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Finger tapping analysis in patients with Parkinson’s disease and atypical parkinsonism
Journal of Clinical Neuroscience 30 (2016) 49–55
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Finger tapping analysis in patients with Parkinson’s disease and atypical parkinsonism Milica Djuric´-Jovicˇic´ a, Igor Petrovic´ b, Milica Jecˇmenica-Lukic´ b, Saša Radovanovic´ c, Nataša Dragaševic´-Miškovic´ b, Minja Belic´ a, Vera Miler-Jerkovic´ d, Mirjana B. Popovic´ d, Vladimir S. Kostic´ b,⇑ a
Innovation Center, School of Electrical Engineering, University of Belgrade, Belgrade, Serbia Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6, Belgrade, Serbia c Institute for Medical Research, University of Belgrade, Belgrade, Serbia d School of Electrical Engineering, University of Belgrade, Department for Signals and Systems, Belgrade, Serbia b
a r t i c l e
i n f o
Article history: Received 20 October 2015 Accepted 27 October 2015
Keywords: Atypical parkinsonism Hypokinesia Kinematic analysis Progressive supranuclear palsy Repetitive finger tapping
a b s t r a c t The goal of this study was to investigate repetitive finger tapping patterns in patients with Parkinson’s disease (PD), progressive supranuclear palsy–Richardson syndrome (PSP-R), or multiple system atrophy of parkinsonian type (MSA-P). The finger tapping performance was objectively assessed in PD (n = 13), PSP-R (n = 15), and MSA-P (n = 14) patients and matched healthy controls (HC; n = 14), using miniature inertial sensors positioned on the thumb and index finger, providing spatio-temporal kinematic parameters. The main finding was the lack or only minimal progressive reduction in amplitude during the finger tapping in PSP-R patients, similar to HC, but significantly different from the sequence effect (progressive decrement) in both PD and MSA-P patients. The mean negative amplitude slope of 0.12°/cycle revealed less progression of amplitude decrement even in comparison to HC ( 0.21°/cycle, p = 0.032), and particularly from PD ( 0.56°/cycle, p = 0.001), and MSA-P patients ( 1.48°/cycle, p = 0.003). No significant differences were found in the average finger separation amplitudes between PD, PSP-R and MSA-P patients (pmsa-pd = 0.726, pmsa-psp = 0.363, ppsp-pd = 0.726). The lack of clinically significant sequence effect during finger tapping differentiated PSP-R from both PD and MSA-P patients, and might be specific for PSP-R. The finger tapping kinematic parameter of amplitude slope may be a neurophysiological marker able to differentiate particular forms of parkinsonism. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Progressive supranuclear palsy (PSP) is the second most common form of neurodegenerative parkinsonism after Parkinson’s disease (PD). Its classical clinical presentation, known as Richardson syndrome (PSP-R), is characterized by early gait instability with falls, vertical supranuclear gaze palsy, symmetrical akineticrigid syndrome, cognitive and behavioral changes, and death within 7–8 years of initial symptom onset [1]. Akinetic-rigid parkinsonian syndrome in PSP-R is predominantly axial, and sometimes out of proportion to limb tone which may be relatively spared [2]. Bradykinesia, defined as ‘‘slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive action” (also known as sequence ⇑ Corresponding author. Tel.: +381 11 2685 596. E-mail address: [email protected] (V.S. Kostic´). http://dx.doi.org/10.1016/j.jocn.2015.10.053 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
effect [SE]) [3], is controversial in PSP patients. A study of 75 pathologically proven PSP patients identified bradykinesia in only 22% of patients in the first disease year [4], in contrast to more recent studies where early bradykinesia was reported in 88% and 75% of pathologically confirmed PSP cases [5], [6]. Recently, Ling et al. objectively assessed repetitive finger tapping (FT) in PSP-R and PD patients and age- and sex-matched healthy controls (HC), and found that PSP-R patients had small finger separation amplitude (<50% of that in controls and PD patients) without progressive decrement (that is, without SE) [7]. Therefore, they concluded that ‘‘the severe hypokinesia (small amplitude movements) irrespective of disease severity and the lack of a sequence effect” were useful in discriminating PSP-R from PD patients and HC, suggesting also that features identified in PSP-R might not adhere to the definition of bradykinesia in PD [3]. We studied the differences in the pattern of repetitive FT in patients with PD, PSP-R, and multiple system atrophy of
M. Djuric´-Jovicˇic´ et al. / Journal of Clinical Neuroscience 30 (2016) 49–55
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predominantly parkinsonian subtype (MSA-P), and compared them with HC.
‘‘start” and ”stop” commands), with a 1 minute pause between trials. Each of the three consecutive trials began and ended with fingers closed (zero angle).
2. Methods 2.3. Kinematic parameters 2.1. Participants This study comprised of four groups of right-handed participants recruited from the Movement Disorders Unit at the Clinic of Neurology, Belgrade: (1) 13 patients with PD diagnosed according to the UK Queen Square Brain Bank Criteria [3]; (2) 15 PSP-R patients diagnosed according to the criteria of Litvan et al. [5]; (3) 14 MSA-P patients, fulfilling the criteria of Gilman et al. [8]; and (4) 14 HC with no history of neurological or psychiatric disease (Table 1). HC were age- and sex-matched with the overall patient group. Patients with tremor/dyskinesia and hand dystonia, as well as any disability of the extremities that might interfere with motor tasks, were excluded from the study. Other exclusion criteria in PD patients were: (1) scores of <26 on the Mini Mental Status Examination [9] or <15 on the Frontal Assessment Battery [10]; (2) score P14 for the Hamilton Depression Rating Scale [11]; and (3) history of psychosis or major medical disease. Disease staging was assessed according to the Hoehn and Yahr system [12] and motor disability using the Unified Parkinson’s Disease Rating Scale (UPDRS III) [13]. Levodopa equivalent dose was also calculated [14]. All the tests, including FT performed in accordance with the recommendations for FT assessment, were conducted in the morning after an overnight treatment withdrawal of at least 12 hours where applicable (patients with PD were tested during ‘‘off ” time) [15]. The research was approved by the Ethical Committee of the School of Medicine, University of Belgrade, and written informed consent was obtained from each participant. 2.2. Experimental setup and testing protocol The system included two inertial measurement sensor units which acquired signals and wirelessly transmitted to a remote computer [16]. The PD group included only patients with predominantly right sided affliction and data were obtained from the right hand. The participants were asked to sit comfortably and were asked to hold their hand in front of them. Participants were instructed to repeatedly tap the index finger and thumb as rapidly and as widely as possible for 15 seconds (the same acoustic signal was used for
Angle amplitude in degrees (°), cycle duration (ms), and speed (°/s) were measured for each cycle of FT from one index finger– thumb separation to the next [7]. Signals were processed by custom-made software [16]. Tapping amplitude was defined as the angle between the long axes of the thumb and index finger. Mean speed was the mean rate of change in aperture regardless of whether the aperture was opening or closing. Closing and opening velocities (°/s) were the peak velocities of aperture closure and opening within a cycle, respectively. The coefficients of variation (CV) of amplitude and speed across the tap trials were calculated [17]. High values of CV illustrated irregularities of kinematic parameters. Progressive changes in amplitude, duration and speed across a 15 s FT trial were represented by the slope of the fitted linear regression line as shown in Figure 1. The slope of change in amplitude was used to assess progressive hypokinesia or ‘‘decrement”. The slope of change in speed that encompassed both amplitude and duration was used to assess progressive slowing of movement. 2.4. Statistical analysis All groups were compared according to their mean values, using parametric one-way analysis of variance (ANOVA) (or Welch ANOVA when group variances were non-equal), and Kruskal– Wallis one-way analysis as a non-parametric test. For parameters with statistically significant differences among groups, we performed multiple comparisons between each two groups (Tukey test within one-way ANOVA, Games-Holwell test within Welch ANOVA, or Holm test within Kruskal–Wallis). Comparisons of slopes of kinematic parameters were carried out by univariate analysis of covariance (ANCOVA) with sex, age and disease duration as covariates. UPDRS total, UPDRS III and disease duration were analyzed with the t-test for two independent samples or Mann–Wilcoxon test. Sex and Hoehn and Yahr score were analyzed with chi-squared or Fisher’s test. The coefficient of Spearman’s correlation (q) was used to quantify correlation between kinematic parameters and clinimetric scores. The Statistical Package for the Social Sciences version 17.0 (IBM, Armonk, NY, USA) and R-studio (2014) version 0.98.976 (Boston, MA, USA) were used for statistical analysis.
Table 1 Demographic and clinical features of patients with PD (n = 13), PSP (n = 15), MSA (n = 14) and HC (n = 14) Parameters
HC
PD
PSP
MSA
All groups (p-value)
HC–PD
HC–PSP
HC–MSA
PSP–MSA
PD–MSA
PSP–PD
Age, years Female/Male Disease duration, years LED, mg/day Hoehn and Yahr stage UPDRS total UPDRS motor part MMSE HDRS FAB
56.8 ± 9.0 8/6 – – – – – 29.4 ± 0.9 4.0 ± 2.1 17.9 ± 0.3
60.9 ± 9.9 6/7 4.6 ± 4.5 664 ± 531 2.1 ± 0.9 47.1 ± 18.9 27.2 ± 10.3 28.8 ± 1.1 8.2 ± 4.7 15.5 ± 1.3
65.8 ± 8.7 6/9 5.2 ± 2.4 746 ± 175 3.8 ± 0.8 81.7 ± 17.6 46.7 ± 10.7 24.1 ± 3.6 13.2 ± 6.3 8.9 ± 3.6
58.0 ± 4.5 9/5 3.5 ± 1.3 541 ± 306 2.0 ± 2.6 78.5 ± 12.5 45.7 ± 8.3 27.5 ± 1.9 16.5 ± 6.3 14.4 ± 2.6
0.074 0.626 0.259 0.149 0.032 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001
– – – – – – – p < 0.001 p = 0.023 p < 0.001
– – – – – p < 0.001 p < 0.001 p < 0.001 – p < 0.001
– – – – – – – p = 0.016 p < 0.001 p < 0.001
– – – – – – – p = 0.002 p < 0.001 p < 0.001
– – – – – – – – p < 0.001 –
– – – – – p < 0.001 p < 0.001 – p = 0.023 p < 0.001
Data are presented as mean ± standard deviation. FAB = Frontal Assessment Battery, HC = healthy controls, HDRS = Hamilton Depression Rating Scale, LED = levodopa equivalent dose, MMSE = Mini Mental Status Examination, MSA = multiple system atrophy of parkinsonian type, PD = Parkinson’s disease, PSP = progressive supranuclear palsy, UPDRS = Unified Parkinson’s Disease Rating Scale.
M. Djuric´-Jovicˇic´ et al. / Journal of Clinical Neuroscience 30 (2016) 49–55
Fig. 1. Kinematic parameters and their slopes (S) during the 15 s finger tapping trials for one representative patient from each group. Unified Parkinson’s Disease Rating Scale scores of the selected Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) patients were 18, 51, and 44, respectively, while their Frontal Assessment Battery total scores were 16, 13, and 16, respectively.
3. Results Our patient groups did not differ in regards to age, sex ratio, disease duration or levodopa equivalent dose (Table 1). One-way ANOVA found significant differences between the four groups for all kinematic parameters, with the exception of the slope of cycle duration (Table 2). Patients with PSP-R had the highest cadence (Table 2), although statistical significance was only obtained when comparing MSA-P (patients with the lowest cadence) with HC (p = 0.006), and comparing MSA-P with PSP-R (p < 0.001). Mean duration per cycle in the PSP-R group was not different from HC, but was significantly shorter when compared to PD (p = 0.039) and MSA-P (p < 0.001) (Fig. 2, Table 2). Regularity of this kinematic parameter assessed by the CV duration in PD and MSA-P groups revealed significant irregularities in comparison to HC (p = 0.035 and p = 0.044, respectively; Fig. 2).
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Differences in the duration slopes (S) between HC (S = 0.043), PD (S = 2.27), PSP-R (S = 0.3), and MSA-P (S = 9.87) were not statistically significant (Fig. 2, Table 2). Therefore, the higher cadence in PSP-R, with its relatively stable amplitude (S = 0.12) and speed slopes (S = 0.64), was probably achieved through short tap duration. Although the PSP-R group had the lowest mean amplitude (MSA-P had the highest), the only significant difference in amplitude was found compared to HC (p < 0.001). The HC group had the highest mean amplitude coupled with the lowest amplitude CV (Fig. 2, Table 2). For both mean and CV amplitudes, all patient groups significantly differed from HC, but not among themselves (Fig. 2). The amplitude slope in PSP-R (S = 0.12) was similar to the HC group (S = 0.21), but the slope was significantly less negative compared to PD (S = 0.56; p = 0.040) and MSA-P (S = 1.48; p < 0.001) (Fig. 2, Table 2). The significant difference from HC (p = 0.032) was revealed after adjusting amplitude slopes for mean amplitude as a covariate (ANCOVA analysis). In general, the PSP-R group had the smallest, while the MSA-P group had the steepest negative slope (Fig. 2). When compared to HC all patient groups had significantly lower velocity parameters (mean velocity, opening and closing velocity), but these parameters did not differ significantly among patient groups. However, the CV of these parameters were significantly different between PSP-R and all other groups (less regular than in HC, but more regular than in PD and MSA-P) (Fig. 2). Slopes for all three velocity parameters in PSP-R were not different from HC, but were significantly less negative than in PD and MSA-P. The mean velocity slope in PSP-R (S = 0.64) was significantly different from PD (S = 2.89; p < 0.001) and MSA-P group (S = 3.99; p = 0.01), but not from HC, even after adjusting for the mean velocity (S = 1.88; p = 0.23). The PSP-R group had the lowest amplitude slope, meaning these patients were almost without amplitude decrement within the tapping sequence (Fig. 2, Table 2). The mean negative amplitude slope of 0.12°/cycle indicated less progression of amplitude decrement even compared to HC ( 0.21°/cycle; p = 0.032), and particularly when compared to PD ( 0.56°/cycle; p = 0.001), and MSA-P patients ( 1.48°/cycle; p = 0.003). Only one patient in PSP-R group had moderately high amplitude slope (S = 0.8°/cycle), while all others fell between 0.24 and 0.11°/cycle (42% of PSP-R patients had positive slopes, 58% negative). Speed slope of the PSP-R group was also the lowest among all four groups, being mostly negative (66% of PSP-R patients, while the remaining 34% showed positive slopes of <0.6°/s/cycle). The amplitude and speed slopes were significantly more negative in the PD and MSA-P groups when compared to the PSP-R or HC groups, consistent with the SE (Fig. 2). Hypokinesia, defined as an amplitude <50% of the mean amplitude in HC [7], was 40.9° in our study, and was found in 86.6% of the FT trials in PSP-R (13/15) patients, 85% of PD (11/13) patients, and 50% of MSA-P (7/14) patients (p = 0.1024). ‘‘Hypokinesia without decrement”, defined as a tapping amplitude <50% of the mean amplitude obtained from HC, coupled with an amplitude slope which is positive or close to zero ( 0.1
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Kinematic parameters Cadence (n/15 s) Duration (ms) Duration CV (%) Duration slope (ms/cycle) Amplitude (°) Amplitude CV (%) Amplitude slope (°/cycle) Speed (°/s) Speed CV (%) Speed slope (°/s/cycle) Open velocity (°/s) Open velocity CV (%) Open velocity slope (°/s/cycle) Close velocity (°/s) Close velocity CV (%) Close velocity slope (°/s/cycle)
HC 47.8 ± 12.6 331.7 ± 76.8 14.5 ± 6.9 0.04 ± 1.15 81.8 ± 33.9 12.3 ± 5.4 0.21 ± 0.46 516.6 ± 213.9 16.1 ± 6.7 1.88 ± 3.89 1148.1 ± 499 13.2 ± 4.5 8.19 ± 12.24 1602.7 ± 503.1 13.8 ± 5.5 8.36 ± 9.34
PD 42.3 ± 18.4 435.8 ± 211.5 22.4 ± 6.5 2.27 ± 5.58 33.8 ± 11.9 32.4 ± 7.8 0.56 ± 0.48 194.5 ± 91.4 32.5 ± 8.4 2.89 ± 2.21 458.8 ± 188.9 31.6 ± 8.3 7.07 ± 4.29 32.7 ± 287.3 34.0 ± 9.8 10.63 ± 9.65
PSP 57.6 ± 9.6 268.3 ± 53.9 18.8 ± 5.1 0.30 ± 1.24 31.4 ± 15.1 26.3 ± 7.3 0.12 ± 0.26 244.8 ± 107.9 24.4 ± 6.5 0.64 ± 0.93 544.3 ± 206.2 20.9 ± 4.6 1.86 ± 2.82 784.8 ± 346.9 21.6 ± 3.8 2.74 ± 3.46
MSA
All groups (p-value)
HC–PD
HC–PSP
HC–MSA
PSP–MSA
PD–MSA
PSP–PD
27.2 ± 16.9 808.4 ± 562.6 24.8 ± 11.4 9.87 ± 21.03 40.6 ± 21.2 37.2 ± 16.5 1.48 ± 1.13 143.0 ± 86.5 36.3 ± 16.0 3.99 ± 2.60 369.6 ± 201.5 34.9 ± 14.7 11.5 ± 11.4 72.9 ± 256.7 40.3 ± 15.6 14.84 ± 11.0
p < 0.001 p = 0.001 p = 0.005 p = 0.144 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p = 0.022 p < 0.001 p < 0.001 p = 0.057 p < 0.001 p < 0.001 p = 0.012
p = 0.035 p < 0.001 p < 0.001 p = 0.012 p = 0.001 p < 0.001 p = 0.014 p = 0.002 p < 0.001 p = 0.081 p < 0.001 p < 0.001 p = 0.018
– – – – p < 0.001 p < 0.001 p = 0.032 p = 0.006 p = 0.026 p = 0.008 p = 0.005 p < 0.001 p = 0.006 -
p = 0.006 p = 0.008 p = 0.044
p < 0.001 p < 0.001 – – – – p = 0.003 – – p = 0.01 – p < 0.001 p = 0.002 – p < 0.001 p = 0.003
– – – – – – p = 0.029 – – – – – – – – –
– p = 0.039 – – – – p = 0.001 – – p < 0.001 – p = 0.0013 p = 0.003 – p < 0.001 p = 0.013
Data are presented as mean ± standard deviation. Statistical significance is expressed as p values for the comparisons of parameter values. CV = coefficients of variation, HC = healthy controls, MSA = multiple system atrophy of parkinsonian type, PD = Parkinson’s disease, PSP = progressive supranuclear palsy.
p = 0.004 p < 0.001 p = 0.001 p < 0.001 p = 0.002 p = 0.018 p < 0.001 p < 0.001 p = 0.021 p < 0.001 p < 0.001 p = 0.02
M. Djuric´-Jovicˇic´ et al. / Journal of Clinical Neuroscience 30 (2016) 49–55
Table 2 Analysis of kinematic parameters during the finger tapping task in patients with PD (n = 13), PSP (n = 15), MSA (n = 14) and HC (n = 14)
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Fig. 2. Kinematic finger tapping parameters (duration – upper panel, amplitude – middle panel, and speed – lower panel) of patients with progressive supranuclear palsy – Richardson syndrome (PSP-R), Parkinson’s disease (PD), multiple system atrophy of parkinsonian type (MSA-P) and healthy controls (HC) are represented as mean values with error bars of 95% confidence intervals. Horizontal lines between the groups indicate statistical significance (solid lines for p < 0.05, dashed lines for p < 0.1). CV = coefficients of variation, deg = degrees.
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M. Djuric´-Jovicˇic´ et al. / Journal of Clinical Neuroscience 30 (2016) 49–55
p = 0.012) correlated with the Frontal Assessment Battery. Also, speed slope in the PSP-R group correlated with age (q = 0.66; p = 0.020). In the MSA-P group age correlated with cadence (q = 0.55; p = 0.039) and mean duration (q = 0.55; p = 0.039).
4. Discussion The main finding of this study was the lack of or only minimal progressive reduction of amplitude during the FT test in PSP-R patients, similar to the pattern seen in HC, but significantly different from the SE in PD or MSA-P patients. This is compatible with previous clinical impressions that PSP-R patients do not exhibit decrement during such repetitive movements [7]. The mean negative amplitude slope of 0.12°/cycle revealed less progression of amplitude decrement of PSP-R patients even in comparison to HC, and particularly when compared to PD and MSA-P patients (Fig. 2). We suggest that this finding might be disease-specific for PSP-R, since the amplitude decrement slope was the steepest in the MSA-P form of atypical parkinsonism of the four groups (Fig. 2, Table 2). We obtained similar patterns regarding the slope of change in speed used to assess ‘‘fatigue” during the FT test. The mean negative speed slope ( 0.64°/s/cycle) in PSP-R was non-significantly lower compared HC ( 1.88°/s/cycle; p = 0.014), but ‘‘fatigue” was significantly more present in PD ( 2.89°/s/cycle) and in MSA-P ( 3.99°/s/cycle), compared to PSP-R (Fig. 2, Table 2). The average index finger-to-thumb separation amplitude during repetitive FT in PSP-R was not different when compared to the other patient groups, but all patient groups differed from HC (Fig. 2, Table 2). To our knowledge, only one study has dealt with that idea of a specific FT pattern in PSP-R in comparison to PD [7]. MSA-P patients were not included, but the authors also found a lack of amplitude and speed decrement during sequential tap cycles in PSP-R when compared to PD patients, suggesting that the former group did not fulfill the criteria for limb bradykinesia. Further, they found that 75% of PSP-R, but only 15% of PD, patients had micrographia, but PSP-R patients did not exhibit decrement in script size. We failed to confirm another important finding of Ling et al. [7]: small index finger-to-thumb separation amplitude in PSP-R patients (average finger separation amplitude in PSP-R was <50% of that in controls and PD patients). The mean amplitudes for PSP-R and PD groups in our study were 31.4° and 33.8°, respectively (p = 0.726). As an explanation for such severe hypokinesia in PSP, Ling et al. suggested the internal segment of the globus pallidus and subthalamic nucleus may be more extensively affected in PSP-R than in PD, also suggesting a possible lack of cerebellar compensation due to the damage of the superior cerebellar peduncles in PSP [7]. Ling et al. analyzed data obtained from both hands, while we tested only the right hand (all our participants were right-handed, and in the PD group only patients with predominant right side affliction were recruited). We believe that focusing on the right hand (the ‘‘dominant hand” in controls and in the groups of PSP-R and MSA-P patients, characterized by symmetrical parkinsonism, as well as in the PD group, where it was also ‘‘a more affected hand”) was a methodologically sound strategy, since calculating the average estimates for both hands, at least in the PD group, might be biased by the pronounced asymmetry of bradykinesia. Ling et al. also reported ‘‘hypokinesia without a decrement” in 87% and 12% of FT trials in the PSP-R and PD group, respectively, suggesting that it might be a particular motor pattern in PSP-R. Despite this discrepancy between our two studies, with a change in definition of ‘‘absence of decrement” (we used the definition of ‘‘positive or close to zero [ 0.1
Dopaminergic mechanisms appeared not to be involved in the SE [18–20]. The structural abnormalities associated with the SE have not yet been identified, but several possibilities include the basal ganglia [20,21], supplementary motor area, premotor cortex, sensorimotor cortex [22], and cerebellum [23]. Recently, Lee et al. reported an association of the anterior cingulate cortex and the cerebellar inferior semilunar lobule with the severity of the SE in de novo PD patients [24]. According to Dickson, the cingulate cortex is moderately affected in PD, but spared in PSP-R [25]. To conclude, the main message of our study was that the lack of clinically significant SE effect differentiated PSP-R from both PD and MSA-P patients, suggesting specificity for PSP-R. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by the Serbian Ministry of Education, Science and Technological Development (grants 175090 and 175016). References [1] Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9. [2] Williams DR. Progressive supranuclear palsy and corticobasal degeneration. In: Burn DJ, Kennard C, editors. Oxford Textbook of Movement Disorders. Oxford: Oxford University Press; 2013. p. 139–50. [3] Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [4] Brusa A, Mancardi GL, Bugiani O. Progressive supranuclear palsy 1979: an overview. Ital J Neurol Sci 1980;1:205–22. [5] Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary ninds neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 1996;55:97–105. [6] Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 2005;128:1247–58. [7] Ling H, Massey LA, Lees AJ, et al. Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson’s disease. Brain 2012;135:1141–53. [8] Gilman S, Wenning GK, Paet al Low DJ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670–6. [9] Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental State". A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Res 1975;12:189–98. [10] Dubois B, Slachevsky A, Litvan I, et al. The FAB: a frontal assessment battery at bedside. Neurol 2000;55:1621–6. [11] Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. [12] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 2001;57:S11–26. [13] Fahn S, Elton RL. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne D, et al., editors. Recent developments in Parkinson’s disease. Florham Park, NJ: McMillan Health Care Information; 1987. p. 153–63. [14] Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010;25:2649–53. [15] Yokoe M, Okuno R, Hamasaki T, et al. Opening velocity, a novel parameter for finger tapping test in patients with Parkinson’s disease. Parkinsonism Relat Disord 2009;15:440–4. [16] Jovicˇic´ NS, Saranovac LV, Popovic´ DB. Wireless distributed functional electrical stimulation system. J Neuroeng Rehabil 2012;9:54. [17] Arias P, Robles-García V, Espinosa N, et al. Validity of the finger tapping test in Parkinson’s disease, elderly and young healthy subjects: is there a role for central fatigue? Clin Neurophysiol 2012;123:2034–41. [18] Iansek R, Huxham F, McGinley J. The sequence effect and gait festination in Parkinson disease: contributors to freezing of gait? Mov Disord 2006;21:1419–24. [19] Espay AJ, Giuffrida JP, Chen R, et al. Differential response of speed, amplitude, and rhythm to dopaminergic medications in Parkinson’s disease. Mov Disord 2011;26:2504–8.
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Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Finger tapping analysis in patients with Parkinson’s disease and atypical parkinsonism Milica Djuric´-Jovicˇic´ a, Igor Petrovic´ b, Milica Jecˇmenica-Lukic´ b, Saša Radovanovic´ c, Nataša Dragaševic´-Miškovic´ b, Minja Belic´ a, Vera Miler-Jerkovic´ d, Mirjana B. Popovic´ d, Vladimir S. Kostic´ b,⇑ a
Innovation Center, School of Electrical Engineering, University of Belgrade, Belgrade, Serbia Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6, Belgrade, Serbia c Institute for Medical Research, University of Belgrade, Belgrade, Serbia d School of Electrical Engineering, University of Belgrade, Department for Signals and Systems, Belgrade, Serbia b
a r t i c l e
i n f o
Article history: Received 20 October 2015 Accepted 27 October 2015
Keywords: Atypical parkinsonism Hypokinesia Kinematic analysis Progressive supranuclear palsy Repetitive finger tapping
a b s t r a c t The goal of this study was to investigate repetitive finger tapping patterns in patients with Parkinson’s disease (PD), progressive supranuclear palsy–Richardson syndrome (PSP-R), or multiple system atrophy of parkinsonian type (MSA-P). The finger tapping performance was objectively assessed in PD (n = 13), PSP-R (n = 15), and MSA-P (n = 14) patients and matched healthy controls (HC; n = 14), using miniature inertial sensors positioned on the thumb and index finger, providing spatio-temporal kinematic parameters. The main finding was the lack or only minimal progressive reduction in amplitude during the finger tapping in PSP-R patients, similar to HC, but significantly different from the sequence effect (progressive decrement) in both PD and MSA-P patients. The mean negative amplitude slope of 0.12°/cycle revealed less progression of amplitude decrement even in comparison to HC ( 0.21°/cycle, p = 0.032), and particularly from PD ( 0.56°/cycle, p = 0.001), and MSA-P patients ( 1.48°/cycle, p = 0.003). No significant differences were found in the average finger separation amplitudes between PD, PSP-R and MSA-P patients (pmsa-pd = 0.726, pmsa-psp = 0.363, ppsp-pd = 0.726). The lack of clinically significant sequence effect during finger tapping differentiated PSP-R from both PD and MSA-P patients, and might be specific for PSP-R. The finger tapping kinematic parameter of amplitude slope may be a neurophysiological marker able to differentiate particular forms of parkinsonism. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Progressive supranuclear palsy (PSP) is the second most common form of neurodegenerative parkinsonism after Parkinson’s disease (PD). Its classical clinical presentation, known as Richardson syndrome (PSP-R), is characterized by early gait instability with falls, vertical supranuclear gaze palsy, symmetrical akineticrigid syndrome, cognitive and behavioral changes, and death within 7–8 years of initial symptom onset [1]. Akinetic-rigid parkinsonian syndrome in PSP-R is predominantly axial, and sometimes out of proportion to limb tone which may be relatively spared [2]. Bradykinesia, defined as ‘‘slowness of initiation of voluntary movement with progressive reduction in speed and amplitude of repetitive action” (also known as sequence ⇑ Corresponding author. Tel.: +381 11 2685 596. E-mail address: [email protected] (V.S. Kostic´). http://dx.doi.org/10.1016/j.jocn.2015.10.053 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
effect [SE]) [3], is controversial in PSP patients. A study of 75 pathologically proven PSP patients identified bradykinesia in only 22% of patients in the first disease year [4], in contrast to more recent studies where early bradykinesia was reported in 88% and 75% of pathologically confirmed PSP cases [5], [6]. Recently, Ling et al. objectively assessed repetitive finger tapping (FT) in PSP-R and PD patients and age- and sex-matched healthy controls (HC), and found that PSP-R patients had small finger separation amplitude (<50% of that in controls and PD patients) without progressive decrement (that is, without SE) [7]. Therefore, they concluded that ‘‘the severe hypokinesia (small amplitude movements) irrespective of disease severity and the lack of a sequence effect” were useful in discriminating PSP-R from PD patients and HC, suggesting also that features identified in PSP-R might not adhere to the definition of bradykinesia in PD [3]. We studied the differences in the pattern of repetitive FT in patients with PD, PSP-R, and multiple system atrophy of
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predominantly parkinsonian subtype (MSA-P), and compared them with HC.
‘‘start” and ”stop” commands), with a 1 minute pause between trials. Each of the three consecutive trials began and ended with fingers closed (zero angle).
2. Methods 2.3. Kinematic parameters 2.1. Participants This study comprised of four groups of right-handed participants recruited from the Movement Disorders Unit at the Clinic of Neurology, Belgrade: (1) 13 patients with PD diagnosed according to the UK Queen Square Brain Bank Criteria [3]; (2) 15 PSP-R patients diagnosed according to the criteria of Litvan et al. [5]; (3) 14 MSA-P patients, fulfilling the criteria of Gilman et al. [8]; and (4) 14 HC with no history of neurological or psychiatric disease (Table 1). HC were age- and sex-matched with the overall patient group. Patients with tremor/dyskinesia and hand dystonia, as well as any disability of the extremities that might interfere with motor tasks, were excluded from the study. Other exclusion criteria in PD patients were: (1) scores of <26 on the Mini Mental Status Examination [9] or <15 on the Frontal Assessment Battery [10]; (2) score P14 for the Hamilton Depression Rating Scale [11]; and (3) history of psychosis or major medical disease. Disease staging was assessed according to the Hoehn and Yahr system [12] and motor disability using the Unified Parkinson’s Disease Rating Scale (UPDRS III) [13]. Levodopa equivalent dose was also calculated [14]. All the tests, including FT performed in accordance with the recommendations for FT assessment, were conducted in the morning after an overnight treatment withdrawal of at least 12 hours where applicable (patients with PD were tested during ‘‘off ” time) [15]. The research was approved by the Ethical Committee of the School of Medicine, University of Belgrade, and written informed consent was obtained from each participant. 2.2. Experimental setup and testing protocol The system included two inertial measurement sensor units which acquired signals and wirelessly transmitted to a remote computer [16]. The PD group included only patients with predominantly right sided affliction and data were obtained from the right hand. The participants were asked to sit comfortably and were asked to hold their hand in front of them. Participants were instructed to repeatedly tap the index finger and thumb as rapidly and as widely as possible for 15 seconds (the same acoustic signal was used for
Angle amplitude in degrees (°), cycle duration (ms), and speed (°/s) were measured for each cycle of FT from one index finger– thumb separation to the next [7]. Signals were processed by custom-made software [16]. Tapping amplitude was defined as the angle between the long axes of the thumb and index finger. Mean speed was the mean rate of change in aperture regardless of whether the aperture was opening or closing. Closing and opening velocities (°/s) were the peak velocities of aperture closure and opening within a cycle, respectively. The coefficients of variation (CV) of amplitude and speed across the tap trials were calculated [17]. High values of CV illustrated irregularities of kinematic parameters. Progressive changes in amplitude, duration and speed across a 15 s FT trial were represented by the slope of the fitted linear regression line as shown in Figure 1. The slope of change in amplitude was used to assess progressive hypokinesia or ‘‘decrement”. The slope of change in speed that encompassed both amplitude and duration was used to assess progressive slowing of movement. 2.4. Statistical analysis All groups were compared according to their mean values, using parametric one-way analysis of variance (ANOVA) (or Welch ANOVA when group variances were non-equal), and Kruskal– Wallis one-way analysis as a non-parametric test. For parameters with statistically significant differences among groups, we performed multiple comparisons between each two groups (Tukey test within one-way ANOVA, Games-Holwell test within Welch ANOVA, or Holm test within Kruskal–Wallis). Comparisons of slopes of kinematic parameters were carried out by univariate analysis of covariance (ANCOVA) with sex, age and disease duration as covariates. UPDRS total, UPDRS III and disease duration were analyzed with the t-test for two independent samples or Mann–Wilcoxon test. Sex and Hoehn and Yahr score were analyzed with chi-squared or Fisher’s test. The coefficient of Spearman’s correlation (q) was used to quantify correlation between kinematic parameters and clinimetric scores. The Statistical Package for the Social Sciences version 17.0 (IBM, Armonk, NY, USA) and R-studio (2014) version 0.98.976 (Boston, MA, USA) were used for statistical analysis.
Table 1 Demographic and clinical features of patients with PD (n = 13), PSP (n = 15), MSA (n = 14) and HC (n = 14) Parameters
HC
PD
PSP
MSA
All groups (p-value)
HC–PD
HC–PSP
HC–MSA
PSP–MSA
PD–MSA
PSP–PD
Age, years Female/Male Disease duration, years LED, mg/day Hoehn and Yahr stage UPDRS total UPDRS motor part MMSE HDRS FAB
56.8 ± 9.0 8/6 – – – – – 29.4 ± 0.9 4.0 ± 2.1 17.9 ± 0.3
60.9 ± 9.9 6/7 4.6 ± 4.5 664 ± 531 2.1 ± 0.9 47.1 ± 18.9 27.2 ± 10.3 28.8 ± 1.1 8.2 ± 4.7 15.5 ± 1.3
65.8 ± 8.7 6/9 5.2 ± 2.4 746 ± 175 3.8 ± 0.8 81.7 ± 17.6 46.7 ± 10.7 24.1 ± 3.6 13.2 ± 6.3 8.9 ± 3.6
58.0 ± 4.5 9/5 3.5 ± 1.3 541 ± 306 2.0 ± 2.6 78.5 ± 12.5 45.7 ± 8.3 27.5 ± 1.9 16.5 ± 6.3 14.4 ± 2.6
0.074 0.626 0.259 0.149 0.032 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001
– – – – – – – p < 0.001 p = 0.023 p < 0.001
– – – – – p < 0.001 p < 0.001 p < 0.001 – p < 0.001
– – – – – – – p = 0.016 p < 0.001 p < 0.001
– – – – – – – p = 0.002 p < 0.001 p < 0.001
– – – – – – – – p < 0.001 –
– – – – – p < 0.001 p < 0.001 – p = 0.023 p < 0.001
Data are presented as mean ± standard deviation. FAB = Frontal Assessment Battery, HC = healthy controls, HDRS = Hamilton Depression Rating Scale, LED = levodopa equivalent dose, MMSE = Mini Mental Status Examination, MSA = multiple system atrophy of parkinsonian type, PD = Parkinson’s disease, PSP = progressive supranuclear palsy, UPDRS = Unified Parkinson’s Disease Rating Scale.
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Fig. 1. Kinematic parameters and their slopes (S) during the 15 s finger tapping trials for one representative patient from each group. Unified Parkinson’s Disease Rating Scale scores of the selected Parkinson’s disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) patients were 18, 51, and 44, respectively, while their Frontal Assessment Battery total scores were 16, 13, and 16, respectively.
3. Results Our patient groups did not differ in regards to age, sex ratio, disease duration or levodopa equivalent dose (Table 1). One-way ANOVA found significant differences between the four groups for all kinematic parameters, with the exception of the slope of cycle duration (Table 2). Patients with PSP-R had the highest cadence (Table 2), although statistical significance was only obtained when comparing MSA-P (patients with the lowest cadence) with HC (p = 0.006), and comparing MSA-P with PSP-R (p < 0.001). Mean duration per cycle in the PSP-R group was not different from HC, but was significantly shorter when compared to PD (p = 0.039) and MSA-P (p < 0.001) (Fig. 2, Table 2). Regularity of this kinematic parameter assessed by the CV duration in PD and MSA-P groups revealed significant irregularities in comparison to HC (p = 0.035 and p = 0.044, respectively; Fig. 2).
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Differences in the duration slopes (S) between HC (S = 0.043), PD (S = 2.27), PSP-R (S = 0.3), and MSA-P (S = 9.87) were not statistically significant (Fig. 2, Table 2). Therefore, the higher cadence in PSP-R, with its relatively stable amplitude (S = 0.12) and speed slopes (S = 0.64), was probably achieved through short tap duration. Although the PSP-R group had the lowest mean amplitude (MSA-P had the highest), the only significant difference in amplitude was found compared to HC (p < 0.001). The HC group had the highest mean amplitude coupled with the lowest amplitude CV (Fig. 2, Table 2). For both mean and CV amplitudes, all patient groups significantly differed from HC, but not among themselves (Fig. 2). The amplitude slope in PSP-R (S = 0.12) was similar to the HC group (S = 0.21), but the slope was significantly less negative compared to PD (S = 0.56; p = 0.040) and MSA-P (S = 1.48; p < 0.001) (Fig. 2, Table 2). The significant difference from HC (p = 0.032) was revealed after adjusting amplitude slopes for mean amplitude as a covariate (ANCOVA analysis). In general, the PSP-R group had the smallest, while the MSA-P group had the steepest negative slope (Fig. 2). When compared to HC all patient groups had significantly lower velocity parameters (mean velocity, opening and closing velocity), but these parameters did not differ significantly among patient groups. However, the CV of these parameters were significantly different between PSP-R and all other groups (less regular than in HC, but more regular than in PD and MSA-P) (Fig. 2). Slopes for all three velocity parameters in PSP-R were not different from HC, but were significantly less negative than in PD and MSA-P. The mean velocity slope in PSP-R (S = 0.64) was significantly different from PD (S = 2.89; p < 0.001) and MSA-P group (S = 3.99; p = 0.01), but not from HC, even after adjusting for the mean velocity (S = 1.88; p = 0.23). The PSP-R group had the lowest amplitude slope, meaning these patients were almost without amplitude decrement within the tapping sequence (Fig. 2, Table 2). The mean negative amplitude slope of 0.12°/cycle indicated less progression of amplitude decrement even compared to HC ( 0.21°/cycle; p = 0.032), and particularly when compared to PD ( 0.56°/cycle; p = 0.001), and MSA-P patients ( 1.48°/cycle; p = 0.003). Only one patient in PSP-R group had moderately high amplitude slope (S = 0.8°/cycle), while all others fell between 0.24 and 0.11°/cycle (42% of PSP-R patients had positive slopes, 58% negative). Speed slope of the PSP-R group was also the lowest among all four groups, being mostly negative (66% of PSP-R patients, while the remaining 34% showed positive slopes of <0.6°/s/cycle). The amplitude and speed slopes were significantly more negative in the PD and MSA-P groups when compared to the PSP-R or HC groups, consistent with the SE (Fig. 2). Hypokinesia, defined as an amplitude <50% of the mean amplitude in HC [7], was 40.9° in our study, and was found in 86.6% of the FT trials in PSP-R (13/15) patients, 85% of PD (11/13) patients, and 50% of MSA-P (7/14) patients (p = 0.1024). ‘‘Hypokinesia without decrement”, defined as a tapping amplitude <50% of the mean amplitude obtained from HC, coupled with an amplitude slope which is positive or close to zero ( 0.1
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Kinematic parameters Cadence (n/15 s) Duration (ms) Duration CV (%) Duration slope (ms/cycle) Amplitude (°) Amplitude CV (%) Amplitude slope (°/cycle) Speed (°/s) Speed CV (%) Speed slope (°/s/cycle) Open velocity (°/s) Open velocity CV (%) Open velocity slope (°/s/cycle) Close velocity (°/s) Close velocity CV (%) Close velocity slope (°/s/cycle)
HC 47.8 ± 12.6 331.7 ± 76.8 14.5 ± 6.9 0.04 ± 1.15 81.8 ± 33.9 12.3 ± 5.4 0.21 ± 0.46 516.6 ± 213.9 16.1 ± 6.7 1.88 ± 3.89 1148.1 ± 499 13.2 ± 4.5 8.19 ± 12.24 1602.7 ± 503.1 13.8 ± 5.5 8.36 ± 9.34
PD 42.3 ± 18.4 435.8 ± 211.5 22.4 ± 6.5 2.27 ± 5.58 33.8 ± 11.9 32.4 ± 7.8 0.56 ± 0.48 194.5 ± 91.4 32.5 ± 8.4 2.89 ± 2.21 458.8 ± 188.9 31.6 ± 8.3 7.07 ± 4.29 32.7 ± 287.3 34.0 ± 9.8 10.63 ± 9.65
PSP 57.6 ± 9.6 268.3 ± 53.9 18.8 ± 5.1 0.30 ± 1.24 31.4 ± 15.1 26.3 ± 7.3 0.12 ± 0.26 244.8 ± 107.9 24.4 ± 6.5 0.64 ± 0.93 544.3 ± 206.2 20.9 ± 4.6 1.86 ± 2.82 784.8 ± 346.9 21.6 ± 3.8 2.74 ± 3.46
MSA
All groups (p-value)
HC–PD
HC–PSP
HC–MSA
PSP–MSA
PD–MSA
PSP–PD
27.2 ± 16.9 808.4 ± 562.6 24.8 ± 11.4 9.87 ± 21.03 40.6 ± 21.2 37.2 ± 16.5 1.48 ± 1.13 143.0 ± 86.5 36.3 ± 16.0 3.99 ± 2.60 369.6 ± 201.5 34.9 ± 14.7 11.5 ± 11.4 72.9 ± 256.7 40.3 ± 15.6 14.84 ± 11.0
p < 0.001 p = 0.001 p = 0.005 p = 0.144 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p < 0.001 p = 0.022 p < 0.001 p < 0.001 p = 0.057 p < 0.001 p < 0.001 p = 0.012
p = 0.035 p < 0.001 p < 0.001 p = 0.012 p = 0.001 p < 0.001 p = 0.014 p = 0.002 p < 0.001 p = 0.081 p < 0.001 p < 0.001 p = 0.018
– – – – p < 0.001 p < 0.001 p = 0.032 p = 0.006 p = 0.026 p = 0.008 p = 0.005 p < 0.001 p = 0.006 -
p = 0.006 p = 0.008 p = 0.044
p < 0.001 p < 0.001 – – – – p = 0.003 – – p = 0.01 – p < 0.001 p = 0.002 – p < 0.001 p = 0.003
– – – – – – p = 0.029 – – – – – – – – –
– p = 0.039 – – – – p = 0.001 – – p < 0.001 – p = 0.0013 p = 0.003 – p < 0.001 p = 0.013
Data are presented as mean ± standard deviation. Statistical significance is expressed as p values for the comparisons of parameter values. CV = coefficients of variation, HC = healthy controls, MSA = multiple system atrophy of parkinsonian type, PD = Parkinson’s disease, PSP = progressive supranuclear palsy.
p = 0.004 p < 0.001 p = 0.001 p < 0.001 p = 0.002 p = 0.018 p < 0.001 p < 0.001 p = 0.021 p < 0.001 p < 0.001 p = 0.02
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Table 2 Analysis of kinematic parameters during the finger tapping task in patients with PD (n = 13), PSP (n = 15), MSA (n = 14) and HC (n = 14)
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Fig. 2. Kinematic finger tapping parameters (duration – upper panel, amplitude – middle panel, and speed – lower panel) of patients with progressive supranuclear palsy – Richardson syndrome (PSP-R), Parkinson’s disease (PD), multiple system atrophy of parkinsonian type (MSA-P) and healthy controls (HC) are represented as mean values with error bars of 95% confidence intervals. Horizontal lines between the groups indicate statistical significance (solid lines for p < 0.05, dashed lines for p < 0.1). CV = coefficients of variation, deg = degrees.
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p = 0.012) correlated with the Frontal Assessment Battery. Also, speed slope in the PSP-R group correlated with age (q = 0.66; p = 0.020). In the MSA-P group age correlated with cadence (q = 0.55; p = 0.039) and mean duration (q = 0.55; p = 0.039).
4. Discussion The main finding of this study was the lack of or only minimal progressive reduction of amplitude during the FT test in PSP-R patients, similar to the pattern seen in HC, but significantly different from the SE in PD or MSA-P patients. This is compatible with previous clinical impressions that PSP-R patients do not exhibit decrement during such repetitive movements [7]. The mean negative amplitude slope of 0.12°/cycle revealed less progression of amplitude decrement of PSP-R patients even in comparison to HC, and particularly when compared to PD and MSA-P patients (Fig. 2). We suggest that this finding might be disease-specific for PSP-R, since the amplitude decrement slope was the steepest in the MSA-P form of atypical parkinsonism of the four groups (Fig. 2, Table 2). We obtained similar patterns regarding the slope of change in speed used to assess ‘‘fatigue” during the FT test. The mean negative speed slope ( 0.64°/s/cycle) in PSP-R was non-significantly lower compared HC ( 1.88°/s/cycle; p = 0.014), but ‘‘fatigue” was significantly more present in PD ( 2.89°/s/cycle) and in MSA-P ( 3.99°/s/cycle), compared to PSP-R (Fig. 2, Table 2). The average index finger-to-thumb separation amplitude during repetitive FT in PSP-R was not different when compared to the other patient groups, but all patient groups differed from HC (Fig. 2, Table 2). To our knowledge, only one study has dealt with that idea of a specific FT pattern in PSP-R in comparison to PD [7]. MSA-P patients were not included, but the authors also found a lack of amplitude and speed decrement during sequential tap cycles in PSP-R when compared to PD patients, suggesting that the former group did not fulfill the criteria for limb bradykinesia. Further, they found that 75% of PSP-R, but only 15% of PD, patients had micrographia, but PSP-R patients did not exhibit decrement in script size. We failed to confirm another important finding of Ling et al. [7]: small index finger-to-thumb separation amplitude in PSP-R patients (average finger separation amplitude in PSP-R was <50% of that in controls and PD patients). The mean amplitudes for PSP-R and PD groups in our study were 31.4° and 33.8°, respectively (p = 0.726). As an explanation for such severe hypokinesia in PSP, Ling et al. suggested the internal segment of the globus pallidus and subthalamic nucleus may be more extensively affected in PSP-R than in PD, also suggesting a possible lack of cerebellar compensation due to the damage of the superior cerebellar peduncles in PSP [7]. Ling et al. analyzed data obtained from both hands, while we tested only the right hand (all our participants were right-handed, and in the PD group only patients with predominant right side affliction were recruited). We believe that focusing on the right hand (the ‘‘dominant hand” in controls and in the groups of PSP-R and MSA-P patients, characterized by symmetrical parkinsonism, as well as in the PD group, where it was also ‘‘a more affected hand”) was a methodologically sound strategy, since calculating the average estimates for both hands, at least in the PD group, might be biased by the pronounced asymmetry of bradykinesia. Ling et al. also reported ‘‘hypokinesia without a decrement” in 87% and 12% of FT trials in the PSP-R and PD group, respectively, suggesting that it might be a particular motor pattern in PSP-R. Despite this discrepancy between our two studies, with a change in definition of ‘‘absence of decrement” (we used the definition of ‘‘positive or close to zero [ 0.1
Dopaminergic mechanisms appeared not to be involved in the SE [18–20]. The structural abnormalities associated with the SE have not yet been identified, but several possibilities include the basal ganglia [20,21], supplementary motor area, premotor cortex, sensorimotor cortex [22], and cerebellum [23]. Recently, Lee et al. reported an association of the anterior cingulate cortex and the cerebellar inferior semilunar lobule with the severity of the SE in de novo PD patients [24]. According to Dickson, the cingulate cortex is moderately affected in PD, but spared in PSP-R [25]. To conclude, the main message of our study was that the lack of clinically significant SE effect differentiated PSP-R from both PD and MSA-P patients, suggesting specificity for PSP-R. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by the Serbian Ministry of Education, Science and Technological Development (grants 175090 and 175016). References [1] Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9. [2] Williams DR. Progressive supranuclear palsy and corticobasal degeneration. In: Burn DJ, Kennard C, editors. Oxford Textbook of Movement Disorders. Oxford: Oxford University Press; 2013. p. 139–50. [3] Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4. [4] Brusa A, Mancardi GL, Bugiani O. Progressive supranuclear palsy 1979: an overview. Ital J Neurol Sci 1980;1:205–22. [5] Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary ninds neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol 1996;55:97–105. [6] Williams DR, de Silva R, Paviour DC, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism. Brain 2005;128:1247–58. [7] Ling H, Massey LA, Lees AJ, et al. Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson’s disease. Brain 2012;135:1141–53. [8] Gilman S, Wenning GK, Paet al Low DJ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670–6. [9] Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental State". A practical method for grading the cognitive state of patients for the clinician. J Psychiatric Res 1975;12:189–98. [10] Dubois B, Slachevsky A, Litvan I, et al. The FAB: a frontal assessment battery at bedside. Neurol 2000;55:1621–6. [11] Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56–62. [12] Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 2001;57:S11–26. [13] Fahn S, Elton RL. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne D, et al., editors. Recent developments in Parkinson’s disease. Florham Park, NJ: McMillan Health Care Information; 1987. p. 153–63. [14] Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord 2010;25:2649–53. [15] Yokoe M, Okuno R, Hamasaki T, et al. Opening velocity, a novel parameter for finger tapping test in patients with Parkinson’s disease. Parkinsonism Relat Disord 2009;15:440–4. [16] Jovicˇic´ NS, Saranovac LV, Popovic´ DB. Wireless distributed functional electrical stimulation system. J Neuroeng Rehabil 2012;9:54. [17] Arias P, Robles-García V, Espinosa N, et al. Validity of the finger tapping test in Parkinson’s disease, elderly and young healthy subjects: is there a role for central fatigue? Clin Neurophysiol 2012;123:2034–41. [18] Iansek R, Huxham F, McGinley J. The sequence effect and gait festination in Parkinson disease: contributors to freezing of gait? Mov Disord 2006;21:1419–24. [19] Espay AJ, Giuffrida JP, Chen R, et al. Differential response of speed, amplitude, and rhythm to dopaminergic medications in Parkinson’s disease. Mov Disord 2011;26:2504–8.
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