Can Digital Mobility Assessment Enhance the Clinical Assessment of Disease Severity in Parkinson’s Disease?

INTRODUCTION

Parkinson’s disease (PD) is a progressive neurological disorder characterized by the cardinal motor symptoms of tremor, rigidity, and bradykinesia [1, 2]. The presence of these motor symptoms manifest as mobility impairments which are detrimental to health and quality of life [3]. Measuring and monitoring the impact of motor severity upon mobility in PD is challenging due to its heterogeneous nature. The Movement Disorder Society– Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III) is the clinical standard to rate motor severity [4]. However, the assessment is conducted episodically in person, is time consuming to administer, and may not reflect the fluctuating nature of PD.

Remote monitoring solutions may exist in the form of home-based smartphone assessments [5], which are based upon semi-structured activities that have their respective advantages. In contrast, walking speed and a battery of clinically relevant gait characteristics (collectively referred to as digital mobility outcomes, (DMOs)) [6] can be measured quantitatively and continuously in the real-world using digital health technology such as body worn sensors. Recent work has explored quantitative assessment of gait to complement clinical assessment of motor severity in PD. Gait impairment appears early, even in the prodromal period, and deteriorates over time [7–10]. Changes in discrete DMOs translate to impaired motor and cognitive function, and increased fall risk [11, 12]. These tools could be used to complement the existing clinical assessment of motor symptom severity in PD [13, 14], addressing some of the limitations of existing scales [6]. Early work demonstrates possible clinical utility. For example, real-world walking speed (RWS) may be sensitive to discriminating PD from older adults (OAs) [7], is able to quantify PD motor symptoms [15] and fall risk [16], and is responsive to medication state (ON/OFF) [17].

Despite the promise, widespread adoption of real-world gait as a clinical mobility endpoint has not yet reached the clinic or clinical trials. To achieve this, comprehensive technical and clinical validation is required [6, 18] to establish what information RWS (or other DMOs) can provide that complement existing clinical assessment. Specifically, whether RWS is sensitive to the presence and progression of PD independent of typical ageing [8]. While walking speed is related to motor disease severity in controlled, supervised testing [19–23], the relationship between RWS and MDS-UPDRS III is yet to be explored [23].

The aims of this study were to cross-sectionally characterize RWS in people with PD compared to a cohort of OAs without PD, and to determine whether RWS changes in PD more rapidly. We also aimed to explore the cross-sectional and longitudinal relationships between RWS and motor disease severity (using MDS-UPDRS III) in PD.

METHODS

RESULTS

Demographic and clinical data, as well as RWS aggregated across all bouts, are shown in Table 1.

1) Cross-sectional comparison of RWS in PD and OA

RWS was significantly different between PD and OAs at each time point and WB duration, excluding >60 s at the 54-month time point. For both cohorts the largest number of available WBs for analysis existed in short durations (10 to 30 s) and the lowest number of WBs were within long WB durations (>60 s). Differences between PD and OAs in the number of WBs undertaken per day, was dependent upon the time point and WB duration (Table 2).

Cross-sectionally at 36 months, RWS was significantly lower in PD comparison to OAs (1.035 m/s vs. 1.097 m/s, p = 0.007) at all WBs and within each WB duration threshold (Table 2 – 36 months).

2) Longitudinal changes in RWS in PD compared to OA

Longitudinally, RWS significantly slowed in PD by 0.021 m/s (or 2 cm/s) per year (p = 0.014) and in OAs by 0.011 m/s (or 1 cm/s) per year (p = <0.001), when aggregated within WBs >10 s (Table 3). When analyzing RWS calculated within each WB threshold RWS slowed significantly at each WB duration, excluding long WBs (>60 s) in PD (Table 3). Rate of decline in RWS was larger in PD in comparison to OAs, at each WB duration threshold, excluding >60 s where we observed no difference with OAs (Table 3).

3) Cross sectional relationship between RWS and MDS-UPDRS-III

At the 36-month time point of the ICICLE-GAIT dataset, there was no significant association with MDS-UPDRS III score with RWS at all WBs (β= 1.25 [95% CI = – 4.29, 1.78] points, p = 0.412).

However, when calculating RWS within WB thresholds, we found a significant negative association with the MDS-UPDRS III at WBs between 30 to 60 s (β= – 3.94, [95% CI = – 7.83, – 0.05] points, p = 0.047) (Fig. 1).

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Fig. 1

Cross-sectional relationship between MDS-UPDRS III and RWS for Walking Bouts between 30 and 60 seconds.

We did not observe any association between RWS and MDS-UPDRS III at ‘All WBs’ (β= – 1.36, [95% CI = – 4.71, 2.03] points, p = 0.42), or any WB duration, in the independent dataset.

4) Longitudinal relationship between RWS and MDS-UPDRS III

MDS-UPDRS III scores significantly increased by 1.86 [95% CI = 1.11, 2.61] points per year across the study duration. However, there was no association between change in RWS with changes in MDS-UPDRS III at all WBs and each other WB duration threshold (Table 4).

DISCUSSION

This study provides a comprehensive exploration of RWS to understand whether it can provide information that is complementary to the clinical assessment of mobility, motor symptom severity, and progression in PD. Cross-sectionally, RWS was significantly slower in PD compared to OAs across a range of different WBs. RWS decreased in both cohorts and the reduction was generally more rapid in PD compared to OAs. Significant cross-sectional associations between motor symptom severity (MDS-UPDRS III) and RWS were seen for medium length WBs. MDS-UPDRS III scores increased annually; however, change in MDS-UPDRS III scores were not significantly associated with change in RWS longitudinally. Therefore, our findings highlight that remote monitoring may add complementary additional information to improve the clinical assessment of PD.

1) Cross-sectional comparison of RWS in PD and OA

RWS was significantly slower in PD in comparison to OAs, which is in agreement with previous research in the same cohort [7], plus the work of others [33]. This finding further validates how a slower RWS corresponds to real-world mobility impairments that occur in PD and are separate or interact with age-related changes. The challenges of modulating RWS to safely navigate complex real-world environments are likely exacerbated by presence of motor symptoms and fluctuations. Thus, real-world mobility measures such as RWS have potential to capture novel insights of PD in comparison to supervised assessments of capacity [34]. RWS reflects a complex measure of real-world mobility that has been assessed across a variety of WBs that differ in their duration, context, and purpose. For example, short WBs may capture more demanding activities such as obstacle negotiation, change in direction, gait initiation and termination. In contrast, longer WBs that require greater physical endurance may reflect steady-state gait and a more consistent gait pattern.

2) Longitudinal changes in RWS in PD compared to OA

RWS slowed in both PD and OAs over six years in the ICICLE-GAIT study. We found that RWS significantly reduced by 0.02 m/s more per year (all WBs) in PD compared to OAs. While there is lack of agreement of what constitutes a clinically meaningful difference in real-world DMOs, in a distribution-based analysis a change in supervised walking speed of 0.06 m/s has been shown to be a meaningful change in PD [35]. However, we would expect meaningful changes in RWS to be more sensitive and dependent upon WB duration [7, 17, 36]. Our findings were in contrast to our work in the same cohort in a laboratory setting [8] where the rate of walking speed decline did not significantly differ between OAs and PD. Thus, supervised laboratory assessments [37] may be a less sensitive measure of more rapid PD-specific deterioration of real-world mobility, reflected by differences in RWS.

Interestingly, we did not observe differences in rate of decline in RWS at long WBs. As time (and disease severity) progressed, the ability to walk for extended periods becomes more challenging and the number of longer walking bouts decreased. Long WBs reflect more optimal walking, where individuals may achieve performance close to that observed in supervised laboratory assessments, so this further supports the view that supervised laboratory assessment may be less sensitive to discrete changes in mobility. This is in agreement with previous research that found only the maximum values of RWS correlated with supervised walking speed [17] and further demonstrates how RWS can provide novel information to existing mobility assessment.

3) Cross sectional relationship between RWS and MDS-UPDRS-III

When considering all WBs >10 s, we found no cross-sectional association between RWS and motor severity in either dataset. This is in contrast to previous studies that found associations of the MDS-UPDRS III with laboratory walking speed; thus both measures were assessed in similar, supervised setting [19–22]. A The MDS-UPDRS III score assesses a wide range of symptoms within a brief clinical visit, which does include a gait-item in its assessment, which makes up a small proportion of the overall score (4 out of 108 points). In contrast, RWS reflects different contexts of mobility dependent upon the WB duration that it is estimated from. This is supported by our finding that RWS of medium length WBs (30–60 s duration) were associated with greater motor disease severity, in contrast to other WB durations. Short to medium length WBs may contain prolonged periods of navigating the household environment, or perhaps intermittent periods of outdoor walking which provide the optimal balance between periods of straight walking, while maintaining some challenge to motor control. These additional explorations of WBs are helpful as they may represent different contexts of mobility, and thus WB duration may moderate the relationship with RWS and disease severity [22, 38]. From our results, a faster RWS of 0.1 m/s was associated with less severe motor disease (equating to four points on the MDS-UPDRS III), which is between the range of minimally and moderate important difference of 2.7 to 5.2 points that has been previously reported [39].

4) Longitudinal relationship between RWS and MDS-UPDRS III

MDS-UPDRS III scores increased by 1.86 points per year, which suggests that after two years our cohort experienced a change above the threshold of minimally clinically important change [39], although note the reference was using a previous version of the UPDRS III (rated out of 108, [40]). Alongside increasing MDS-UPDRS III scores, RWS increased per year; however, we did not find an association between the two measures. This is not necessarily surprising, given that we compared changes in RWS, a complex measure of real-world mobility, with changes in the MDS-UPDRS III, a large composite score that assesses many upper and lower body signs, some of which are not directly related to gait (tremor, speech, etc.). Previous studies conducted in supervised, laboratory setting have found associations between walking speed and MDS-UPDRS III [14, 35]. Interestingly Hass et al. [35] found that a 0.02 m/s change in walking speed was associated with the minimally important change in MDS-UPDRS III score as reported by Shulman et al. [39]. However, they assessed walking speed across a short distance and duration, and participants were optimally medicated. MDS-UPDRS III scores have been demonstrated to reflect slower rates of progression within unmedicated compared to medicated groups [14]. Thus, RWS may only be associated with motor severity when assessed in a similar medication state [17]. Despite the lack of statistical association, both MDS-UPDRS III and RWS changed independently over time, which suggests that RWS may be able to capture additional insights into the impact of progression upon real-world mobility, that is not currently captured by the MDS-UPDRS III.