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Quantification of the dopaminergic response in Parkinson's disease
Parkinsonism & Related Disorders Parkinsonism and Related Disorders 8 (2002) 181±186
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Quanti®cation of the dopaminergic response in Parkinson's disease T. MuÈller*, S. Benz Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany Received 12 April 2000; revised 5 February 2001; accepted 8 February 2001
Abstract Background: Various investigators have developed complex quantitative procedures for objective assessment of parkinsonian motor impairment, since drawbacks of rating scales are interrater variability, subjective impression, insensitivity to subtle modi®cations. Objectives: To determine whether standardized performance of inserting pegs (i) differentiates between parkinsonian subjects and healthy controls and (ii) re¯ects quanti®cation of the dopaminergic response with rating scales within a levodopa challenge test design. Subjects and methods: We used an easy-to-operate Purdue Pegboard-like apparatus, which measures the total time taken to insert 25 pegs from a rack into a series of appropriate holes by a computer to 100 ms accuracy, and simultaneous rating with part III of the Uni®ed Parkinson's Disease Rating Scale for assessment of motor impairment in 28 idiopathic parkinsonian patients before and during a levodopa challenge test. Additionally we compared data of the instrumental task to age- and sex-matched healthy controls. Results: We found signi®cant differences between parkinsonian subjects and controls and signi®cant correlations to the rated severity of Parkinson's disease. Within-subject comparisons and correlation analysis demonstrated the ability of this tool to re¯ect scored motor improvement after intake of levodopa. Conclusion: Inserting pegs provides an objective quantitative estimation of changes in motor impairment within a typical levodopa challenge test design. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Inserting of pegs; Levodopa challenge; Parkinson's disease
1. Introduction Neurological examination of parkinsonian symptomatology encompasses a range of procedures that gauge the status of the extrapyramidal motor system [1]. These procedures typically consist of clinical rating scales, which estimate motor function, but are variable from one examiner to the other and relatively insensitive to subtle modi®cations [1±4]. Rater's subjective impression of the parkinsonian patient may additionally in¯uence the scores [1]. Therefore, investigators developed complex quantitative instrumental procedures for objective assessment of parkinsonian motor impairment [4,5]. These instrumental tools quantify tremor and motor slowness, characterized by two components: failure to initiate a willed movement (akinesia) and slowness of the ongoing movement (bradykinesia) [4,5]. However, such techniques are dif®cult to handle for routine assessment of motor symptoms and evaluation of therapeutic procedures in Parkinson's disease (PD) and do not chie¯y re¯ect all main parkinsonian motor features [4,5]. In contrast, the * Corresponding author. Tel.: 149-234-509-2426; fax: 149-234-5092426. E-mail address: [email protected] (T. MuÈller).
widely used Purdue Pegboard represents a simple apparatus, which shows a good test-retest reliability, correlates to the parkinsonian dopaminergic nigrostriatal de®cit and thus re¯ects akinesia, rigidity and tremor to a certain extent [6±10]. The conventional practice is the count of the number of pegs inserted in 30 s. This methodology is able (i) to evaluate peak perfomance after antiparkinsonian drug application, (ii) to avoid fatiguability at the end of the test and (iii) to circumvent the possibility that for some severe patients it would be impossible to complete the insertion of all 25 pegs in one column [7±11]. We used a modi®ed easyto-operate Purdue Pegboard-like apparatus, which measures the total time taken to insert 25 pegs from a rack into a series of appropriate holes, by a computer to 100 ms accuracy. A previous study showed that this method also re¯ects disturbed parkinsonian ®ne motor skills and, thus, represents an unspeci®c marker for the diagnosis of PD [12]. To date, no study showed whether our modi®ed Purdue Pegboard-like apparatus is sensitive enough to detect improvement of parkinsonian motor impairment after intake of levodopa/decarboxylase inhibitor or apomorphine. Both drugs are used to test the so-called dopaminergic response, which represents a further more speci®c criterion for the diagnosis of PD [13,14]. Investigators usually employ
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parkinsonian rating scales for the evaluation of this dopaminergic response in clinical practice, but a pragmatic approach would be the additional use of a simple but sensitive Manual task [11]. The objective of this study was to determine whether performance of a Purdue Pegboard-like paradigm (i) differs between parkinsonian patients and controls and (ii) re¯ects the quanti®cation of the dopaminergic response with rating scales. 2. Subjects and methods 2.1. Subjects We enrolled 28 right-handed idiopathic, non-¯uctuating parkinsonian subjects into the study. Fifteen (10 male, ®ve female) of them were previously untreated, 13 (12 male, one female) were taken off medication for at least 12 h (Table 1) [15]. All parkinsonian participants fasted for at least 4 h. They ful®lled clinical diagnostic criteria for PD [14]. We also performed the apparative paradigm in an age- and sexmatched control group under identical standardized conditions. 2.2. Exclusion criteria We excluded individuals with cerebral parenchymal lesions or atrophy, previous exposure to drugs affecting the dopaminergic system, dementia or depression. 2.3. Clinical assessment We scored parkinsonian subjects at timepoint 0 before intake of levodopa with (i) the Hoehn and Yahr Scale (HYS), (ii) the Uni®ed Parkinson's Disease Rating Scale (UPDRS), (iii) the Beck's Inventory of Depression (BID) [16] and 30, 60 and 90 min after levodopa/benserazide intake only with part III (motor behavior) of the UPDRS. We subdivided suitable items of UPDRS part III into the right and left side (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, Table 1 Demographic data of parkinsonian patients and controls. Age is given in years; BID, Beck's Inventory of Depression; CO, controls; HYS, Hoehn and Yahr Scale; SD, standard deviation; PP, parkinsonian patients; UPDRS, Uni®ed Parkinson's Disease Rating Scale; I, mental behaviour; II, activities of daily living
PP Age HYS UPDRS I UPDRS II UPDRS BID CO Age
Mean ^ SD
Range
58.6 ^ 8.3 2.3 ^ 0.7 1.3 ^ 1.4 8.3 ^ 3.8 39.8 ^ 16.3 6.9 ^ 5.4
37±72 1±3 0±5 1±15 19±75 0±18
58.8 ^ 8.7
37±37
26) to score motor symptoms (UPDRS part III right/left). We scored parkinsonian patients immediately after the subjects` test performance. Raters were blinded to the results of the task. 2.4. Apparatus We asked subjects to transfer 25 pegs (diameter 2.5 mm, length 5 cm) from a rack into one of 25 holes (diameter 2.8 mm) in a computer-based contact board individually and as quickly as possible. The distance between rack and appropriate holes was exactly 32 cm. The board was positioned in the center, when the task was carried on each side. When transferring each peg from rack to hole, elbows were allowed to be in contact with the table. We measured the time interval between the insertion of the ®rst and the last pin initially with the right and then the left hand. We assessed the time period for this task using a computer to 100 ms accuracy. The peg insertion score (PIS) represents the sum of results of the right (PIS right) and left (PIS left) hand [12]. We allowed all participants to get familiar with the task for just 1 min, to avoid learning and training effects [17]. 2.5. Levadopa challenge test The hospitalized subjects took 250 mg levodopa/benserazide (Madoparw) within a standardized test protocol, which eliminated putative in¯uencing factors such as sleep de®cits, time of day etc. [18±20]. We pretreated patients with the peripheral dopamine receptor blocker domperidone (Motiliumw) (t.i.d.) with a total daily dose of 120 mg on the day before [21]. The last application of 40 mg domperidone was 30 min before the challenge test performance. Thus we reduced the severity and appearance of side effects of levodopa. We performed the test paradigm before (time point: 0), 30, 60 and 90 min after levodopa intake, since levodopa has a half life of approximately 1 h [18±20]. 2.6. Ethics Informed consent was obtained from each subject. The local ethical committee approved this study. 2.7. Statistics Levodopa half life may vary to a certain extent in parkinsonian individuals and, thus, in¯uence onset of clinical ef®cacy within the 90-min period of repeated standardized test performance after levodopa application [22,23]. We therefore additionally concentrated data according to the formula: mean change 30 1 60 1 90=3 time point 30 1time point 60 1 time point 90=3 Moreover we calculated the difference of the mean
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Table 2 Assessed and calculated data of the UPDRS part III and inserting of pegs of parkinsonian patients and controls in the course of the levodopa challenge test. CO, controls; L, left side; PIS, peg insertion score (s £ 10 21); PP, parkinsonian patients; R, right side; SD, standard deviation; Time 0, before levodopa intake; Time 30 (60, 90), 30 (60, 90) min after levodopa intake; UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26) PP
CO
UPDRS III Mean ^ SD R1L Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0 R Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0 L Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0
PIS Mean ^ SD
Range
Mean ^ SD
Range
11±64 8±59 8±49 9±52 8.3±53.3 2.0±20.3
1129.0 ^ 218.7 1047.9 ^ 177.5 1025.3 ^ 162.5 1011.5 ^ 168.8 1028.3 ^ 166.2 100.8 ^ 94.1
796±1623 776±1416 741±1316 749±1317 758.3±1341.7 232.3±431.7
824.1 ^ 93.1
645±1072
10.9 ^ 5.8 8.6 ^ 5.3 8.6 ^ 4.7 8.5 ^ 5.3 8.5 ^ 4.9 2.3 ^ 2.1
0±21 1±25 2±21 0±22 1.0±22.7 21.7±7.3
555.7 ^ 111.7 505.3 ^ 87.7 497.4 ^ 79.6 487.0 ^ 76.9 496.5 ^ 78.3 59.2 ^ 52
415±804 372±730 385±693 373±654 384.3±683 210±208
405.5 ^ 53.9
300±555
11.8 ^ 7.2 9.5 ^ 6.9 9.0 ^ 5.8 9.3 ^ 5.5 9.3 ^ 5.9 2.6 ^ 2.2
0±29 0±27 0±20 0±20 0±20.3 20.7±8.7
573.3 ^ 128.0 542.7 ^ 109.0 527.9 ^ 105.3 524.6 ^ 102.9 531.7 ^ 104.0 41.6 ^ 51.5
361±844 344±752 327±788 340±708 337.0±743.3 232.0±223.7
418.6 ^ 44.6
345±530
30.2 ^ 13.5 24.7 ^ 13.6 23.6 ^ 11.5 23.9 ^ 11.4 24.1 ^ 11.9 6.1 ^ 3.7
Range
PIS
change to data of time point 0 according to the formula: 30 1 60 1 90=3 2 0 time point 30 1time point 60 1 time point 90=3 2 time point 0 Data of the instrumental task showed no normal distribution according to the Kolmogorow±Smirnow test. Therefore, we only performed non-parametric tests. 2.8. Comparisons We used the Mann±Whitney U test with an a -adjustment to 0.015 for comparison of data between controls and parkinsonian subjects at time point 0 (Table 3). We employed Friedman ANOVA and Kendall Coef®cient of Concordance and for post hoc analysis Wilcoxon matched Pairs test with an a -adjustment to 0.002 for the withinsubject comparisons of data of the levodopa challenge test (Table 4). 2.9. Correlation analysis We performed Spearman Rank Order Correlation. We adjusted the P-value (i) to 0.005 for the relations between severity of PD, depression and PIS at time point 0 (Table 5), (ii) to 0.017 for analysis of data of the levodopa challenge test (Table 6) and (iii) to 0.05 for the relation between results of PIS and age in the control group (Table 5).
3. Results 3.1. Comparisons The time interval necessary to insert the pegs with both hands, respectively the right and the left one (Table 2), signi®cantly differed between parkinsonian patients and healthy controls (Table 3). Within-subject comparisons of the elapsed time periods for the test, using data from both hands (Table 2), were signi®cant different between timepoint 0 and measurements after 30, 60 and 90 min (ANOVA Chi Square (n 28, df 3) 41.46; P , 0.000001; Coef®cient of Concordance 0.49; average rank r 0.47; post hoc analysis; see Table 4). Time intervals for inserting pegs performed by the right hand (Table 2) were signi®cantly distinguishable between Table 3 Comparison of peg insertion scores between controls and parkinsonian patients. signi®cant P-values are bold. CO, controls; Mann±Whitney U test (U, T, p); PIS, peg insertion score; PP, parkinsonian patients
PIS PIS right PIS left
CO CO CO
vs vs vs
PP PP PP
Time point
U
Z
P
0 0 0
60 90.5 71
25.4 24.9 25.3
5.4E-08 7.8E-07 1.4E-07
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Table 4 Performed comparisons between data of timepoint 0 vs 30, 60, 90 min and calculated mean change in the course of the levodopa challenge test. Signi®cant Pvalues are bold. mean change, (30 1 60 1 90)/3; PIS, peg insertion score; PIS right/left, peg insertion score of right/left hand; Time 0, before levodopa intake; Time 30 (60, 90), 30 (60, 90) min after levodopa intake; vs, versus; UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26); Wilcoxon Matched Pairs test (T, Z, p) Time point UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III PIS PIS PIS PIS PIS right PIS right PIS right PIS right PIS left PIS left PIS left PIS left
right right right right left left left left
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs
Time point
T
Z
P
30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3
4 0 0 0 28 10.5 9 23 3.5 0 15 2.5 31 13 0 8 25.5 16 6 7.5 85.5 41 19 37
4.4 4.5 4.5 4.6 3.7 3.8 4.0 4.1 4.2 4.2 3.7 4.4 3.9 4.3 4.5 4.4 4.0 4.3 4.5 4.5 2.7 3.7 4.1 3.8
8.8E-06 8.3E-06 5.6E-06 3.8E-06 1.8E-04 1.7E-04 5.6E-05 4.2E-05 2.9E-05 2.7E-05 1.8E-04 1.1E-05 9.0E-05 1.5E-05 5.6E-06 9.0E-06 5.3E-05 2.1E-05 7.3E-06 8.5E-06 7.5E-03 2.3E-04 4.4E-05 1.6E-04
assessments at timepoint 0 compared to the ones at time point 30, 60 and 90 (ANOVA Chi Square (n 28, df 3) 35.53; P , 0.000001; Coeffecient of Concordance 0.42; average rank r 0.40; post hoc analysis; see Table 4). PIS of the left hand (Table 2) also signi®cantly differed by comparing the time interval for inserting pegs between the initial measurement and 30, 60 and 90 min after levodopa intake (ANOVA Chi Square (n 28, df 3) 23.55; P , 0.00003; Coef®cient of Concordance 0.28; average rank r 0.25); post hoc analysis; see Table 4). Comparison of the mean change of the time period for the task performance at 30, 60 and 90 min after levodopa intake to the data at time point 0 (Table 2) was signi®cant for both hands, respectively for the right and left one (Table 4). Analogously to the statistical analysis of the various PIS performed within-subject comparisons of the UPDRS part III scores, respectively scores of UPDRS part III of the right and left side (Table 2), also showed signi®cant results (Table 4). 3.2. Correlation analysis PIS signi®cantly related to severity of PD, scored by the UPDRS, but not to intensity of depression, evaluated by the BID, in parkinsonian subjects (Table 5). Signi®cant correlations appeared between PIS and UPDRS part II and UPDRS
part III (Table 5). PIS right did not correlate to UPDRS part III right in contrast to the signi®cant relation between PIS left and UPDRS part III left (Table 5). Age signi®cantly in¯uenced PIS in the controlÐin contrast to the parkinsonian group (Table 5). A signi®cant correlation between the calculated difference of the mean change to data of time point 0 of the Table 5 Correlation analysis between scores of parkinsonian patients and data of inserting of pegs before levodopa intake signi®cant P-values are bold. HYS, Hoehn and Yahr Scale; BID, Beck's Inventory of Depression; PIS, peg insertion score (PIS); PIS right/left, peg insertion score of right/left hand; PP, parkinsonian patients; CO, controls; UPDRS, Uni®ed Parkinson's Disease Rating Scale; I, mental behaviour; II, activities of daily living; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26); Time 0, before levodopa intake; Spearman rank correlation (Spearman R, t(N 2 2), p) PP Age BID UPDRS I UPDRS II UPDRS III UPDRS UPDRS III right UPDRS III left CO Age
Spearman R
t(N 2 2)
P
PIS PIS PIS PIS PIS PIS PIS right PIS left
0.17 0.11 0.27 0.52 0.74 0.72 0.49 0.63
0.9 0.6 1.4 3.1 5.6 5.3 2.8 4.2
4.0E-01 5.8E-01 1.6E-01 4.8E-03 7.9E-06 1.6E-05 8.7E-03 2.9E-04
PIS
0.65
4.3
2.1E-04
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Table 6 Correlation analysis between calculated mean change of UPDRS scores and results of the apparative test minus their corresponding data at timepoint 0 in the course of the levodopa challenge in the parkinsonian group. Signi®cant P-values are bold. Computed data of [(time point 30 1 time point 60 1 time point 90)/ 3 2 time point 0] [(30 1 60 1 90)/3] 2 0; PIS, peg insertion score; PIS right/left, peg insertion score of right/left hand; Spearman rank correlation, (Spearman R, t(N 2 2), p); UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26) [(30 1 60 1 90)/3] 2 0
[(30 1 60 1 90)/3] 2 0
Spearman R
t(N 2 2)
P
UPDRS III UPDRS III right UPDRS III left
PIS PIS right PIS left
0.54 0.23 0.45
3.2 1.2 2.6
0.003 0.24 0.0166
UPDRS part III score and analogously computed results of both hands of the task appeared (Table 6). This relationship was also signi®cant on the left but not on the right side (Table 6).
4. Discussion 4.1. Comparison of patients vs controls and relation to severity of PD The tool we used, which only demonstrates disturbed ®ne motor skills of upper limbs, distinguished between parkinsonian participants and controls (Table 3). Our earlier study on a larger sample of previously untreated patients especially with mild PD demonstrated the sensitivity of inserting pegs for the discrimination between parkinsonian subjects and controls [12]. Results of this test are not a speci®c diagnostic marker, because other diseases and/or fatigue may also in¯uence ®ne motor skills [9,12,24]. A more detailed evaluation and analysis of participants` cognition instead of the UPDRS part I and the self rating scale BID would have improved the quality of our study results. Previous trials showed that depression may affect motor performance and relates to intensity of PD [25,26]. We assume that the missing signi®cant relations between PIS and UPDRS part I and BID score are in¯uenced by the reduced sensitivity of our applied rating scales, despite the fact that their use is common for the evaluation of severity of PD (Table 5) [16]. Nevertheless, the signi®cant associations between PIS and UPDRS part II- and UPDRS part III scores support the validity of our tool with respect to examination of motor behaviour in PD und con®rm a previous study (Table 5) [12]. The relation between PIS right and UPDRS part III score of the right dominant side showed a higher P-value and a lower correlation coef®cient compared to the left hand and did not reach a level of signi®cance (Table 5). Thus, our study con®rms an earlier trial demonstrating a better re¯ection of motor symptoms on the nondominant side in parkinsonian subjects [5]. The signi®cant in¯uence of age on PIS in our study in healthy subjects is consistent with previous results, which revealed an age dependence of ®ne motor skills [12,27]. We assume that individual different disturbed ®ne motor control in the
parkinsonian group led to the missing relationship between PIS and age of parkinsonian participants (Table 5). 4.2. Value of the apparative task within the levodopa challenge test Like the UPDRS, the applied Purdue Pegboard-like apparatus re¯ected the improvement of motor impairment after levodopa application, as shown by the within-subject comparisons of the PIS at various time points (Table 4). Thus, we suggest that this tool is helpful for the objective assessment of the dopaminergic response in PD, despite the fact that we only performed measurements for a time period of 90 min, in contrast to a previous study using a conventional Purdue Pegboard with detecting motor improvement during a time interval of 210 min [11]. Moreover, our results revealed that computed [30 1 60 1 90/3] 2 0 of PIS correlates to calculated [(30 1 60 1 90)/3] 2 0 of the UPDRS part III score even with inclusion of some of the axial components of disability of UPDRS part III, which may dilute this result. The absence of signi®cance of this correlation analysis for the right dominant side in contrast to the left one con®rms a previous trial. One major drawback of our study represents the missing performance of the whole design in healthy controls mainly due to ethical reasons. A further disadvantage of our trial is the levodopa application in an open label fashion. Thus, we did not control results with placebo in the parkinsonian subjects. Therefore, we cannot rule out a certain impact of a placebo effect. Moreover, despite the 1 min training phase, our study design cannot exclude a certain impact of learning effects on the results of the apparative test. But this problem may also in¯uence the repeatedly performed scoring with UPDRS part III. 5. Conclusion Inserting of pegs in the applied form may facilitate the clinical diagnosis and objective evaluation of severity of PD. Moreover, this apparatus quantitatively estimates modi®cations of motor impairment within a typical levodopa challenge test design and represents an easy-to-operate objective instrumental tool as adjunct to the scoring of subjects. Further studies will evaluate the ability of this
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task to follow intra-patient long-term responses to therapeutic interventions in PD and will compare the conventional Purdue Pegboard with this modi®ed one. Acknowledgements We thank B. Marchewitz and U. Clauûnitzer for technical assistance. References [1] Henderson L, Kennard C, Crawford TJ, Day S, Everitt BS, Goodrich S, Jones F, Park DM. Scales for rating motor impairment in Parkinson's disease: studies of reliability and convergent validity. J Neurol Neurosurg Psychiatry 1991;54:18±24. [2] Geminiani G, Cesana BM, Tamma F, Contri P, Pacchetti C, Carella F, Piolti R, Martignoni E, Giovannini P, Girotti F, et al. Interobserver reliability between neurologists in training of Parkinson's disease rating scales. A multicenter study. Mov Disord 1991;6:330±5. [3] Hely MA, Chey T, Wilson A, Williamson PM, O'Sullivan DJ, Rail D, Morris JG. Reliability of the Columbia scale for assessing signs of Parkinson's disease. Mov Disord 1993;8:466±72. [4] Watts RL, Mandir AS. Quantitative methods of evaluating Parkinson's disease. In: Olanow CW, Lieberman AN, editors. The scienti®c basis for the treatment of Parkinson's disease, Amsterdam: The Parthenon Publishing Group, 1992. p. 13±32. [5] van Hilten JJ, Middelkoop HA, Kuiper SI, Kramer CG, Roos RA. Where to record motor activity: an evaluation of commonly used sites of placement for activity monitors. Electroencephalogr Clin Neurophysiol 1993;89:359±62. [6] Tif®n J. Purdue pegboard. Chicago: Scienti®c Research Association (II), 1941. [7] Vingerhoets FJG, Schulzer M, Calne DB, Snow BJ. Which clinical sign of Parkinson's disease best re¯ects the nigrostriatal lesion? Ann Neurol 1997;41:58±64. [8] Brown RG, Jahanshahi M. An unusual enhancement of motor performance during bimanual movement in Parkinson's disease. J Neurol Neurosurg Psychiatry 1998;64:813±6. [9] Brown RG, Jahanshahi M, Marsden CD. The execution of bimanual movements in patients with Parkinson's, Huntington's and cerebellar disease. J Neurol Neurosurg Psychiatry 1993;56:295±7. [10] Jankovic J, Ben Arie L, Schwartz K, Chen K, Khan M, Lai EC, Krauss JK, Grossman R. Movement and reaction times and ®ne coordination tasks following pallidotomy. Mov Disord 1999;14:57±62. [11] Shinotoh H, Vingerhoets FJ, Lee CS, Uitti RJ, Schulzer M, Calne DB, Tsui J. Lamotrigine trial in idiopathic parkinsonism: a double-blind, placebo- controlled, crossover study. Neurology 1997;48:1282±5.
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Quanti®cation of the dopaminergic response in Parkinson's disease T. MuÈller*, S. Benz Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany Received 12 April 2000; revised 5 February 2001; accepted 8 February 2001
Abstract Background: Various investigators have developed complex quantitative procedures for objective assessment of parkinsonian motor impairment, since drawbacks of rating scales are interrater variability, subjective impression, insensitivity to subtle modi®cations. Objectives: To determine whether standardized performance of inserting pegs (i) differentiates between parkinsonian subjects and healthy controls and (ii) re¯ects quanti®cation of the dopaminergic response with rating scales within a levodopa challenge test design. Subjects and methods: We used an easy-to-operate Purdue Pegboard-like apparatus, which measures the total time taken to insert 25 pegs from a rack into a series of appropriate holes by a computer to 100 ms accuracy, and simultaneous rating with part III of the Uni®ed Parkinson's Disease Rating Scale for assessment of motor impairment in 28 idiopathic parkinsonian patients before and during a levodopa challenge test. Additionally we compared data of the instrumental task to age- and sex-matched healthy controls. Results: We found signi®cant differences between parkinsonian subjects and controls and signi®cant correlations to the rated severity of Parkinson's disease. Within-subject comparisons and correlation analysis demonstrated the ability of this tool to re¯ect scored motor improvement after intake of levodopa. Conclusion: Inserting pegs provides an objective quantitative estimation of changes in motor impairment within a typical levodopa challenge test design. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Inserting of pegs; Levodopa challenge; Parkinson's disease
1. Introduction Neurological examination of parkinsonian symptomatology encompasses a range of procedures that gauge the status of the extrapyramidal motor system [1]. These procedures typically consist of clinical rating scales, which estimate motor function, but are variable from one examiner to the other and relatively insensitive to subtle modi®cations [1±4]. Rater's subjective impression of the parkinsonian patient may additionally in¯uence the scores [1]. Therefore, investigators developed complex quantitative instrumental procedures for objective assessment of parkinsonian motor impairment [4,5]. These instrumental tools quantify tremor and motor slowness, characterized by two components: failure to initiate a willed movement (akinesia) and slowness of the ongoing movement (bradykinesia) [4,5]. However, such techniques are dif®cult to handle for routine assessment of motor symptoms and evaluation of therapeutic procedures in Parkinson's disease (PD) and do not chie¯y re¯ect all main parkinsonian motor features [4,5]. In contrast, the * Corresponding author. Tel.: 149-234-509-2426; fax: 149-234-5092426. E-mail address: [email protected] (T. MuÈller).
widely used Purdue Pegboard represents a simple apparatus, which shows a good test-retest reliability, correlates to the parkinsonian dopaminergic nigrostriatal de®cit and thus re¯ects akinesia, rigidity and tremor to a certain extent [6±10]. The conventional practice is the count of the number of pegs inserted in 30 s. This methodology is able (i) to evaluate peak perfomance after antiparkinsonian drug application, (ii) to avoid fatiguability at the end of the test and (iii) to circumvent the possibility that for some severe patients it would be impossible to complete the insertion of all 25 pegs in one column [7±11]. We used a modi®ed easyto-operate Purdue Pegboard-like apparatus, which measures the total time taken to insert 25 pegs from a rack into a series of appropriate holes, by a computer to 100 ms accuracy. A previous study showed that this method also re¯ects disturbed parkinsonian ®ne motor skills and, thus, represents an unspeci®c marker for the diagnosis of PD [12]. To date, no study showed whether our modi®ed Purdue Pegboard-like apparatus is sensitive enough to detect improvement of parkinsonian motor impairment after intake of levodopa/decarboxylase inhibitor or apomorphine. Both drugs are used to test the so-called dopaminergic response, which represents a further more speci®c criterion for the diagnosis of PD [13,14]. Investigators usually employ
1353-8020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S 1353-802 0(01)00010-4
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parkinsonian rating scales for the evaluation of this dopaminergic response in clinical practice, but a pragmatic approach would be the additional use of a simple but sensitive Manual task [11]. The objective of this study was to determine whether performance of a Purdue Pegboard-like paradigm (i) differs between parkinsonian patients and controls and (ii) re¯ects the quanti®cation of the dopaminergic response with rating scales. 2. Subjects and methods 2.1. Subjects We enrolled 28 right-handed idiopathic, non-¯uctuating parkinsonian subjects into the study. Fifteen (10 male, ®ve female) of them were previously untreated, 13 (12 male, one female) were taken off medication for at least 12 h (Table 1) [15]. All parkinsonian participants fasted for at least 4 h. They ful®lled clinical diagnostic criteria for PD [14]. We also performed the apparative paradigm in an age- and sexmatched control group under identical standardized conditions. 2.2. Exclusion criteria We excluded individuals with cerebral parenchymal lesions or atrophy, previous exposure to drugs affecting the dopaminergic system, dementia or depression. 2.3. Clinical assessment We scored parkinsonian subjects at timepoint 0 before intake of levodopa with (i) the Hoehn and Yahr Scale (HYS), (ii) the Uni®ed Parkinson's Disease Rating Scale (UPDRS), (iii) the Beck's Inventory of Depression (BID) [16] and 30, 60 and 90 min after levodopa/benserazide intake only with part III (motor behavior) of the UPDRS. We subdivided suitable items of UPDRS part III into the right and left side (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, Table 1 Demographic data of parkinsonian patients and controls. Age is given in years; BID, Beck's Inventory of Depression; CO, controls; HYS, Hoehn and Yahr Scale; SD, standard deviation; PP, parkinsonian patients; UPDRS, Uni®ed Parkinson's Disease Rating Scale; I, mental behaviour; II, activities of daily living
PP Age HYS UPDRS I UPDRS II UPDRS BID CO Age
Mean ^ SD
Range
58.6 ^ 8.3 2.3 ^ 0.7 1.3 ^ 1.4 8.3 ^ 3.8 39.8 ^ 16.3 6.9 ^ 5.4
37±72 1±3 0±5 1±15 19±75 0±18
58.8 ^ 8.7
37±37
26) to score motor symptoms (UPDRS part III right/left). We scored parkinsonian patients immediately after the subjects` test performance. Raters were blinded to the results of the task. 2.4. Apparatus We asked subjects to transfer 25 pegs (diameter 2.5 mm, length 5 cm) from a rack into one of 25 holes (diameter 2.8 mm) in a computer-based contact board individually and as quickly as possible. The distance between rack and appropriate holes was exactly 32 cm. The board was positioned in the center, when the task was carried on each side. When transferring each peg from rack to hole, elbows were allowed to be in contact with the table. We measured the time interval between the insertion of the ®rst and the last pin initially with the right and then the left hand. We assessed the time period for this task using a computer to 100 ms accuracy. The peg insertion score (PIS) represents the sum of results of the right (PIS right) and left (PIS left) hand [12]. We allowed all participants to get familiar with the task for just 1 min, to avoid learning and training effects [17]. 2.5. Levadopa challenge test The hospitalized subjects took 250 mg levodopa/benserazide (Madoparw) within a standardized test protocol, which eliminated putative in¯uencing factors such as sleep de®cits, time of day etc. [18±20]. We pretreated patients with the peripheral dopamine receptor blocker domperidone (Motiliumw) (t.i.d.) with a total daily dose of 120 mg on the day before [21]. The last application of 40 mg domperidone was 30 min before the challenge test performance. Thus we reduced the severity and appearance of side effects of levodopa. We performed the test paradigm before (time point: 0), 30, 60 and 90 min after levodopa intake, since levodopa has a half life of approximately 1 h [18±20]. 2.6. Ethics Informed consent was obtained from each subject. The local ethical committee approved this study. 2.7. Statistics Levodopa half life may vary to a certain extent in parkinsonian individuals and, thus, in¯uence onset of clinical ef®cacy within the 90-min period of repeated standardized test performance after levodopa application [22,23]. We therefore additionally concentrated data according to the formula: mean change 30 1 60 1 90=3 time point 30 1time point 60 1 time point 90=3 Moreover we calculated the difference of the mean
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Table 2 Assessed and calculated data of the UPDRS part III and inserting of pegs of parkinsonian patients and controls in the course of the levodopa challenge test. CO, controls; L, left side; PIS, peg insertion score (s £ 10 21); PP, parkinsonian patients; R, right side; SD, standard deviation; Time 0, before levodopa intake; Time 30 (60, 90), 30 (60, 90) min after levodopa intake; UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26) PP
CO
UPDRS III Mean ^ SD R1L Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0 R Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0 L Time 0 Time 30 Time 60 Time 90 (30 1 60 1 90)/3 [(30 1 60 1 90)/3]-0
PIS Mean ^ SD
Range
Mean ^ SD
Range
11±64 8±59 8±49 9±52 8.3±53.3 2.0±20.3
1129.0 ^ 218.7 1047.9 ^ 177.5 1025.3 ^ 162.5 1011.5 ^ 168.8 1028.3 ^ 166.2 100.8 ^ 94.1
796±1623 776±1416 741±1316 749±1317 758.3±1341.7 232.3±431.7
824.1 ^ 93.1
645±1072
10.9 ^ 5.8 8.6 ^ 5.3 8.6 ^ 4.7 8.5 ^ 5.3 8.5 ^ 4.9 2.3 ^ 2.1
0±21 1±25 2±21 0±22 1.0±22.7 21.7±7.3
555.7 ^ 111.7 505.3 ^ 87.7 497.4 ^ 79.6 487.0 ^ 76.9 496.5 ^ 78.3 59.2 ^ 52
415±804 372±730 385±693 373±654 384.3±683 210±208
405.5 ^ 53.9
300±555
11.8 ^ 7.2 9.5 ^ 6.9 9.0 ^ 5.8 9.3 ^ 5.5 9.3 ^ 5.9 2.6 ^ 2.2
0±29 0±27 0±20 0±20 0±20.3 20.7±8.7
573.3 ^ 128.0 542.7 ^ 109.0 527.9 ^ 105.3 524.6 ^ 102.9 531.7 ^ 104.0 41.6 ^ 51.5
361±844 344±752 327±788 340±708 337.0±743.3 232.0±223.7
418.6 ^ 44.6
345±530
30.2 ^ 13.5 24.7 ^ 13.6 23.6 ^ 11.5 23.9 ^ 11.4 24.1 ^ 11.9 6.1 ^ 3.7
Range
PIS
change to data of time point 0 according to the formula: 30 1 60 1 90=3 2 0 time point 30 1time point 60 1 time point 90=3 2 time point 0 Data of the instrumental task showed no normal distribution according to the Kolmogorow±Smirnow test. Therefore, we only performed non-parametric tests. 2.8. Comparisons We used the Mann±Whitney U test with an a -adjustment to 0.015 for comparison of data between controls and parkinsonian subjects at time point 0 (Table 3). We employed Friedman ANOVA and Kendall Coef®cient of Concordance and for post hoc analysis Wilcoxon matched Pairs test with an a -adjustment to 0.002 for the withinsubject comparisons of data of the levodopa challenge test (Table 4). 2.9. Correlation analysis We performed Spearman Rank Order Correlation. We adjusted the P-value (i) to 0.005 for the relations between severity of PD, depression and PIS at time point 0 (Table 5), (ii) to 0.017 for analysis of data of the levodopa challenge test (Table 6) and (iii) to 0.05 for the relation between results of PIS and age in the control group (Table 5).
3. Results 3.1. Comparisons The time interval necessary to insert the pegs with both hands, respectively the right and the left one (Table 2), signi®cantly differed between parkinsonian patients and healthy controls (Table 3). Within-subject comparisons of the elapsed time periods for the test, using data from both hands (Table 2), were signi®cant different between timepoint 0 and measurements after 30, 60 and 90 min (ANOVA Chi Square (n 28, df 3) 41.46; P , 0.000001; Coef®cient of Concordance 0.49; average rank r 0.47; post hoc analysis; see Table 4). Time intervals for inserting pegs performed by the right hand (Table 2) were signi®cantly distinguishable between Table 3 Comparison of peg insertion scores between controls and parkinsonian patients. signi®cant P-values are bold. CO, controls; Mann±Whitney U test (U, T, p); PIS, peg insertion score; PP, parkinsonian patients
PIS PIS right PIS left
CO CO CO
vs vs vs
PP PP PP
Time point
U
Z
P
0 0 0
60 90.5 71
25.4 24.9 25.3
5.4E-08 7.8E-07 1.4E-07
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Table 4 Performed comparisons between data of timepoint 0 vs 30, 60, 90 min and calculated mean change in the course of the levodopa challenge test. Signi®cant Pvalues are bold. mean change, (30 1 60 1 90)/3; PIS, peg insertion score; PIS right/left, peg insertion score of right/left hand; Time 0, before levodopa intake; Time 30 (60, 90), 30 (60, 90) min after levodopa intake; vs, versus; UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26); Wilcoxon Matched Pairs test (T, Z, p) Time point UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III UPDRS III PIS PIS PIS PIS PIS right PIS right PIS right PIS right PIS left PIS left PIS left PIS left
right right right right left left left left
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs vs
Time point
T
Z
P
30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3 30 60 90 (30 1 60 1 90)/3
4 0 0 0 28 10.5 9 23 3.5 0 15 2.5 31 13 0 8 25.5 16 6 7.5 85.5 41 19 37
4.4 4.5 4.5 4.6 3.7 3.8 4.0 4.1 4.2 4.2 3.7 4.4 3.9 4.3 4.5 4.4 4.0 4.3 4.5 4.5 2.7 3.7 4.1 3.8
8.8E-06 8.3E-06 5.6E-06 3.8E-06 1.8E-04 1.7E-04 5.6E-05 4.2E-05 2.9E-05 2.7E-05 1.8E-04 1.1E-05 9.0E-05 1.5E-05 5.6E-06 9.0E-06 5.3E-05 2.1E-05 7.3E-06 8.5E-06 7.5E-03 2.3E-04 4.4E-05 1.6E-04
assessments at timepoint 0 compared to the ones at time point 30, 60 and 90 (ANOVA Chi Square (n 28, df 3) 35.53; P , 0.000001; Coeffecient of Concordance 0.42; average rank r 0.40; post hoc analysis; see Table 4). PIS of the left hand (Table 2) also signi®cantly differed by comparing the time interval for inserting pegs between the initial measurement and 30, 60 and 90 min after levodopa intake (ANOVA Chi Square (n 28, df 3) 23.55; P , 0.00003; Coef®cient of Concordance 0.28; average rank r 0.25); post hoc analysis; see Table 4). Comparison of the mean change of the time period for the task performance at 30, 60 and 90 min after levodopa intake to the data at time point 0 (Table 2) was signi®cant for both hands, respectively for the right and left one (Table 4). Analogously to the statistical analysis of the various PIS performed within-subject comparisons of the UPDRS part III scores, respectively scores of UPDRS part III of the right and left side (Table 2), also showed signi®cant results (Table 4). 3.2. Correlation analysis PIS signi®cantly related to severity of PD, scored by the UPDRS, but not to intensity of depression, evaluated by the BID, in parkinsonian subjects (Table 5). Signi®cant correlations appeared between PIS and UPDRS part II and UPDRS
part III (Table 5). PIS right did not correlate to UPDRS part III right in contrast to the signi®cant relation between PIS left and UPDRS part III left (Table 5). Age signi®cantly in¯uenced PIS in the controlÐin contrast to the parkinsonian group (Table 5). A signi®cant correlation between the calculated difference of the mean change to data of time point 0 of the Table 5 Correlation analysis between scores of parkinsonian patients and data of inserting of pegs before levodopa intake signi®cant P-values are bold. HYS, Hoehn and Yahr Scale; BID, Beck's Inventory of Depression; PIS, peg insertion score (PIS); PIS right/left, peg insertion score of right/left hand; PP, parkinsonian patients; CO, controls; UPDRS, Uni®ed Parkinson's Disease Rating Scale; I, mental behaviour; II, activities of daily living; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26); Time 0, before levodopa intake; Spearman rank correlation (Spearman R, t(N 2 2), p) PP Age BID UPDRS I UPDRS II UPDRS III UPDRS UPDRS III right UPDRS III left CO Age
Spearman R
t(N 2 2)
P
PIS PIS PIS PIS PIS PIS PIS right PIS left
0.17 0.11 0.27 0.52 0.74 0.72 0.49 0.63
0.9 0.6 1.4 3.1 5.6 5.3 2.8 4.2
4.0E-01 5.8E-01 1.6E-01 4.8E-03 7.9E-06 1.6E-05 8.7E-03 2.9E-04
PIS
0.65
4.3
2.1E-04
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Table 6 Correlation analysis between calculated mean change of UPDRS scores and results of the apparative test minus their corresponding data at timepoint 0 in the course of the levodopa challenge in the parkinsonian group. Signi®cant P-values are bold. Computed data of [(time point 30 1 time point 60 1 time point 90)/ 3 2 time point 0] [(30 1 60 1 90)/3] 2 0; PIS, peg insertion score; PIS right/left, peg insertion score of right/left hand; Spearman rank correlation, (Spearman R, t(N 2 2), p); UPDRS, Uni®ed Parkinson's Disease Rating Scale; III, motor behaviour (items 18±31); UPDRS III right/left (items 20b, 20c, 21, 22b, 22c, 23, 24, 25, 26) [(30 1 60 1 90)/3] 2 0
[(30 1 60 1 90)/3] 2 0
Spearman R
t(N 2 2)
P
UPDRS III UPDRS III right UPDRS III left
PIS PIS right PIS left
0.54 0.23 0.45
3.2 1.2 2.6
0.003 0.24 0.0166
UPDRS part III score and analogously computed results of both hands of the task appeared (Table 6). This relationship was also signi®cant on the left but not on the right side (Table 6).
4. Discussion 4.1. Comparison of patients vs controls and relation to severity of PD The tool we used, which only demonstrates disturbed ®ne motor skills of upper limbs, distinguished between parkinsonian participants and controls (Table 3). Our earlier study on a larger sample of previously untreated patients especially with mild PD demonstrated the sensitivity of inserting pegs for the discrimination between parkinsonian subjects and controls [12]. Results of this test are not a speci®c diagnostic marker, because other diseases and/or fatigue may also in¯uence ®ne motor skills [9,12,24]. A more detailed evaluation and analysis of participants` cognition instead of the UPDRS part I and the self rating scale BID would have improved the quality of our study results. Previous trials showed that depression may affect motor performance and relates to intensity of PD [25,26]. We assume that the missing signi®cant relations between PIS and UPDRS part I and BID score are in¯uenced by the reduced sensitivity of our applied rating scales, despite the fact that their use is common for the evaluation of severity of PD (Table 5) [16]. Nevertheless, the signi®cant associations between PIS and UPDRS part II- and UPDRS part III scores support the validity of our tool with respect to examination of motor behaviour in PD und con®rm a previous study (Table 5) [12]. The relation between PIS right and UPDRS part III score of the right dominant side showed a higher P-value and a lower correlation coef®cient compared to the left hand and did not reach a level of signi®cance (Table 5). Thus, our study con®rms an earlier trial demonstrating a better re¯ection of motor symptoms on the nondominant side in parkinsonian subjects [5]. The signi®cant in¯uence of age on PIS in our study in healthy subjects is consistent with previous results, which revealed an age dependence of ®ne motor skills [12,27]. We assume that individual different disturbed ®ne motor control in the
parkinsonian group led to the missing relationship between PIS and age of parkinsonian participants (Table 5). 4.2. Value of the apparative task within the levodopa challenge test Like the UPDRS, the applied Purdue Pegboard-like apparatus re¯ected the improvement of motor impairment after levodopa application, as shown by the within-subject comparisons of the PIS at various time points (Table 4). Thus, we suggest that this tool is helpful for the objective assessment of the dopaminergic response in PD, despite the fact that we only performed measurements for a time period of 90 min, in contrast to a previous study using a conventional Purdue Pegboard with detecting motor improvement during a time interval of 210 min [11]. Moreover, our results revealed that computed [30 1 60 1 90/3] 2 0 of PIS correlates to calculated [(30 1 60 1 90)/3] 2 0 of the UPDRS part III score even with inclusion of some of the axial components of disability of UPDRS part III, which may dilute this result. The absence of signi®cance of this correlation analysis for the right dominant side in contrast to the left one con®rms a previous trial. One major drawback of our study represents the missing performance of the whole design in healthy controls mainly due to ethical reasons. A further disadvantage of our trial is the levodopa application in an open label fashion. Thus, we did not control results with placebo in the parkinsonian subjects. Therefore, we cannot rule out a certain impact of a placebo effect. Moreover, despite the 1 min training phase, our study design cannot exclude a certain impact of learning effects on the results of the apparative test. But this problem may also in¯uence the repeatedly performed scoring with UPDRS part III. 5. Conclusion Inserting of pegs in the applied form may facilitate the clinical diagnosis and objective evaluation of severity of PD. Moreover, this apparatus quantitatively estimates modi®cations of motor impairment within a typical levodopa challenge test design and represents an easy-to-operate objective instrumental tool as adjunct to the scoring of subjects. Further studies will evaluate the ability of this
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