Fiedlerc,
H. Klajblováa, P. KulištÕákd, P. Ressnere, J. Svátováf, K. Urbánekg and J. Velı́skovág
a
First Department of Neurology, Masaryk University, St Anne’s Teaching Hospital, Brno, Czech Republic; bDepartment of Neurology,
Hospital Pardubice, Pardubice, Czech Republic; cDepartment of Neurology, Charles University, Teaching Hospital, Plzen, Czech Republic;
d
Postgraduate Medical School, Department of Neurology, Prague, Czech Republic; eDepartment of Neurology, University Hospital, Ostrava,
Czech Republic; fDepartment of Neurology, Charles University, Teaching Hospital, Královske´ Vinohrady, Prague, Czech Republic;
g
Department of Neurology, Palacky University, Teaching Hospital, Olomouc, Czech Republic

Keywords: In a randomized prospective multi-centre study, we evaluated the cognitive per-

cognitive, depression,
dopamine receptor agon-
ists, Parkinson’s disease
Received 2 October 2003
Accepted 2 July 2004
formances of a group of 41 non-demented patients, all with advanced Parkinson’s
disease (PD) and a current depressive episode, in whom the effects of pramipexole
(PPX) and pergolide (PRG) in an add-on to L-dopa therapy were also studied and
published with regard to motor symptoms of PD, motor complications and depres-
sion. The Trail Making Test, the Stroop test and four subtests (arithmetic, picture
completion, digit symbols and similarities) of the Wechsler Adult Intelligence Scale-
Revised were performed prior to and 8 months after the administration of either PPX
or PRG. We found no statistically significant difference between the two tested drugs
or between the first and the last visit in any of the above-listed neuropsychological
tests. All patientsÕ motor outcomes significantly improved and we conclusively de-
monstrated the anti-depressive effect of PPX. The dissociation of dopaminomimetic
effects on the different tested domains indicates that there are different pathological
mechanisms of cognitive, motor and affective disturbances in advanced PD patients.
In our non-demented group of fluctuating depressed PD subjects, both PPX and PRG
administration in combination with L-dopa were safe in terms of the effect on cog-
nitive performance.

or the interference section of the Stroop test), might be

Introduction
Neuropsychological studies have provided evidence
that executive function is usually affected in non-
demented patients with Parkinson’s disease (PD; Lees
and Smith, 1983; Pillon et al., 1996). Executive pro-
cesses are involved in the planning and allocation of
attentional resources to ensure that goal-directed
behaviour is initiated, maintained and monitored ade-
quately to achieve goals. According to this definition,
executive processes are also an integral part of tasks for
which appropriate response generation requires the
suppression of habitual responses (Jahanshahi et al.,
2000). Recent findings have indicated that selective
frontal dysfunction early in the course of the disease (as
measured, e.g. by the picture completion subtest of the
Wechsler Adult Intelligence Scale, a verbal fluency test,
Correspondence: Irena Rektorová, First Department of Neurology,
Masaryk University, St Anne’s Teaching Hospital, Pekařská 53,
65691 Brno, Czech Republic (tel.: +420 543 182 639; fax:
+420 543 182 624; e-mail: irena.rektorova@fnusa.cz).
an indicative factor for the development of dementia
later in course of the disease (Piccirilli et al., 1997;
Mahieux et al., 1998). These subtle cognitive difficulties
might underlie the mental inflexibility and rigidity of
PD, and could be attributed to the destruction of the
ascending dopaminergic mesocorticolimbic pathway
(Lees and Smith, 1983).
Dopaminergic medication, however, does not produce
a consistent effect on cognitive function in PD. Whilst
some aspects of executive function and working memory
are improved with dopaminergic medication (Girotti
et al., 1986; Gotham et al., 1988; Cooper et al., 1992;
Lange et al., 1992), others remain unchanged (Girotti
et al., 1986; Lange et al., 1992) or even become impaired
(Gotham et al., 1988) following medication. According
to Kulisevsky, dopamine modulation may transiently
improve some cognitive dysfunction in untreated people
with PD; in advanced fluctuating patients, L-dopa ther-
apy may be associated with a decline in cognition
(Kulisevsky et al., 1996, 2000). On the other hand,
Taylor demonstrated that PD subjects with fluctuations

2005 EFNS 9
10 I. Rektorová et al.
and dyskinesias maintained a cognitive profile equal to
the untreated PD patients or PD subjects with good re-
sponses to dopaminergic treatment (Taylor et al., 1987).
The long-term cognitive effects of dopamine modu-
lation with D1, D2 or D3, D2 preferential dopamine
agonists (pergolide [PRG] and pramipexole [PPX],
respectively) in fluctuating PD are not known. In our
8-month national multi-centre prospective randomised
study, we evaluated the cognitive effects of PPX (Mir-
apexin, Pharmacia C̀eská republica s.r.o., Prague,
Czech Republic) and PRG (Permax, Eli Lilly, Eli Lilly
C̀R s.r.o., Prague, Czech Republic), in an add-on to
L-dopa therapy, in a group of advanced PD patients
with a current depressive episode of mild or moderate
intensity. Motor and mood outcomes of both tested
drugs in the same group of subjects have already been
published (Rektorova et al., 2003).
Subjects and methods
Subjects
The group comprised 41 patients – 16 women (39%)
and 25 men (61%) – suffering from advanced idiopathic
PD according to the ÔParkinson’s Disease Society Brain
BankÕ criteria (Gibb and Lees, 1988; Hughes et al.,
1992), fluctuations and/or dyskinesias, and a current
depressive episode of mild or moderate intensity,
defined according to the 10th edition of the Interna-
tional Classification of Diseases (World Health Organ-
ization, 1993). None of the patients was demented
(Mini-mental Status Examination [MMSE] score £ 24),
for exclusion criteria see Rektorova et al., 2003. All
patients were treated with L-dopa, and none of them
were on antidepressants and/or anxiolytics, neuroleptics
or anticholinergic drugs, neither during the study nor in
a 4-week period of stable medication prior to entering
the study. The presence of any other psychiatric illness,
a history of a psychotic disorder and the presence of
hallucinations, delusions and/or delirium excluded a
patient from the study. For demographic data, see
Table 1. No significant difference was observed between
the groups in any of the entry characteristics.
Study design and assessments
Patients were randomised to receive either PPX or PRG
in an Ôadd-onÕ to L-dopa therapy. The total duration of
the study was 8 months. For a detailed description of the
methods, see Rektorova et al. (2003). The recommended
stable daily dose in both PPX and PRG groups was 3 mg
(a daily milligram conversion 1:1; Goetz et al., 1999) and
the permissible dosage ranged from 1.5 to 4.5 mg per day.
The doses of each preparation were increased in
accordance with the titration procedures recommended
by the manufacturing companies (Pharmacia for Mir-
apexin and Eli Lilly for Permax). It was recommen-
ded that the total daily dose of L-dopa be decreased
gradually during the study, and L-dopa doses were
monitored at every visit. The study was open for both the
patient and the physician; for the psychologist who per-
formed the psychometric tests, the study was blind as to
which of the preparations was used. All subjects gave
written informed consent to the research protocol, which
was approved by the appropriate ethics committee.
Neuropsychological tests used for screening
The Trail Making Test (TMT), parts A and B (Hal-
stead, 1947); the words (A), colours (B), and coloured
word (C) tasks of the Stroop test (Golden, 1978), each
limited to 45 s; and the picture completion, arithmetic,
digit symbols and similarities subtests of the Wechsler
Adult Intelligence Scale-Revised (WAIS-R) (Wechsler,
1981) were performed during the ÔonÕ state prior to and
8 months after the administration of either PPX or
PRG. The IQ score (see the Table 1) was calculated
prior to DA agonist administration using the four
subtests of the WAIS-R (Cyr and Brooker, 1984).
The TMT has two versions. TMT A requires the
subject to connect a sequence of numbers dispersed
across a page as quickly as possible without lifting the
pen from the paper, and is a simple measure of beha-
vioural regulation and motor speed. In TMT B, the
subject alternates between sequences of numbers and
letters, which necessitates alternating the mental sets
(switching attention between two types of items). For
each version, the time to complete the task is recorded.
Attentional set shifting has been a frequently reported
deficit in PD (Cools et al., 1999).
The Stroop test consists of three sections. In the first,
patients are required to read aloud, as quickly as
Table 1 Patient characteristics by group
Pramipexole Pergolide
Age (years) 59.7 ± 7.7 63.5 ± 7.5
L-Dopa administration (years) 5.9 (1–16) 5.4 (1–19)
UPDRS III score 31.5 ± 12.0 31.8 ± 10.5
Hoehn and Yahr scale 2.7 ± 0.8 3.0 ± 1.0
Mini-Mental State examination 28.5 ± 1.6 28.9 ± 1.9
WAIS-R: IQ 99.7 ± 9.8 103.2 ± 14.4
Zung Self-Rating Depression Scale 59.6 ± 6.7 60.4 ± 7.3
Motor fluctuations (%) 100 100
Dyskinesias (%) 77 53
Where appropriate, data are mean values ± SD.
UPDRS III, Unified Parkinson’s Disease Rating Scale, Motor
examination; WAIS-R, Wechsler Adult Intelligence Scale-Revised.

2005 EFNS European Journal of Neurology 12, 9–15
 Effects of dopamine agonists on cognitive performance in PD 11

possible, words (colour names) written in columns. The
second section consists of series of crosses printed in
coloured ink, the task being to name the ink colours as
quickly as possible. The third (interference) section
consists of words (names of colours), ink colours dif-
fering from the written word (incongruent ink colour).
The task is to name the ink colours as quickly as
possible, ignoring the written word. The third section
specifically concerns proactive interference and the
ability to ignore habitual responses. We used the
interference score calculated as follows: CW – Ôexpected
CWÕ ; [Ôexpected CWÕ ¼ (C · W)/(C + W), where W
corresponds to read names, C to colour names of col-
oured crosses, and CW to incongruent colour names of
colour word (Golden, 1978)].
The Picture Completion subtest (WAIS-R) consists
of finding, in a card series, a missing detail in a familiar
picture. The task is known to require several cognitive
abilities, such as sustained attention, shape or situa-
tional analysis, and the development of new strategies
across different cards. The Arithmetic subtest of WAIS-
R requires sustained attention, intact working memory,
logical judgement, and memory retrieval of previously
acquired knowledge. The Digit Symbols subtest reflects
visuomotor coordination, level of attention and con-
centration, motor speed, and the ability to learn a new
task and maintain a steady response. The Similarities
subtest of WAIS-R again requires several cognitive
abilities, such as abstract reasoning and generalisation.
Screening of motor status and depression
Apart from cognitive evaluation, motor status [Unified
Parkinson’s Disease Rating Scale (UPDRS) (Fahn
et al., 1987)] and depression [Montgomery–Asberg
Depression Rating Scale (MADRS) (Montgomery and
Asberg, 1975)]; Zung Self-Rating Depression Scale
(Zung, 1965) during the ÔonÕ state, daily L-dopa doses,
and adverse effects were studied; these results have been
published elsewhere (Rektorova et al., 2003).
Data analysis
When possible, raw scores were converted into T-scores
or profile scores based on corrected norms. For the
evaluation of changes in the scores of the tests under
observation, we used variance analysis – a model with
fixed effects and repeated measuring – and the multiple
comparison method, based on the methods of Newman
and Keuls. For the simple analysis of change between
the starting and final values in tests that were performed
only twice, we used the t-test or the non-parametric
Wilcoxon test.
Results
Table 2 shows the valid numbers of subjects in whom
the cognitive test scores were accurately obtained and
analysed out of 19 (PPX group) and 17 (PRG group)
subjects that completed the study. There was no sta-
tistically significant difference, neither between the
group of subjects that received PPX and the group
that received PRG, nor between the baseline and the
last visit of the trial in any of the psychometric tests
results (see Table 2 for test results). The difference
between both tested drugs with regard to the Stroop
interference test tended to approach a statistical
significance (ANOVA; F ¼ 3.98, P ¼ 0.06), but there
was no significant difference between the first and the
sixth visit, neither in the PPX nor in the PRG group

Table 2 Neuropsychological tests results at

baseline and the last visit (indicated as visit 1 Pramipexole Pergolide
and visit 6)
Cognitive test Visit 1 Visit 6 n Visit 1 Visit 6 n

Picture completiona 10.7 ± 2.6 11.1 ± 3.2 15 11.1 ± 2.6 12.2 ± 2.7 12
Arithmetica 10.7 ± 2.3 9.9 ± 2.9 15 10.1 ± 2.5 10.1 ± 3.1 12
Digit symbolsa 8.1 ± 1.8 8.5 ± 2.4 15 9.0 ± 3.2 9.8 ± 3.0 12
Similaritiesa 10.1 ± 1.5 10.2 ± 2.1 15 10.8 ± 2.2 11.0 ± 3.0 12
TMT, part Ab 64.1 ± 26.2 72.6 ± 63.8 17 62.9 ± 32.3 70.4 ± 72.4 17
TMT, part Bb 113.7 ± 58.8 145.4 ± 77.1 16 128.1 ± 79.5 132.8 ± 91.8 15
Stroop interferencec 53.1 ± 12.8 61.5 ± 7.9 13 59.5 ± 11.0 61.5 ± 8.2 12

Where appropriate, data are mean values ± SD.

Picture completion, arithmetic, digit symbols and similarities are subtests of Wechsler Adult
Intelligence Scale-revised.
ÔnÕ indicates the total number of patients that completed the test correctly.
TMT, Trail Making Test.
a
Profile scores.
b
Raw scores.
c
T-scores.

2005 EFNS European Journal of Neurology 12, 9–15

12 I. Rektorová et al.
(Wilcoxon match-pair test; P ¼ 0.07 for PPX and
P ¼ 0.38 for PRG).
A statistically significant (at a 1% level of signifi-
cance) decrease occurred in motor and depression
scores as measured by the UPDRS and the Zung Self-
Rating Depression Scale similarly in both groups; the
decrease of MADRS scores reached a level of statistical
significance (at a 5% level of significance) only in the
PPX group (see Rektorova et al., 2003). The mean daily
dose of PPX was 2.7 ± 0.5 mg; the mean daily dose of
PRG was 3.0 ± 0.3 mg for PRG. The mean daily
L-dopa dose dropped significantly (at a 1% level of
significance) in both groups. Five patients dropped out
of the study because of side effects, which included
orthostatic hypotension, aggravation of dyskinesias,
excessive daytime sleepiness and visual hallucinations,
and which ceased after the discontinuation of the
tested drugs. For further details in motor and mood
outcomes, L-dopa decrease and adverse events see
Rektorova et al., 2003.
Discussion
DA modulation and cognitive tests
In PD, cognitive impairment, in particular executive
dysfunction, has been related to the dysfunction of the
dorsolateral striatoprefrontal loop consecutive to the
loss of dopaminergic nigral neurons (Alexander et al.,
1986; Mega and Cummings, 1994). However, the effect
of dopamine stimulation (dopaminergic treatment) on
cognitive functions in PD has not yet been resolved. In
some studies, the positive effect of L-dopa on working
memory and other frontal functions has been demon-
strated (e.g. Cooper et al., 1992; Lange et al., 1992;
Owen et al., 1995; Growdon et al., 1998); other studies
have demonstrated the opposite (e.g. Gotham et al.,
1988; Poewe et al., 1991; Kulisevsky et al., 1996). The
discrepancies between studies can be at least partially
explained on the basis of different evolution of patients
examined: de novo patients and/or good responders
versus fluctuating patients tending to deteriorate with
L-dopa (Taylor et al., 1987; Kulisevsky et al., 1996,
2000; Mattay et al., 2002). It has been suggested that
high L-dopa levels in the latter subgroup of patients
may be associated with ÔoverstimulationÕ of some areas
of the frontal cortex where dopamine transmission is
relatively intact, with a consequent decline in cognitive
function (Gotham et al., 1988; Kulisevsky et al., 1996;
Nieoullon, 2002). In our study, all fluctuating patients
improved after the administration of either PPX or
PRG in terms of the motor symptoms of PD (UPDRS
III) and the treatment complications (UPDRS IV), and
could therefore be classified as good responders in this
respect. It is noteworthy that the mean adjusted profile
scores and T-scores in all performed tests were within
the normal ranges, except for the tests reflecting the
motor speed (such as TMT or the digit symbols subtest
of WAIS-R). Even though consecutive patients were
enrolled in the study it should be pointed out that the
presence of dementia as measured by the MMSE
(MMSE score £ 24) as well as the presence of halluci-
nations, delusions, or delirium and a medical history of
a psychotic disorder excluded a patient from the study
in accordance with the exclusion criteria (see also
Rektorova et al., 2003 for details). It may be possible
that long-term dopaminergic stimulation has little or no
impact on subjects that do well on frontal lobe tests,
whilst it may be different for subjects with prominent
cognitive impairment. The absence of cognitive effects,
in contrast with the modulation of motor and mood
symptoms, indicates that the pathological mechanisms
of cognitive, motor and affective disturbances are dif-
ferent in advanced non-demented PD patients.
Stimulation of different DA receptor subtypes by
respective DA agonists
Even though some experimental data in animal models
and human volunteers have shown a preferential role of
D1 versus D2 receptors for prefrontal task modulation
(Williams and Goldman-Rakic, 1995; Muller et al.,
1998), our results did not reveal any difference between
direct stimulation of D1, D2 and D3, D2 preferential
DA agonists or between L-dopa alone versus combined
dopaminergic stimulation with L-dopa plus DA agonist.
To our knowledge, there has not yet been a study that
directly addresses this topic in PD patients. Kulisevsky
showed the lack of remarkable cognitive differences
between direct (PRG) and indirect (L-dopa) combined
stimulation of D1 and D2 receptors with regard to
cognitive performance in previously untreated patients
with PD (Kulisevsky et al., 2000).
Dissociation between cognitive performance, motor
disability and depression
In our study, we demonstrated the dissociation of
cognitive performance and motor disability as meas-
ured by UPDRS III and UPDRS IV, as well as the
dissociation of cognitive function and mood, with a
more pronounced difference in the PPX group as
measured by MADRS and the Zung Self-Rating Scale.
Whilst all patients improved in motor scores, and
patients in the PPX group also improved consistently in
mood outcomes, there was no significant change in
cognitive performance for either the PPX or PRG
group. Cooper examined some cognitive domains and

2005 EFNS European Journal of Neurology 12, 9–15
 Effects of dopamine agonists on cognitive performance in PD
the relationship between cognition, depression and
motor disability in sixty newly diagnosed and untreated
PD patients and 37 matched healthy controls (Cooper
et al., 1991). They found deficits in executive processes
(set-formation, cognitive sequencing and working
memory), visuomotor construction and semantic flu-
ency that were not correlated with motor disability.
Cognitive sequencing, set-formation and set-shifting
deficits tended to be associated with depression, but
otherwise there was no association between cognition
and depression. Cools et al. (2001) demonstrated the
lack of correlation between depression (as measured by
the Beck Depression Inventory scores) and switch costs
in task-set switching in PD patients. The dissociation
between cognitive and motor performance has been
demonstrated by others (i.e. Rafal et al., 1984; Taylor
et al., 1987), but the situation may be more complicated
with regard to major depression and frontal lobe related
cognitive impairment. PD patients with major depres-
sion tend to be more cognitively impaired than non-
depressed patients (Starkstein et al., 1989; Troster
et al., 1995; Kuzis et al., 1997). Kuzis et al. (1997)
suggest that frontal lobe related cognitive impairments
may result from an interaction between the mechanisms
of major depression and neuropathologic factors in PD.
In our study, we did not compare depressed and non-
depressed subjects, so we cannot make any conclusions
in this respect. The dissociation of effects of dopamin-
ergic stimulation on different domains of PD sympto-
matology may be explained by the fact that the
cholinergic system has also been implicated in cognitive
dysfunction (Dubois et al., 1987; Pillon et al., 1989).
Other neurotransmitter systems, such as serotoninergic
or noradrenergic pathways, display projections to the
prefrontal cortex and could also be involved (Cooper
et al., 1992). Anticholinergic drug treatment in PD
patients have led to a long-term cholinergic blockade
and a deteroriation of executive functions (Cooper
et al., 1992; Bedard et al., 1999). These deficits are
probably related to cholinergic deficits in the nucleus
basalis and tegmental nuclei (pedunculopontine and
laterodorsal) projecting to the thalamus, the basal
ganglia and the prefrontal cortex (Jellinger, 1988;
Dujardin et al., 2001). Furthermore, a blockade of
muscarinic receptors in PD has been associated with
increased Alzheimer-type pathology (Perry et al., 2003).
The positive cognitive effects of acetylcholinesterase
(ACHE) inhibitors in PD and dementia with Lewy
bodies that may be attributable to the same biological
abnormality (Colosimo et al., 2003) seem to support
this notion (e.g. McKeith et al., 2000; Reading et al.,
2001; Aarsland et al., 2002).
The limitations of our preliminary trial include the
small number of subjects, the absence of a control

2005 EFNS European Journal of Neurology 12, 9–15
13
group (e.g. a placebo group and a non-depressed
advanced PD group) and the Ôsemi-openÕ design
(performed by an independent ÔblindÕ neuropsycholo-
gist). The possible susceptibility of some components
of the neurocognitive tests to practice effects was
limited by the fact that the battery was performed only
twice with an 8-month interval period between the two
measurements. The strengths of the present study in-
clude the use and comparison of D1, D2 (PRG) and
D3, D2 (PPX) preferential DA agonists over an
extended period in a Ôreal lifeÕ manner, and the inclu-
sion of a unique population of advanced PD with
depression that is believed to be a PD subgroup more
susceptible to cognitive changes (Starkstein et al.,
1992). Nevertheless, testing effects of DA agonists
administration made it impossible to study the sub-
group of patients with dementia (MMSE score £ 24)
and/or a history of a psychotic disorder and the
presence of hallucinations, delusions or delirium be-
cause of safety reasons. The primary purpose of this
study was to monitor and compare the safety of long-
term use of PPX and PRG in combination with L-
dopa in non-demented subjects with fluctuating PD
and mild or moderate depression with regard to their
cognitive performance. We conclude that both PPX
and PRG administration in combination with L-dopa
are safe in fluctuating depressed non-demented PD
subjects in terms of cognitive performance. Further
studies are indicated, involving larger sample sizes, and
specifically addressing the long-term cognitive effects
of different DA agonists in fluctuating PD with and
without mood change.
Acknowledgements
We thank J. Vorlicek, Institute of Physiology, Academy
of Science of the Czech Republic, for his assistance with
data analysis, and to the neuropsychologists in various
centres for their assistance in neuropsychological test-
ing.
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