ARTICLE IN PRESS Parkinsonism and Related Disorders xxx (2008) 1–4

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Parkinsonism and Related Disorders

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Movement irregularities in atypical parkinsonian syndromes

Maxime Philibert a, b, Francois Richer a, b, *, Pierre J. Blanchet a, d, Sylvain Chouinard a, Anne-Sophie Dubarry c, Eric Fimbel c a

Centre Hospitalier de l’Universite´ de Montre´al, Montreal, Quebec, Canada ` Montre´al, Montreal, Quebec, Canada Department of Psychology, Universite´ du Que´bec a c Ecole de Technologie Supe´rieure, Montreal, Quebec, Canada d Department of Stomatology, Faculty of Dental Medicine, Universite´ de Montre´al b

a b s t r a c t

Article history: Received 20 May 2008 Received in revised form 28 October 2008 Accepted 1 November 2008

This study examined discrete motor irregularities in ballistic aiming movements in patients with atypical parkinsonian syndromes (APS). Nine patients with APS were compared to 9 patients with idiopathic Parkinson’s disease (PD) and 9 controls on ballistic arm extension movements performed on a digitizing tablet without visual feedback and without accuracy constraints. Patients with APS showed a higher number of irregularities in the acceleration and jerk time series compared to PD patients and controls. No difference was found between PD patients and controls. These discrete irregularities were not associated with general motor impairment, tremor, akinesia, or rigidity. These results suggest that atypical parkinsonism is associated with movement irregularities in ballistic movements, which may help differentiate APS from PD. Ó 2008 Elsevier Ltd. All rights reserved.

Keywords: Movement disorders Basal ganglia Movement irregularity Parkinsonism

1. Introduction

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Parkinsonism is associated with abnormalities in voluntary movements such as rapid aiming movements, including bradykinesia and irregularity in the velocity profile [1,2]. However, there is evidence that little movement irregularity is present in idiopathic Parkinson’s disease (PD) when no visual feedback is available [3], suggesting that movement irregularity in PD may be linked to movement control demands. Atypical parkinsonian syndromes (APS) including progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration (CBD) produce early damage in motor cortico-striatal loops not present in PD [4,5], but there are few reliable movement abnormalities associated with this differential damage. The present study examined whether APS affect movement irregularity when control demands are minimal, i.e. in short ballistic discrete extensions of the forearm with no visual feedback and minimal accuracy demands. In both controls and PD patients, these discrete movements have short latencies and a bell-shaped velocity profile. Any anomaly of APS patients in such simple movements could help differentiate movement problems in PD and APS.

* Corresponding author. Department of Psychology, Universite´ du Que´bec a` Montre´al, Box 8888, Montreal, Quebec, Canada H3C 3P8. Tel.: þ1 514 987 3000. E-mail address: [email protected] (F. Richer).

2. Methods

2.1. Participants

Nine patients diagnosed with APS (55–86 yrs (mean 68.2)), 3 patients with PSP, 4 patients with MSA and 2 patients with CBD were compared to 9 patients diagnosed with idiopathic PD (56–77 yrs (mean 63.9)) and to 9 control subjects (57–80 yrs (mean 65.3)) with no history of neurological problems. All patients were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) [6]. The diagnosis of APS was made by a movement disorders specialist on the basis of early distinctive neurological features including ophthalmoparesis, prominent axial symptoms, apraxia, cortical sensory loss, rapid progression, and dopa-resistance. APS and PD groups were clinically matched on the UPDRS motor score (Section 3). The upper limb motor UPDRS score was similar in the two groups [F(1,15) ¼ 0.89, p ¼ 0.36]. PD and APS groups did not significantly differ on the UPDRS rigidity [F(1,15) ¼ 1.4, p ¼ 0.26]; akinesia [F(1,15) ¼ 0.04, p ¼ 0.84]; bradykinesia [F(1,15) ¼ 0.01, p ¼ 0.92] or gait-stability scores [F(1,15) ¼ 3.39, p ¼ 0.09]. All patients were deliberately evaluated on standard optimized medication both to minimize involuntary movements and to minimize voluntary movement abnormalities in PD patients. Prior informed consent according to the rules of the institutions was obtained from all subjects. All subjects used their dominant right hand to perform the task. 2.2. Task

Subjects executed rapid externally triggered arm movements without visual feedback and with low precision requirements. Subjects were instructed to draw a diagonal line as fast as possible on a digitizing tablet (Wacom A4, X–Y spatial precision 0.025 mm, sampling frequency 100 Hz.) after a start signal LED light accompanied by a sound (800 Hz, 80 db, duration: 1 s) appearing after a random delay between 1 and 3 s. The forearm extension movement averaged 23 cm in length (angular variation of 30  5 ). The elbow rested on the desk and remained partly flexed at the end of the movement. When overshooting occurred, the subject was instructed to reduce movement amplitude within the tablet’s boundaries.

1353-8020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2008.11.004

Please cite this article in press as: Philibert M et al., Movement irregularities in atypical parkinsonian syndromes, Parkinsonism and Related Disorders (2008), doi:10.1016/j.parkreldis.2008.11.004

ARTICLE IN PRESS M. Philibert et al. / Parkinsonism and Related Disorders xxx (2008) 1–4

Undershooting was left uncorrected since no accuracy constraints were imposed. Subjects maintained their gaze on the device and their arm was hidden from view. These conditions were chosen to avoid visual feedback and movement anticipation. A practice session was used to train the subjects to remain within the pad without visual feedback. After the initial training, subjects performed movements until 30 correct movements (non-anticipated start, end of movement in the limits of the tablet) had been recorded. The digitizing tablet was connected to a PC and movements were monitored by the experimenter. 2.3. Data analysis

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Linear displacement was determined from the X–Y positions of the stylus, and linear speed and higher order derivatives (acceleration and jerk, the derivative of acceleration) were calculated and filtered. Incomplete (i.e. final speed above 20% of the maximum speed (Vmax)) and anticipated movements (i.e. 5% of Vmax reached before the start signal) were discarded. The main speed peak was determined as the highest speed in the movement and the rest of the recording (threshold: 1% of Vmax) was truncated. Computed movement parameters included reaction time (RT), movement time (MT), movement length (ML), and maximum linear speed (Vmax). In addition, discrete irregularities corresponding to qualitative changes in the acceleration and jerk time series were detected by means of a qualitative pattern recognition software developed in our lab [7]. Qualitative changes were defined as sign inversion patterns in the acceleration or jerk profiles. A speed burst was defined as a sequence of three qualitative steps in the acceleration profile: positive, followed by null and then by negative acceleration. A temporary plateau in acceleration followed by re-acceleration would generate a characteristic sequence in the jerk profile: negative, followed by null, and then by positive jerk. The two opposite patterns were also detected. For each movement, derivatives of displacement data were calculated and smoothed using a 9 Hz cut-off low-pass filter. Patterns were then matched on the derivatives profiles and counted as an index of irregularity. The minimum detectable amplitude of variations in derivatives was controlled by means of a symmetrical trapezoidal convolution kernel. Prior analyses on preliminary data [7] found several threshold values for which the irregularity index was constant. The sensitivity of the threshold used by the program was set at 2 to match the number of irregularities counted in a representative set of movement recordings by naive human judges. Identical filter and threshold parameters were used for all groups. Movement irregularity has often been quantified using total jerk, however such global metrics may not be optimal in slow or ballistic movements [8]. When velocity profiles are complex and variations in acceleration and jerk are linked to discrete motor irregularities, detection of irregularities may be more appropriate. After examining the distributions of the different measures, a logarithmic transformation was applied to the irregularity data to minimize skewness. Group differences were examined with analyses of variance (ANOVAs) using RT, MT, ML, Vmax and the number of irregularities as dependent variables. To further assess group differences, post-hoc comparisons were made using Tukey’s HSD tests. Bivariate Pearson correlations were also used in our analysis.

UPDRS motor score [F(1,16) ¼ 0.04, p ¼ 0.86] did not differ between patient groups. Duration of illness was shorter in the APS group than in the PD group [F(1,16) ¼ 4.5, p ¼ 0.05]. Movement length (ML) was similar in the three groups. However, groups differed on maximum linear speed (Vmax) [F(2,24) ¼ 4.2, p ¼ 0.03]. Tukey posthoc comparisons of the three groups indicated that APS patients reached significantly lower Vmax than controls (p ¼ 0.02). Groups also differed on movement time (MT) [F(2,24) ¼ 21.6, p < 0.0001]. Post-hoc comparisons indicated that the APS group showed significantly longer MT than both control (p < 0.0001) and PD groups (p < 0.0001). Reaction time (RT) was significantly different in the three groups [F(2,24) ¼ 12.8, p ¼ 0.0002]. Post-hoc comparisons revealed that the APS patients showed significantly longer RT than both PD patients (p ¼ 0.0009) and controls (p ¼ 0.0004). No significant post-hoc differences were found between control and PD groups on Vmax (p ¼ 0.69), MT (p ¼ 0.96) or RT (p ¼ 0.95). Fig. 1A shows representative speed, acceleration and jerk profiles during individual movements in the three groups. Control subjects presented smooth bell-shaped speed profiles. Zero-crossings in the acceleration and jerk profiles reflected normal changes in velocity for such a simple ballistic task, movement length was covered by a single transport phase and no secondary corrections were needed as no target was specified. Medicated PD patients showed similar movement kinematics. However, irregularities were clearly present in the APS group (see Fig. 1B). The average number of irregularities per trajectory in each group was significantly different between the three groups [F(2,24) ¼ 20,8 p < 0.0001]. Post-hoc comparisons indicated that the APS group differed from the control group (p < 0.0001) and from the PD group (p ¼ 0.0002), but that controls and PD patients presented a similar number of irregularities (p ¼ 0.39). There was no significant correlation between the number of irregularities and age (r ¼ 0.32, p ¼ 0.11) in all subjects, and no correlation between the number of irregularities and illness duration (r ¼ 0.29, p ¼ 0.25) in patients. Within the APS group, no significant correlation was found between the number of irregularities and illness duration [r ¼ 0.33, p ¼ 0.37], the motor score of the UPDRS (r ¼ 0.17, p ¼ 0.68), or the upper limb motor score of the UPDRS (r ¼ 0.46, p ¼ 0.25). Action tremor was observed in only one APS patient and three PD patients. Moreover, the irregularities showed no predominant frequency (range 4.7–13.8 Hz, 95% confidence interval 5.2–12.2 Hz). This suggests that the observed irregularities were not caused by tremor. When PD and APS patients were grouped on the basis of

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3. Results Table 1 summarizes the demographic and clinical data for the APS and PD patients. Age [F(1,16) ¼ 1.3, p ¼ 0.26] and pre-test Table 1 Clinical data for Parkinson’s disease and atypical parkinsonian patients. No.

Sex

Age (yrs)

APS 1 2 3 4 5 6 7 8 9

Disease duration (yrs)

F F F M F F F M F

57 55 68 86 70 68 64 71 75

3 2 6 8 2 1 8 1 2

PD 1 2 3 4 5 6 7 8 9

F M F M M F M M M

56 61 60 77 66 66 67 64 58

11 5 8 7 15 11 7 1 2

Diagnosis

Motor UPDRS

Upper limb UPDRS

Medication

MSA MSA MSA MSA PSP PSP PSP CBD CBD

35.5 19.0 23.0 18.0 28.5 9.0 42.0 29.0 –

12 10.5 4 7 13.5 5 18 10 –

L-dopa,

pramipexole, orphenadrine pramipexole L-dopa, pramipexole, entacapone L-dopa L-dopa, pramipexole Bupropion Bupropion L-dopa L-dopa

Hoehn & Yahr stage 3 2 2 3 3 2 2 1 2

15.5 32.0 16.5 38.0 44.5 22.5 28.0 10.0 16.0

10 13 5.5 21.5 20 12.5 18 2 11

L-dopa,

L-dopa,

L-dopa, L-dopa, L-dopa, L-dopa, L-dopa,

pergolide, amantadine pramipexole pramipexole pramipexole pramipexole, clozapine amantadine, selegiline

L-dopa Pramipexole L-dopa, Entacapone, gabapentin

Please cite this article in press as: Philibert M et al., Movement irregularities in atypical parkinsonian syndromes, Parkinsonism and Related Disorders (2008), doi:10.1016/j.parkreldis.2008.11.004

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Acceleration profile

Jerk profile

B

*

Control

PD

C 1.5

RT

1.5

Vmax

MT

Time (s)

1.3

PD

1.3

*

1.0 0.8 0.5

*

APS

Control

PD

1.0 0.8

*

0.3 0.0

APS

0.5

Velocity (m/s)

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Control

Movement irregularities 10 9 8 7 6 5 4 3 2 1 0

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Speed profile

irregularities per trajectory

A

3

0.3 APS

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Fig. 1. (A) Sample speed, acceleration and jerk profiles in a single ballistic movement in a control subject, a PD patient and an atypical parkinsonian patient (APS). (B) Average number of movement irregularities per trajectory in the three groups. (C) Maximum linear speed (Vmax) in meters per second, reaction time (RT) in seconds and movement time (MT) in seconds in the three groups. Error bars are standard errors. *p < 0.05.

4. Discussion

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UPDRS cut-off scores (20 or less, and over 20) or on symptom duration (more or less than 5 yrs), no significant differences were observed in the number of irregularities between the new groups. Also, when gender was used as a covariate, the number of irregularities was not linked to gender in our analysis of group differences in irregularities [F(2,24) ¼ 0.29, p ¼ 0.60]. Finally, in order to detect possible asymmetries in the time distribution of irregularities, the average time of occurrence of irregularities was determined and compared to the time of occurrence of the main speed peak for each group. No significant difference was found between the number of irregularities preceding and following the main speed peak [F(2,24) ¼ 0.07, p ¼ 0.95].

Patients with atypical parkinsonian syndromes showed more irregularities in movement trajectories than both controls and PD patients with comparable UPDRS motor scores (see Fig. 1B). Although APS patients were able to complete each trial in a single transport phase, their movements were fragmented and irregular. Fig. 1A shows a large number of zero-crossings in the acceleration and jerk profiles of a representative APS patient. Irregularities seen in APS showed no predominant frequency, and they were not correlated with tremor, rigidity, akinesia or bradykinesia. Idiopathic PD patients with equivalent clinical motor deficits (UPDRS scores) did not show such irregularities. This suggests that irregularities seen in APS patients may not be attributed to core parkinsonian symptoms. These results cannot be attributed to medication since most patients in both groups received similar medications most often l-dopa and/or a dopamine agonist, and no medication was associated with a higher number of irregularities. The irregularities observed cannot be ascribed to feedbackbased corrective commands since these were minimized by the absence of visual input during movement. Also, corrective commands are unlikely to contribute significantly to the irregularities observed since no constraining target was specified in the present task. Moreover, irregularities did not present higher densities towards the end of the movement, as would occur with

end-point corrections [2]. It could be argued that the irregularities observed correspond to action myoclonus previously described in APS [9], however these jerks were mainly associated with posture and movement onset. In our study, irregularities were present throughout movement execution. Further investigations using neurophysiological measures will be necessary to clarify the origin of these discrete motor irregularities. APS patients also showed longer MT and RT than both controls and PD patients (see Fig. 1C), confirming the dopa-resistant bradykinesia observed in atypical parkinsonism. In contrast to APS patients, PD patients executed smooth movements in the absence of visual feedback and accuracy constraints. PD patients showed normal acceleration and jerk profiles, as well as normal Vmax and RT. These results support earlier findings showing that PD patients can achieve normal velocity profiles when tasks demands are minimal [3] and show reduced RT when movements are externally triggered [10]. Pharmacological treatment may have normalized performance in PD patients. However, similar results were previously obtained with non-medicated PD patients [3]. The present results indicate that patients with APS present slow and irregular ballistic movements even when task demands are minimal. In the same condition, controls and medicated idiopathic PD patients showed smooth movements. Although the UPDRS provides a valid general clinical assessment of motor functions in APS [11], it was not sensitive to the motor irregularities that we observed in APS patients. No correlation was obtained between the number of irregularities and illness duration or severity in the patient groups. This could suggest that the irregularities observed are linked to corticostriatal or striatopallidal damage associated with APS and not to midbrain damage typical of idiopathic PD [4,5]. Movement irregularities in such a low requirement task suggest a general motor control deficit in APS, confirming previous suggestions [12]. Irregularities may reflect small-scale temporal coordination anomalies linked to damaged pathways. These data also suggest that detection of discrete motor irregularities may be a useful tool in the characterization of the motor impairments in atypical parkinsonian syndromes and other movement disorders.

Please cite this article in press as: Philibert M et al., Movement irregularities in atypical parkinsonian syndromes, Parkinsonism and Related Disorders (2008), doi:10.1016/j.parkreldis.2008.11.004

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Acknowledgements This study was supported in part by the Natural Sciences and Engineering Research Council of Canada. We would like to thank Wacef Guerfali for software development, Dr. Helene Masson for patient referrals, as well as the subjects who took part in this study. References

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Please cite this article in press as: Philibert M et al., Movement irregularities in atypical parkinsonian syndromes, Parkinsonism and Related Disorders (2008), doi:10.1016/j.parkreldis.2008.11.004