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 Statistical Analysis 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- 1. Quencer K, Okun MS, Crucian G, Fernandez HH, Skidmore F, ruption of so called innervatory patterns putatively Heilman KM. Limb-kinetic apraxia in Parkinson disease. Neurol- stored in the premotor cortex (PM) including the sup- 2. Goldenberg G. Apraxia and beyond: life and work of Hugo Liep- plementary motor area (SMA).23 The innervatory pat- mann. Cortex 2003;39:509–524.
terns project time-space representations of movements, 3. Leiguarda RC, Marsden CD. Limb apraxias: higher-order disor- also known as visuo-kinaesthetic engrams, to appropri- ders of sensorimotor integration. Brain 2000;123:860–879.
4. Denes G, Mantovan MC, Gallana A, Cappelletti JY. Limb-ki- ate targets in downstream primary motor cortex.4,5 In a netic apraxia. Mov Disord 1998;13:468–476.
parkinsonian state, innervatory patterns may be dys- 5. Jacobs DH, Adair JC, Macauley B, Gold M, Gonzalez Rothi LJ, functional due to underactivation of premotor areas.
Heilman KM. Apraxia in corticobasal degeneration. Brain Cogn1999;40:336–354.
Premotor dysfunction as demonstrated by neuroimag- 6. Hanna-Pladdy B, Mendoza JE, Apostolos GT, Heilman KM. Lat- ing studies24,25 is considered responsible for cardinal eralised motor control: hemispheric damage and the loss of deft- parkinsonian motor features such as bradykinesia-rigid- ness. J Neurol Neurosurg Psychiatry 2002;73:574–577.
7. Zadikoff C, Lang AE. Apraxia in movement disorders. Brain ity reflecting a cortical deafferentiation within basal- ganglia-thalamo-cortical circuits.26 Accordingly, dopa- 8. Leiguarda R, Lees AJ, Merello M, Starkstein S, Marsden CD.
mine depletion in substantia nigra eventually reduces The nature of apraxia in corticobasal degeneration. J Neurol Neu-rosurg Psychiatry 1994;57:455–459.
the excitatory thalamocortical input to the lateral PM 9. Tsuchiya K, Ikeda K, Uchihara T, Oda T, Shimada H. Distribu- and SMA as well as to the motor cortex. Hence, pre- tion of cerebral cortical lesions in corticobasal degeneration: a motor dysfunction in PD may represent a common clinicopathological study of five autopsy cases in Japan. ActaNeuropathol (Berl) 1997;94:416–424.
neural basis for both bradykinesia-rigidity and LKA.
10. Agostino R, Curra A, Giovannelli M, Modugno N, Manfredi M, However, our findings suggest that LKA may be rela- Berardelli A. Impairment of individual finger movements in Par- tively independent of basal ganglia function, since kinson's disease. Mov Disord 2003;18:560–565.
11. Leiguarda RC, Pramstaller PP, Merello M, Starkstein S, Lees AJ, responsiveness of dexterity to dopaminergic treatment Marsden CD. Apraxia in Parkinson's disease, progressive supra- is markedly reduced.
nuclear palsy, multiple system atrophy and neuroleptic-induced The CR task is clearly more demanding with respect parkinsonism. Brain 1997;120(Part 1):75–90.
12. Barkemeyer CA, Santa Maria MP, Browndyke JN, Callon EB, to individuated finger use than the FT task. Further- Dunn AM. The coin rotation task: a convenient and sensitive more, the CR task involves a sensorimotor interaction measure of fine motor control. Arch Clin Neuropsychol 1998;18: with an object. It is therefore plausible that motor con- 13 (Abstract).
13. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What fea- trol during CR relies more on cortical mechanisms. A tures improve the accuracy of clinical diagnosis in Parkinson's recent study of recovered patients with pure hemipa- disease: a clinicopathologic study. Neurology 1992;42:1142– retic stroke27 demonstrated that the independent move- 14. Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state''. A ments of thumb and index finger were relatively spared practical method for grading the cognitive state of patients for compared with the more ulnar fingers when cortical or the clinician. J Psychiatr Res 1975;12:189–198.
corticospinal system was damaged. Hence, the CR task 15. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113.
by involving the middle finger may be inherently more 16. Benecke R, Rothwell JC, Dick JP, Day BL, Marsden CD. Simple vulnerable to cortical dysfunction than FT.
and complex movements off and on treatment in patients with In conclusion, the fact that impaired fine motor skills Parkinson's disease. J Neurol Neurosurg Psychiatry 1987;50:296–303.
in PD are only mildly responsive to dopaminergic 17. Demirci M, Grill S, McShane L, Hallett M. A mismatch between treatment underscores the importance of neurorehabili- kinesthetic and visual perception in Parkinson's disease. Ann tation in the management of dexterity problems.
18. Zia S, Cody F, O'Boyle D. Joint position sense is impaired by Although conventional occupational therapy improves Parkinson's disease. Ann Neurol 2000;47:218–228.
dexterity in PD, the effects were not maintained28 and 19. Sailer A, Molnar GF, Paradiso G, Gunraj CA, Lang AE, Chen R.
specific treatment approaches for limb kinetic deficits Short and long latency afferent inhibition in Parkinson's disease.
Brain 2003;126(Part 8):1883–1894.
in PD are not available.29 It is expected that better 20. Leiguarda R, Merello M, Balej J, Starkstein S, Nogues M, understanding of neural basis underlying LKA in PD Marsden CD. Disruption of spatial organization and interjoint Movement Disorders, Vol. 23, No. 12, 2008 A. GEBHARDT ET AL.
coordination in Parkinson's disease, progressive supranuclear 25. Rowe J, Stephan KE, Friston K, Frackowiak R, Lees A, Passing- palsy, and multiple system atrophy. Mov Disord 2000;15:627–640.
ham R. Attention to action in Parkinson's disease: impaired 21. Nakamura K, Christine CW, Starr PA, Marks WJ, Jr. Effects of effective connectivity among frontal cortical regions. Brain 2002; unilateral subthalamic and pallidal deep brain stimulation on fine motor functions in Parkinson's disease. Mov Disord 2007;22: 26. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends 22. Landau WM, Mink JW. Is decreased dexterity in Parkinson dis- ease due to apraxia? Neurology 2007;68:90–91.
27. Lang CE, Schieber MH. Differential impairment of individuated 23. Heilman KM, Meador KJ, Loring DW. Hemispheric asymmetries finger movements in humans after damage to the motor cortex or of limb-kinetic apraxia: a loss of deftness. Neurology 2000;55: the corticospinal tract. J Neurophysiol 2003;90:1160–1170.
28. Gauthier L, Dalziel S, Gauthier S. The benefits of group occupa- 24. Jahanshahi M, Jenkins IH, Brown RG, Marsden CD, Passingham tional therapy for patients with Parkinson's disease. Am J Occup RE, Brooks DJ. Self-initiated versus externally triggered move- ments. I. An investigation using measurement of regional cere- 29. Jobges EM, Spittler-Schneiders H, Renner CI, Hummelsheim H.
bral blood flow with PET and movement-related potentials in Clinical relevance of rehabilitation programs for patients with id- normal and Parkinson's disease subjects Brain 1995;118 (Part iopathic Parkinson syndrome. II. Symptom-specific therapeutic approaches. Parkinsonism Relat Disord 2007;13:203–213.
Movement Disorders, Vol. 23, No. 12, 2008

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