Poor dopaminergic response of impaired dexterity in parkinson's disease: bradykinesia or limb kinetic apraxia?
Movement DisordersVol. 23, No. 12, 2008, pp. 1701–1706
Ó 2008 Movement Disorder Society
Poor Dopaminergic Response of Impaired Dexterity in
Parkinson's Disease: Bradykinesia or Limb Kinetic Apraxia?
Andreas Gebhardt, MD,1 Tim Vanbellingen, MSc,1 Fabio Baronti, MD, PhD,1
Bernd Kersten, PhD,2 and Stephan Bohlhalter, MD3*
1Parkinson Center, Klinik Bethesda, Tschugg, Switzerland
2Department of Psychology, University of Bern, Bern, Switzerland
3Division of Cognitive and Restorative Neurology, Inselspital, Department of Neurology,
Bern University Hospital, Bern, Switzerland
Abstract: Patients with Parkinson's disease (PD) often show
or 1st vs. 2nd trial), task (FT vs. CR), and handedness (domi-
impaired manual dexterity even when being only minimally
nant vs. nondominant) as within-subject factors. In patients
bradykinetic, suggesting that they may have limb kinetic
with PD, regardless of hand involved, dopaminergic treatment
apraxia (LKA), that is, a loss of ﬁne motor skill not explained
only mildly improved CR performance, in contrast to the
by elemental motor deﬁcits. To explore this dissociation, we
strong increase in FT scores (up to the level of controls), as
investigated the differential dopaminergic responsiveness of
demonstrated by the signiﬁcant triple interaction of the factors
dexterity and bradykinesia in PD. Twelve patients with PD (4
group, medication, and task (F
7.9, P 5 0.01; h2 5
women, age 64.4 6 8.3, mean 1 SD) and 12 matched healthy
0.26). Furthermore, CR scores were considerably lower, both
controls (64.8 6 8.9) were tested twice in ON vs. OFF and 1st
in OFF and ON, than in normal controls, pointing to a
vs. 2nd trial, respectively. A coin rotation (CR) task was
substantial impairment of dexterity in PD (P < 0.001). In con-
applied to assess dexterity and a ﬁnger tapping (FT) task to
clusion, impaired manual dexterity showing signiﬁcantly
assess bradykinesia. Performance was followed by video re-
diminished response to dopaminergic treatment suggests that
cording and analyzed by measuring the frequency of CR and
dextrous deﬁcits in PD are related to LKA rather than
FT during three 10-second periods. Statistical analysis was
bradykinesia. Ó 2008 Movement Disorder Society
done by a mixed factorial design with group (PD vs. controls)
Key words: limb kinetic apraxia; Parkinson's disease;
as between-subject factor and medication (ON- vs. OFF-state
coin rotation; ﬁnger tapping; premotor cortex
Impairment of ﬁne motor control is a frequent com-
recently suggested that loss of dexterity in PD may
plaint in Parkinson's disease (PD). The patients typi-
qualify for the presence of a motor disorder called
cally report difﬁculties with everyday tasks, such as
limb kinetic apraxia (LKA), which is relatively inde-
tying laces or buttoning clothing. Other daily chal-
pendent of bradykinesia-rigidity.1 Hugo Liepmann in
lenges are the use of mobile phones, remote controls
1920 ﬁrst coined the term LKA as loss of ﬁne motor
for TVs, or computer keyboards. The dextrous deﬁcit
control not explained by elementary motor deﬁcit such
may be prominent even when motor functioning is rea-
as, for instance, weakness or ataxia.2 LKA has been
sonably well, that is, when patients are in good ON
considered as a higher-order motor disorder since it is
without disturbing dyskinesias. Therefore, it has been
thought to be based on the dysfunction of premotorareas, which are located upstream to primary motor
*Correspondence to: Dr. Stephan Bohlhalter, Department of Neu-
cortex.3 However, in contrast to other types of apraxia
rology, Division of Cognitive and Restorative Neurology Inselspital,
it does not represent a true cognitive-motor disorder
Bern University Hospital, Switzerland
with temporal-spatial or conceptual deﬁcits. LKA
No potential conﬂict of interest.
rather results when the transmission between time-
Received 8 May 2008; Revised 4 June 2008; Accepted 6 June
space representations of skilled movements to target
areas of motor cortex is interrupted,4,5 thereby adopting
Published online 22 July 2008 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22199
an intermediate position between higher-level apraxia
A. GEBHARDT ET AL.
and elemental motor disorder. LKA is frequently seen
TABLE 1. Demographic and clinical data
in stroke6 and neurodegenerative disorders,7 particu-
larly corticobasal degeneration.8,9 It is well-known thatprecise and independent ﬁnger movements, which are
typically impaired in LKA, are particularly affected in
PD.10 However, these deﬁcits have traditionally not
been considered to be limb kinetic apraxic in nature
but have been rather attributed to the parkinson-
ism.4,7,11 Therefore, the concept of LKA in PD remains
Disease duration (years)
In this study, we chose the coin rotation (CR)1,6,12
Levodopa equivalent (mg/d)
and ﬁnger tapping (FT) tasks as paradigms for motor
assessment. CR represents a measure of both ﬁnger dex-terity and motor speed. FT mainly registers slowness of
regular medication produced a predictable and good
motion (bradykinesia), is part of clinical routine assess-
ON state. All patients with PD were examined in the
ment and is item 23 of the Uniﬁed Parkinson Disease
morning in the ‘‘practically deﬁned OFF'' state (at least
Rating Scale (UPDRS). The aim of this study is to
12 hours after the last dose of dopaminergic treatment)
investigate the differential response of dexterity (CR)
and in their ‘‘best ON'' (on average 1.5 to 2 hours after
and bradykinesia (FT) to dopaminergic treatment in
dopaminergic treatment). For the assessment of dexter-
patients with PD compared to age-matched normal con-
ity, the subjects were instructed to rotate a Swiss 50-
trols. We hypothesized that dexterity will be consider-
Rappen coin (corresponding exactly in size to a US-
ably less responsive to dopaminergic treatment than bra-
Nickle) between their thumb, index, and middle ﬁnger
dykinesia supporting the concept of LKA in PD.
(CR task). For measurement of bradykinesia they wereasked to tap their index ﬁnger against the thumb (FT
SUBJECTS AND METHODS
task). Each task was performed as fast as possible and
with both hands separately. In the CR task, the limbkinetic deﬁcit is indicated by the reduced number of
Twelve patients with PD and wearing off ﬂuctua-
half turns per time unit and coin drops. The CR scores
tions as well as 12 age- and sex-matched healthy con-
were calculated according to the following formula12:
trols participated in the study. Details of demographic
CR score 5 half turns 2 [(coin drops 3 0.1) 3 half
and clinical data are listed in Table 1.
turns]. Since in patients the order of testing in OFF
Patients were diagnosed with PD according to UK
and ON was not counterbalanced, the healthy volun-
Brain Bank diagnostic criteria13 and recruited from our
teers were studied twice (within the same day or up to
specialized Parkinson Center. They were included in the
2 days later) to control for the potential bias of task
study if stable wearing off ﬂuctuations and/or early
morning off were present. Exclusion criteria were sig-
All patients were given a short period of practice
niﬁcant medical comorbidity or dementia as deﬁned by
before the test started. All trials were videotaped dur-
Mini Mental Status Examination (MMSE)14 scores
ing three periods lasting 10 seconds, for each hand
below 27. Patients with dyskinesias, tremor, or musculo-
separately. CR and FT alternated as ﬁrst task from sub-
skeletal disorders interfering with the CR task were also
ject to subject. After test performance, the trials were
excluded. All subjects were right-handed as assessed by
analyzed with VLC media player (Version 0.8.6d Janus
the Edinburgh Handedness Inventory.15 The total daily
(Intel)) in slow motion. CR (half turns) and FT during
dosage of levodopa ‘‘equivalent'' was determined as fol-
10 seconds were counted, respectively. The last half-
lows: 100 mg levodopa 5 1 mg cabergoline 5 1 mg
turn or ﬁnger tap of an individual 10-second period
pramipexole 5 1 mg pergolide 5 5 mg ropinirole. Writ-
was included when at least half of the movement was
ten informed consent was obtained from all patients
according to the Declaration of Helsinki, 1975.
Motor Assessment: Manual
Dexterity and Bradykinesia
Statistical analyses were performed using SPSS for
Patients were tested during their hospital stay, when
Windows (version 15.0.0; SPSS, Inc. Chicago, IL). We
medical treatment was optimized, that is, when their
employed a mixed factorial design with group (patients
Movement Disorders, Vol. 23, No. 12, 2008
LIMB KINETIC APRAXIA IN PARKINSON'S DISEASE
with PD vs. normal controls) as between-subject factorand medication (ON- vs. OFF-state and 1st vs. 2ndtrial, respectively), task (FT vs. CR), and handedness(dominant vs. nondominant) as 2 3 2 3 2 within-sub-ject factors. In addition, differences of interest in per-formances either within or between subjects were ana-lyzed using post hoc paired and unpaired t-tests,respectively. Finally, we analyzed the potential rela-tionship of disease duration and age with CR task per-formances by Pearson's correlation analysis. Levels ofsigniﬁcance was set at P 5 0.05 (two-tailed). All val-
FIG. 1. The ﬁgure demonstrates that, irrespective of hand involved,
ues are expressed as mean 6 SEM (standard error).
dopaminergic medication, in contrast to FT, only mildly improvedCR performance in patients with PD, which is reﬂected in the signiﬁ-cant triple interaction effect of the factors group (PD vs. controls),medication (ON vs. OFF and 1st vs. 2nd trial, respectively), and task(FT vs. CR). No signiﬁcant differences could be detected between
the 2 trials of normal controls. Note the considerably lower mean CRscores of patients compared to controls, while FT scores in ON
None of the patients had tremor in OFF or dyskine-
reached almost normal levels.
sias in ON interfering with the tasks. Two patients hadmild dyskinesias of the neck and trunk during the tasksin ON. Overall, in 6 patients mild peak-dose dyskine-
From the factorial analysis further results emerged.
sias were present in the history.
As predictable in a right-handed study population,
The main ﬁnding of this study was that, regardless
there was a signiﬁcant main effect of handedness (F1,22
of hand involved and taking into account the potential
5 6.63; P 5 0.02; h2 5 0.23) indicating that perform-
practice effect of task repetition, dopaminergic treat-
ances were generally better on the right than left side.
ment in patients with PD, in contrast to FT, only
This was more pronounced in OFF states or ﬁrst trials,
slightly improved CR performance, as demonstrated by
respectively, as shown by the signiﬁcant interaction
the signiﬁcant triple interaction effect of the factors
handedness by medication (F
4.5, P 5 0.04, h2
group (PD vs. controls), medication (ON vs. OFF and
5 0.17). Furthermore, differences in right and left
1st vs. 2nd trial, respectively), and task (CR vs. FT)
hand performances were tentatively more pronounced
7.9, P 5 0.01; h2 5 0.26). The ﬁndings are
in the CR task of PD patients (CR-L vs. CR-R, see Ta-
depicted in Figure 1.
ble 2). However, overall, handedness played a minor
Assessed by post hoc paired t-tests in patients with
role, as all other interactions with handedness did not
PD the mild improvement of CR task from OFF to ON
reach signiﬁcance. Most importantly, the effect of
state was signiﬁcant (P 5 0.02), it was insigniﬁcant
handedness did not differ between patients and con-
when analyzed for both hands separately (see Table 2).
trols, as evidenced by insigniﬁcant interactions with
By contrast, differences in FT scores between OFF and
the factor group, e.g., the interactions handedness by
ON were, as expected, highly signiﬁcant even when
0.49, P 5 0.49; h2 5 0.02).
each hand was considered alone (P < 0.001). The dis-
In line with the different task demands, both patients
sociation of CR and FT response to dopaminergic
and controls performed considerably better in the FT
treatment was present in all patients. Performance
than CR task, which is reﬂected by the highly signiﬁ-
scores of corresponding 1st and 2nd trials within
cant main effect of task (F
120.1, P < 0.001; h2
healthy controls were not different for all experimental
5 0.85). High signiﬁcance could also be detected for
the main effect of medication (F
Post hoc unpaired t-tests revealed that the PD
0.001; h2 5 0.7). However, this medication effect was
patients scored signiﬁcantly lower in CR task than nor-
explained mainly by the better performance in ON of
mal controls, both in ON and OFF, indicating that the
patients with PD as demonstrated by the large interac-
impairment of dexterity was substantial (P < 0.001;
tion of medication and group (F
see also Table 2). By contrast, although in ON the FT
scores of patients with PD did not reach the level of
We ﬁnally performed Pearson's correlation analyses
healthy controls, the difference was not statistically
of the CR task performances as a function of age or
signiﬁcant (P 5 0.11). The results of descriptive and t-
disease duration. The ﬁndings demonstrated a signiﬁ-
test statistics are summarized in Table 2.
cant negative correlation of age with CR task perform-
Movement Disorders, Vol. 23, No. 12, 2008
A. GEBHARDT ET AL.
TABLE 2. Mean performance scores of patients with PD
measure of bradykinesia than is FT. However, this pos-
and age-matched healthy controls
sibility is unlikely, since bradykinesia as a cardinalsign of PD is typically most responsive to dopaminer-
gic treatment. Moreover, dopaminergic efﬁcacy has
been demonstrated to be particularly prominent for the
15.1 6 0.5§ 15.3 6 0.5
frequently observed extra slowness of complex sequen-
tial movements in PD.16
19.2 6 2.4** 26.6 6 2.7**,§§ 29.8 6 1.5
It is conceivable that abnormal sensorimotor integra-
tion, in particular if based on defective kinesthesia as
demonstrated during passive movements in PD,17,18
Data shown as mean 6 SEM.
may contribute to the poor performance in CR and
*P 5 0.02; **P < 0.001, incl. OFF vs. ON of FT-L and –R, all
explain in part the deﬁcient response to dopaminergic
other paired t-tests between OFF vs. ON and 1st vs. 2nd trials were
treatment.19 The low CR scores may also be reﬂected
insigniﬁcant; §P < 0.001, for all OFF vs. 1st trial conditions and allON vs. 2nd trial comparisons of CR; §§P 5 0.11, incl. insigniﬁcant
by some impairment of interjoint coordination as has
ON vs. 2nd trial comparisons of FT-L and –R.
been shown by kinematic analysis.20 However, at the
CR, coin rotation; FT, ﬁnger tapping; L, left; R, right.
clinical level, our patients did not show any sensoryabnormality which could account for the deﬁcit in CR.
ance of the dominant hand in OFF state (r 5 20.59, P
Therefore, although the etiology of dexterity problems
5 0.04) of patients with PD. Other task conditions did
in PD is certainly multifaceted, we think the loss of
not signiﬁcantly correlate with age in both patients and
individual digital control measured by CR is best
normal subjects, and there were not any signiﬁcant cor-
described as LKA.
relations with disease duration for all measurements.
Recently, signiﬁcant improvement of both movement
time as well as dexterity has been demonstrated withdeep brain stimulation (DBS) and/or medication inadvanced PD.21 In contrast to this study, dexterity was
measured using a rotation task involving only the index
Loss of manual dexterity is an important source of
ﬁnger and thumb, which did not assess segregated ﬁnger
disability in PD. The deﬁcit is particularly apparent
innervations as required for the CR task. Furthermore,
when manipulating small objects that require the abil-
the ﬁndings were probably inﬂuenced by an additional
ity to selectively innervate and control individual ﬁnger
reduction of tremor and dyskinesias after DBS.
muscles. Loss of this type of independent digital dex-
The dextrous disability in our patients was substan-
terity not explained by elemental motor deﬁcit has
tial as their mean CR scores were more than 50%
been deﬁned as LKA and can be assessed straightfor-
below those of healthy controls, irrespective of medica-
wardly by the CR task.1,6,12 These ﬁndings demon-
tion status. CR scores were particularly low for the left
strate that within the group of patients with PD dopa-
hand, which is probably related to the handedness.
minergic treatment had only little inﬂuence on CR
Nonetheless, handedness did not play greater role in
scores, while, as expected, clearly improved FT scores
patients than controls as the insigniﬁcant interaction of
by almost 40%. In addition, in line with a previous
group and handedness demonstrated. The discrepancy
report,1 a dissociation of strongly reduced CR and
is less likely explained by asymmetry of the disease,
almost normal FT scores in ON stage compared with
since in patients, FT scores were only minimally dif-
healthy controls could be detected. Some improvement
ferent between left and right hand.
of CR scores in ON was expected, since this task
It has been speculated that learned non-use of hands
measures both dexterity and motor speed. However,
due to long-term bradykinesia-rigidity may underlie the
the differential response of ﬁnger dexterity and brady-
development of LKA in patients with PD.1 Therefore,
kinesia clearly demonstrates that difﬁculties with dex-
the LKA may be more pronounced in later stages of
trous movements are only partially related to elemen-
the disease. However, in this study, disease duration
tal, speciﬁcally, extrapyramidal deﬁcits. Therefore, the
did not correlate with CR scores. There was a weak
ﬁndings support the concept that patients with PD suf-
negative correlation of dexterity with age on the domi-
fer from LKA, which is independent of dopaminergic
nant hand suggesting that limb kinetic impairment may
deﬁcit. Based on the almost normal FT but consider-
be greater in elderly patients. More studies are needed,
ably reduced CR scores in ON the question may arise
though, to clarify the inﬂuence of these demographic
whether the CR task is simply a much more sensitive
factors on dexterity in PD.
Movement Disorders, Vol. 23, No. 12, 2008
LIMB KINETIC APRAXIA IN PARKINSON'S DISEASE
It has been argued that introducing a new term such
may eventually provide a more rational basis for their
as LKA to describe dexterity problems in PD adds lit-
tle to the current knowledge and elucidation of under-lying mechanism.22 Nonetheless, we think that the con-
Acknowledgment: We are very grateful to Dr. Brian
cept of LKA in PD may have in fact heuristic implica-
Martin for skillful editing.
tions by providing a model for better understanding ofthe pathophysiology underlying impaired ﬁne motorskill and ultimately for the prospective of more tar-
geted treatment. LKA is thought to be caused by a dis-
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Journal of Affective Disorders 126 (2010) 293–298 Contents lists available at Journal of Affective Disorders Benzodiazepine and cyclopyrrolone reduction in general practice — Doesthis lead to concomitant change in the use of antipsychotics?A study based on a Danish population Viggo Rask Kragh Jørgensen Medicine Team, Central Denmark Region, Lægårdvej 12, 7500 Holstebro, Denmark
(*Medications, illicit drugs, & other substances) Stewart B. Leavitt, MA, PhD; Executive Director, Pain Treatment Topics; January 2006 Reviewed but not revised June 2010 Medical Reviewers: James D. Toombs, MD; Lee Kral, PharmD, BCPS Prior Publication History 3rd Edition: November 2005 Revision/Update, Addiction Treatment Forum Special Report, ATForum.com.