Using the PGR, we recorded the daily walking profiles of 14 PD patients (11 men and 3 women) with a mean age of 62.1 ± 14.9 years (±SD), including two patents reported (22). The profiles of patients are shown in Table 1. They represented all patients admitted to Tokyo Women’s Medical University Hospital between June 2010 and March 2013 who could walk unaided and showed no peak-dose dyskinesia during the “on” time. They included six patients with Hoehn and Yahr stage II and eight with stage III. The clinical status was examined using the UPDRS motor score "on" state (mean score of UPDRS Part III: 17.5 ± 9.0) (7). Clinically, 12 patients exhibited motor fluctuations. All patients were taking antiparkinsonian medication as follows: selegiline hydrochloride (2.5 mg/day, n = 3), levodopa (300–500 mg/day, n = 13), pramipexole (1.5–2.5 mg/day, n = 7), ropinirole (6 mg/day, n = 2), cabergoline (2 mg/day, n = 2), pergolide (750 μg/day, n = 1), amantadine (100–200 mg/day, n = 9), trihexyphenidyl (2.0–3.0 mg/day, n = 6), and zonisamide (100 mg/day, n = 1). l-DOPA equivalent doses were calculated for each patient (23), and the average was 591 mg. The study also included 17 age- and height-matched healthy controls (8 men and 9 women, age: 64.7 ± 4.5 years). Matching for age and height was based on the finding that gait cycle and floor reaction forces are influenced by these two parameters.

Written informed consent was obtained from all subjects following a full explanation of this study. This study was conducted in accordance with the guidelines of the Committee of Medical Ethics of Tokyo Women’s Medical University (approval number 2439).

Motor function was assessed before and 3 months after the addition or increase in dose of selegiline using part III of UPDRS. Gait severity was assessed using UPDRS item 29. This item classifies patients into four grades according to the severity of gait symptoms: (0) none, (1) rare freezing when walking; may have start hesitation, (2) occasional freezing when walking, (3) frequent freezing, occasionally falls from freezing, and (4) frequent falls from freezing. UPDRS was evaluated when patients were in the “on” state. Patients were asked to complete a freezing of gait (FOG) questionnaire (24) before and 3 months after the addition or increase in dose of selegiline.

Results were expressed as mean ± SD. The Student’s t-test was used for statistical analyses of the comparison of gait parameters between before and after the addition or increase in dose of selegiline. p-Values <0.05 were considered to indicate statistically significant differences.

A 75-year-old man, who was diagnosed with PD 6 years ago, was being treated with 500 mg l-DOPA, 300 mg COMT inhibitor, and 2.5 mg selegiline. The amount of overall movements per 24 h was 0.35 m/s² and extremely low compared with healthy controls (0.69 ± 0.19 m/s²) (Figure 1A). In the gait acceleration-cycle plot (Figure 1B), the regression curve for this patient was shifted to the left. The amplitude of the average acceleration (1.82 m/s²) was lower compared with healthy controls (2.78 ± 0.42 m/s²). Furthermore, the slope of the linear regression was steep, at 1.70, compared with healthy controls (healthy controls: 1.20 ± 0.29). When changes in the cadence (steps/min) and the gait acceleration amplitude were traced throughout the test day (Figure 1C), the patient showed an increase in the cadence >220 steps/min accompanied with a decrease in the gait acceleration amplitude at 19:00–21:00 and 05:00. Since a step cycle increase over 3 Hz is assumed to be FOG (25), the patient showed FOG at night, resulting in motor fluctuations. Three months after increasing the dose of selegiline to 5.0 mg, the amount of overall movements per 24 h remained almost unchanged (0.35 m/s²) (Figure 1D). In contrast, the regression curve in the gait acceleration-cycle plot (Figure 1E) was shifted to the right, almost within the range of the healthy controls. The average acceleration increased in amplitude (pre: 1.82 m/s², post: 1.94 m/s²). The slope of the linear regression line flattened, decreasing from 1.70 to 0.8. Throughout the test day, the cadence was almost within the normal range, suggesting a disappearance of FOG (Figure 1F). Although UPDRS III changed from 23 to 19, the UPDRS III gait score remained unchanged (pre: 1, post: 1). By contrast, the patient’s FOG score improved from 14 to 10 points.

A 37-year-old man who had been living with PD symptoms for 9 years, was taking 200 mg l-DOPA, 200 mg amantadine, and 3 mg pramipexole. He showed the normal amount of overall movements per 24 h (0.70 m/s²) (Figure 2A), and an average acceleration of 2.86 m/s². In the gait acceleration-cycle plot (Figure 2B), the regression curve for this patient was shifted to the left. The slope of the linear regression line was steep, at 0.84. Figure 2C shows the fluctuations in cadence. The patient showed an increase in the cadence >160 steps/min accompanied with a decrease in the gait acceleration amplitude at 07:00–08:00, 10:00, and 14:00–15:00. After starting the patient on 2.5 mg selegiline, the slope of the linear regression line increased from 0.84 to 1.2 (Figure 2E). Throughout the test day, fluctuations in cadence improved, suggesting a disappearance of the fluctuations in gait (Figure 2F). Although the UPDRS III and UPDRS III gait scores changed from 21 to 15 and from 2 to 1, respectively, the FOG score did not change (pre: 13, post: 13).

A 67-year-old woman who was suffered from the disease since 20 years ago, was taking 500 mg l-DOPA, 750 µg pergolide, 300 mg COMT inhibitor, and 2 mg trihexyphenidyl. She showed a decreased amount of overall movements per 24 h (0.36 m/s²) (Figure 3A). In the gait acceleration-cycle plot (Figure 3B), the regression curve for this patient was shifted to the left. Her average acceleration was low (1.68 m/s²), and the slope of the linear regression line was steep, at 1.97. Figure 3C shows the fluctuations in cadence. At 20:00 and 22:00 and 08:00, 10:00, and 12:00, the cadence slowed, suggesting that the patient walked with a bradykinetic movement. Due to her gait disorders and wearing off, 2.5 mg selegiline was added to her medicine regimen. After the addition of selegiline, the amount of overall movements per 24 h slightly increased from 0.36 to 0.44 m/s² (Figure 3D). In the gait acceleration-cycle plot (Figure 3E), the regression curve was shifted slightly to the right, and the amplitude of the average acceleration increased (pre: 1.68 m/s², post: 2.04 m/s²). However, the slope of the linear regression line flattened, decreasing from 1.97 to 0.95. Throughout the test day, the cadence was almost within the normal range, suggesting a disappearance of the fluctuations in gait (Figure 3F). Although the UPDRS III score changed from 23 to 18, the UPDRS III gait score remained unchanged (pre: 1, post: 1). No changes were detected in the modified gait score (pre: 12, post: 12).

Average UPDRS III, item 29 (gait), and FOG scores were significantly improved after the addition or increase in dose of selegiline; however, item 29 of UPDRS was improved in only six patients (46.2%). PGR quantitatively revealed changes in the gaits of the patients. Although the amount of overall movements per 24 h changed in 5 of 8 patients, the amplitude of the gait acceleration increased in 4 of 10 patients, the range of the gait acceleration correspondingly widened in 4 of 10 patients, and the slow cadence improved in 4 of 4 patients after increase in dose of selegiline. That is, the addition or increase in dose of selegiline (average dose: 4.0 mg/day) did not significantly improve the hypokinesia, but did increase the amplitude and range of forces some patients used when walking. Due to these improvements, the patients would be subjectively consciousness of improvements in their gait. In 12 of 14 patients, motor fluctuations disappeared. For example, FOG disappeared in the patient 1, and the duration of a slower cadence shortened in patient 2. These results show that the PGR had high sensitivity to detect anti-PD drug-induced changes in gait disorders.

Walking in daily life differs from that in short-distance walking examinations. Figure 1C shows the range of the cadence from 70 to 260 steps/min for walking in daily life. This variability in the cadence suggests that subjects change the mode of their gait depending on the circumstances. When a suitable mode of the gait is chosen, a particular set of the cycle and the amplitude for the gait is automatically determined, as shown by the regression line in the gait acceleration-cycle plot, (see Figures 1B,E, 2B,E and 3B,E). Although there are numerous combinations of the cycle and amplitude, it is interesting that a particular set of these parameters is determined as if they attract the neural controls. Thus, the goal of this method is to measure the average value and the range using the gait acceleration-cycle plot to examine the abilities of the patient to generate forces and the scaling of the amplitudes of these forces in the patient’s gait during daily life. These elemental capacities for gait cannot be detected in short-distance walking, and are clarified in context-dependent voluntary walking in daily life. The present results suggest that after the addition or increase in dose of selegiline to their medicine regimen, some patients were able to produce sufficient forces enough for propelling their body during walking and to scale their amplitudes depending on the circumstances when walking. Consequently, it was possible to define the physiological aspects of the gait disorders that were improved by the medication.

To minimize differences in daily activities depending on the test day, it is better to record continuously for 3 days. However, our previous report showed that significant differences were not observed in the average parameters, such as the amount of overall movements per 24 h and the mean gait acceleration, when the patients were asked to perform similar patterns of movement during their daily lives (26). Differences depending on the test day might be small if the mean and the range of these values are examined.

The present results also show that improvements in hypokinesia (a decrease in the amount of overall movements per 24 h) and gait disorders did not occur in parallel, suggesting that manifestation of movements and gait might be controlled independently. Moreover, the improvements in gait parameters were heterogeneous. When all patients were compared between before and after the addition or increase in dose of selegiline to their medicine regimen, significant differences were observed in cadence, not gait amplitude parameters (mean gait accelerations and slope of the regression line), which might also suggest heterogeneous improvement between rhythm control and force production. This assumption is supported by a heterogeneous impairment between rhythm generation mechanisms and force production mechanisms in the early stage of PD (26).

Walking movement is assumed to be manifested through activation of the midbrain locomotor region–reticulospinal tract system on the rhythm generators in the spinal cord (27). This neural circuit is controlled by dopaminergic and noradrenergic pathways. The dopaminergic nigra-striatum pathways facilitate the disinhibition in the basal ganglia, resulting in excitatory effects on the midbrain locomotor region to initiate walking as well as on the thalamo-cortical circuits to initiate voluntary limb movements (27). Furthermore, the noradrenergic pathways appear to facilitate rhythm generation in the spinal cord. Selegiline is reported to elicit two kinds of pharmacological effects, (1) an inhibition of MAO-B, which increases endogenous dopamine levels and (2) an increase in synthesis of phenylamine, which facilitates the release of noradrenaline (28). The present finding that selegiline improved differentially the gait disorder, but not the hypokinesia, suggests that selegiline might facilitate the noradrenergic pathways alone at a low dose (2.5–5.0 mg). Such a heterogeneous improvement in motor symptoms might occur when taking anti-PD drugs, which would be elucidated by monitoring simultaneously the index of hypokinesia in all movements and the physiological parameters in gait disorders.

The PGR was able to detect motor fluctuations and improvement during walking in daily life in a small number of PD patients. However, to confirm these results, a prospective cohort study with a larger number of patients is needed. Quantitative evaluations of gait by the PGR could be useful for evaluating motor function in patients with cognitive impairment who are unable to describe properly their symptoms in a patient diary or in patients who live alone and are unable to evaluate their motor symptoms themselves.