Laboratory based assessment of gait and balance impairment in Patients with Progressive Supranuclear Palsy

Abstract

Background:

Gait and balance abnormalities are a significant source of morbidity and mortality in progressive supranuclear palsy (PSP). Gait impairment in PSP is primarily assessed clinically on exam or with the use of rating scales. Three dimensional video based gait and balance analysis performed in a laboratory setting is a highly accurate method of motion analysis¹, however limited data is available in patients with PSP.

Research question:

In this study we assess the objective features of postural control, kinematics, kinetic and temporal-spatial gait metrics in PSP, using three-dimensional video motion analysis in a laboratory setting compared to normal controls.

Methods:

Three-dimensional motion was captured using a 10-camera motion capture system, 41 body markers and ground embedded force plates in 16 patients with PSP patients and compared to motorically normal controls.

Results:

Spatiotemporal, kinematic, and kinetic gait measures effectively differentiated patients with PSP from controls. Patients had slower gait velocity, lower cadence, increased double support time and abnormal antero-posterior sway. Joint kinematics and kinetics were reduced and showed less variation among patients with PSP compared to controls which is suggestive of bradykinesia. Objective gait measures of abnormality correlated with clinical disease severity. Postural sway metrics distinguished PSP from controls and captured gait imbalance.

Significance:

Objective measures of gait and balance abnormalities in patients with PSP provide an outcome measure that can be potentially used for early disease detection, in clinical trials and to validate portable motion capture devices in the future.

Introduction

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder which can cause severe postural instability, falls and vertical supranuclear gaze palsy^2,3. The most common phenotype is referred to as Richardson syndrome (PSP-RS)². Additional phenotypes of PSP have been described including parkinsonism (PSP-P), frontal predominant cognitive impairment (PSP-F), postural instability (PSP-PI), progressive gait freezing (PSP-PGF), ocular motor (PSP-OM), speech and language disorder (PSP-SL) and cortico-basal syndrome (PSP-CBS)⁴. In most phenotypes, gait impairment and postural instability is present and varies in severity across different stages of the disease. Falls resulting from gait impairment are a major cause of morbidity and mortality^5–7.

In clinical practice, the assessment of postural instability is made by the pull test which involves pulling the patient backwards and assessing if they can maintain upright posture. Pull test is part of both the Unified Parkinson’s Disease Rating Scale (UPDRS) and the progressive supranuclear palsy rating scale (PSPRS), which are recommended for assessment of PSP ^8–10. A principal component analysis of UPDRS in a cohort of PSP patients did not identify postural instability as an independent component, pointing to possible limitations in the use of this scale in detecting imbalance PSP¹¹. The PSPRS combines motor, autonomic, cognitive, and ocular motor features. While a cumulative score represents overall disease severity, the gait midline sub score can be used for assessment of postural instability and gait impairment⁸. For interventions targeting gait impairment and postural instability, the gait and midline sub score of PSPRS can be used as an outcome measure, however there may be a potential application of motion analysis to obtain more precise information. While longitudinal studies will be needed for direct comparison of clinical scales and motion analysis, we present preliminary observations on three-dimensional gait assessment in PSP compared to normal controls.

Various devices have been used to assess gait impairment in PSP and other forms of parkinsonism. Most studies are done in Parkinson’s disease (PD) while some compare PD to atypical parkinsonism^12–17. Noted gait abnormalities in PSP include increased postural sway, wider steps, reduced stride length and speed, with abnormalities being distinct and more severe than PD^18–22. Gait analysis methods vary ranging from phone based applications²³, axial versus appendicular accelerometry^24–26, body worn motion sensors such as inertial monitoring units (IMUs)²⁷ or pressure sensitive walkways like the GAIT Rite belt^28,14. Balance has been reportedly assessed using force plates, tilting surfaces, treadmills or static postural control on level ground^24,12,29,30. Conditions for gait analysis have included different durations of timed walking, lifting weights or objects, dual-task strategies, self-paced versus fastest speed, sensors placed on different body parts, and use of different types of motion sensors.

Lab-based three-dimensional video capture of gait and postural stability is considered one of the most accurate methods of objective motion assessment.¹ The environment can be controlled, and testing methods are standardized. The main aim of this study is to provide a preliminary lab-based motion analysis profile of gait and balance abnormalities in patients with PSP and across PSP clinical phenotypes. This study will lay groundwork for future examination of larger cohorts, longitudinal studies for the development of outcome measures and validation of remote monitoring or body worn devices to analyze motion.

Methods

Participants

Sixteen subjects with PSP were recruited from the Department of Neurology, Mayo Clinic, Rochester, MN, by the Neurodegenerative Research Group (NRG) between 7/2/2019 and 1/22/2020. All subjects met the 2017 Movement Disorder Society clinical criteria for PSP⁴, including the clinical phenotypes of Richardson’s Syndrome (PSP-RS, n=11), Parkinsonism (PSP-P, n=2), speech and language (PSP-SL, n=2), and corticobasal syndrome (PSP-CBS, n=1). Subjects included in the present study were able to ambulate independently or with assistance and were excluded if they were immobile due to advanced disease stage or had an alternative cause of gait impairment such as severe degenerative arthritis or amputation. Patients were not on dopaminergic medications. This study was approved by the Mayo Clinic Internal Review Board and informed written consent was obtained from each subject.

Clinical scoring

All subjects underwent a detailed neurological evaluation, which included two standardized scales: the movement disorders sponsored revision of the Unified Parkinson’s Disease Rating Scale part III (UPDRS) and the PSP rating scale (PSPRS). For both scales, a higher score indicates greater disability (Table 1).

Table 1:

Demographics

Subject ID	Sex	PSP phenotype	PSPRS Score	PSPRS Gait midline score	UPDRS Score	Age at gait exam	Symptom at onset	Disease duration (years)	Duration of motor symptoms (years)
1	M	PSP-RS	31	4	20	59	Falls	2	2
2	M	PSP-RS/PSP-F	24	6	36	77	Imbalance	2	2
3	M	PSP-SL/PSP-CBS	55	12	85	76	Apraxia of speech	9	2
4	M	PSP-SL/PSP-RS	58	16	73	75	Apraxia of speech	6	3
5	M	PSP-RS	42	16	62	72	Falls	3	3
6	F	PSP-P	54	18	67	73	Parkinsonism	12	8
7	M	PSP-RS	37	10	56	75	Imbalance	3	3
8	M	PSP-RS	35	9	39	68	Imbalance	5	5
9	F	PSP-RS	33	10	34	68	Imbalance	2	2
10	F	PSP-P	39	15	42	59	Imbalance	3	3
11	F	PSP-RS	42	14	45	79	Imbalance	4	4
12	M	PSP-RS	29	10	30	55	Parkinsonism	3	3
13	F	PSP-CBS	23	8	59	70	Apraxia	4	4
14	M	PSP-RS	38	11	36	76	Imbalance	2	2
15	F	PSP-CBS	48	16	70	73	Falls	6	6
16	M	PSP-RS	35	13	52	71	Imbalance	4	4

Subject level variables: sex, predominant PSP phenotype, symptom at onset of neurodegenerative syndrome, duration between disease onset and gait exam and duration between motor symptom onset and gait exam.

Standing Postural Sway

To assess balance performance, standing postural sway was assessed. The subjects stood with feet on two force plates (Optima HPS, AMTI, Watertown, MA, 600 Hz) for 30 seconds under two conditions: looking directly ahead with 1) eyes open (EO) and 2) eyes closed (EC). The aggregate center of pressure (COP) was calculated from each force plate. The root mean square error (RMS) of the COP, as well as the Romberg ratio of the two (RMS_EC/EO) were calculated for both test conditions³¹.

Gait Analysis

To obtain temporal-spatial gait metrics, reflective markers were placed on each subject with respect to bony landmarks on the trunk, pelvis, thighs, shanks, and feet using a modified Helen-Hayes marker set to create local coordinate systems for each segment^32,33. Up to three additional markers were applied to each body segment to track movement. Two additional markers were located bilaterally on the medial femoral condyles and medial malleoli during a static collection to define joint centers of the knee and ankle, respectively. For safety, the subjects wore a harness which was attached to a track in the ceiling. The harness was adjusted for each subject to ensure that the subject did not contact the floor if a fall occurred. The subjects walked barefoot on a 10-meter walkway at their self-selected speed. A minimum of three trials with foot contacts on a force plate were collected from each subject.

A ten camera (Raptor-12, Motion Analysis Corporation, Santa Rosa, CA, 120 Hz) motion capture system was used to collect three-dimensional marker trajectories from 41 markers. Ground reaction force information was collected using five force plates (Optima HPS, AMTI, Watertown, MA, 600 Hz) embedded in the walkway. The temporal-spatial parameters of velocity, cadence, stride length, step width, gait stability ratio (GSR), step length, and length of gait phases including single limb support, initial double limb support, and total support were calculated from the marker data. Joint kinematics and kinetics were calculated using a commercial software program (Visual3D, C-Motion Inc., Rockville, MD). 3D kinematics were reported in degrees and kinetics were normalized to body mass. Data for all subjects were compared to a healthy community dwelling older adult population collected within the laboratory (25 female, 72.7±6.6 years, BMI: 27.5±5.7 kg/m2). The control population was motorically and cognitively normal adults over the age of 60.

Statistical methods

Means and standard deviations for temporal-spatial and balance parameters as well as sagittal plane hip, knee, and ankle range of motion (ROM) were reported. A two-sample t-test was used to explore differences between patients with PSP and healthy individuals. Correlations between gait and balance parameters and both the UPDRS and PSPRS were determined using Spearman correlation coefficients. Analyses were performed using JMP (SAS Institute, Cary, NC) software with statistical significance was set to p=0.05.

Results

Sixteen subjects with PSP were enrolled (10/16 males, 70.4±7.1 years, BMI: 28.1±5.6). Time between onset of symptoms and gait assessment was 4.4±2.8 years (range: 2, 12). Patient with disease duration of 12 years was diagnosed as having PSP-Parkinsonism subtype which may have an atypically long-life expectancy.^34,35 Other demographic features are summarized in Table 1. The UPDRS scores were average 50 (range: 20, 85) while PSPRS scores average was 39 (range:24, 58).

During the standing postural sway tasks, individuals with PSP exhibited significantly larger amplitudes of COP displacement (RMS) compared to the healthy individuals for the eyes open task (p<0.01) (Table 2). For both tasks, individuals with PSP exhibited less displacement in the mediolateral (ML) but significantly increased displacement in the anteroposterior (AP) direction compared to the healthy individuals, with significance found in the eyes closed task (p<0.04). The Romberg Ratio was calculated by dividing the center of pressure sway in the eyes closed and eyes open scenarios and was increased in PSP compared to controls.

Table 2:

Standing postural control of individuals with PSP compared to a healthy older adult population.

	PSP	Unimpaired	p-level
RMSEO (cm)	7.0±3.9	3.4±2.2	0.01*
RMSEO ML (cm)	3.0±1.5	3.4±2.2	0.51
RMSEO AP (cm)	6.3±3.8	4.8±1.8	0.20
RMSEC (cm)	7.6±4.0	5.9±1.6	0.16
RMSEC ML (cm)	2.2±1.1	2.8±1.1	0.12
RMSEC AP (cm)	7.2±4.0	5.1±1.6	0.04*
RMSEC/EO	1.1±0.5	1.0±0.3	0.55

Significant correlations are marked with an asterisk (* p<0.05). Root Mean Square Error (RMS) of the center of pressure with eyes open (EO), Eyes closed (EC) in the anteroposterior (AP) and mediolateral (ML) and the ratio of the two (Romberg Ratio) were reported.

All temporal-spatial parameters were significantly different (p<0.05) between the patients with PSP and healthy adult cohort (Figure 1). The individuals with PSP walked with a slower velocity, lower cadence, shorter stride, and step lengths, and reduced single support times compared to healthy older adults. Patients with PSP spent more time in initial double and total support (time spent with both feet in contact with the ground). They also had increased step width. The gait stability ratio (GSR) is an indicator of walking stability. A higher GSR indicates a greater proportion of the walking cycle was spent in contact with the floor suggesting more instability and was found to be increased in PSP.

Figure 1:

Temporal spatial parameters of patients with PSP compared to a healthy older adult population. There was no significant difference between right and left side hence temporal spatial parameters from the right leg are reported. Velocity – stride length/stride time; Cadence – number of steps per minute; Stride length – distance between two consecutive heel strikes of the same foot; Step width – distance between proximal end positions of the ipsilateral and contralateral heel strikes; GSR – cadence/velocity; Total support – the percentage of the gait cycle spent on stance; Single Support – the percentage of the gate cycle spent with one limb on the ground; Initial Double Support – percentage of the gait cycle from heel strike to opposite toe off; Step Length – distance between two consecutive heel strikes of opposite feet

Total sagittal plane ROM in the hip, knee and ankle showed significant decreased ROM (p<0.05) when comparing patients with PSP to healthy adults (Table 3).

Table 3:

Kinematic parameters of patients with PSP compared to a healthy older adult population.

	PSP	Unimpaired	p-level
Sagittal Plane Hip ROM (°)	29.0±9.4	44.0±6.2	<0.0001
Sagittal Plane Knee ROM (°)	52.3±10.6	64.0±7.1	0.001
Sagittal Plane Ankle ROM (°)	17.5±6.9	22.0±3.1	0.03

Total sagittal plane range of motion (ROM) in hip, knee and ankle showed significantly decreased ROM in patients with PSP when compared to unimpaired adults.

A range of gait patterns was evident within the individuals with PSP. There were significant correlations between PSPRS and UPDRS with gait velocity, (r_s=0.597, p=0.015; r_s=0.756, p=0.001), total support (r_s=0.591, p=0.016; r_s=0.546, p=0.029), single support (r_s=0.557, p=0.025; r_s=0.500, p=0.049), and step length (r_s=0.561, p=0.024; r_s=0.764, p=0.001) please see Table 4. An example of this association using gait velocity is illustrated in Figure 2.

Table 4:

Spearman rank correlation coefficients between gait parameters and clinical scores.

	PSPRS	UPDRS
Velocity	rs=0.597, p=0.015	rs=0.756, p=0.001
Total Support	rs=0.591, p=0.016	rs=0.546, p=0.029
Single Support	rs=0.557, p=0.025	rs=0.500, p=0.049
Step Length	rs=0.561, p=0.024	rs=0.764, p=0.001
Initial Double Support	-	rs=0.582, p=0.018
Hip ROM	-	rs=0.728, p=0.003

Variables that correlated with PSP rating scale (PSPRS) and Unified Parkinson’s Disease Rating Scale (UPDRS) respectively are listed along with spearman rank correlation coefficients.

Figure 2:

Scatter plot of velocity with each clinical score: PSPRS (black circles) and UPDRS (red triangle). For both clinical scores, as the score increases, representing increasing impairment, velocity decreases. The subjects with the lowest and highest clinical scores have the lowest and highest velocities.

There were also significant correlations between UPDRS only and initial double support (r_s=0.582, p=0.018) and hip ROM (r_s=0.728, p=0.003).

A graphic representation of the kinematic and kinetic gait patterns for the two least (blue line) and two most impaired (red line) subjects compared to unimpaired individuals is shown in Figure 3. As the level of impairment increased, the joint excursion and joint moments decreased.

Figure 3:

Kinematic and kinetic gait patterns of four subjects with PSP, representing the least (lowest clinical scores) and largest (highest clinical scores) impairment, compared to an unimpaired population (gray). The two subjects with the lowest clinical scores (blue) achieve greater range of motion than the two with higher scores (red). The two subjects with the lowest scores had more normal flexion moments in midstance, where the two subjects with higher scores only produced extension moments.

No significant relationship was found between clinical scores and the standing postural sway tasks. This could mean either that static postural testing may not capture dynamic balance impairment in PSP. However, this will need to be explored further in larger longitudinal cohort studies.

Gait characteristics were different between the subjects with the least impairment (subjects 1 and 2) and most impairment (subjects 3 and 4) as measured with the UPDRS and PSPRS clinical scores (Figure 2 and Figure 3). Gait velocity was the primary variable that differentiated the mildly affected subject 1 (11.7 cm/s) and subject 2 (103.3 cm/s) from each other and the most severely affected subject 3 (54 cm/sec) and subject 4 (99.8 cm/s) (3 and 4) from each other. Patients with the least impairment (subjects 1 and 2) had PSP-RS but a short disease duration of only 2 years. Patients with most impairment (subjects 3 and 4) started out as PSP-SL with speech/language disorder and then evolved to PSP-CBS and PSP-RS respectively, hence their total disease duration was longer (6–9 years), while duration since motor symptom onset was comparable to the group at 2–3 years. Patients with more clinical impairment as measured by clinical scales over all had greater gait abnormalities. The subjects with the highest clinical scores had the greatest disability, as demonstrated by decreased walking velocity, stride length, step length, single support times and sagittal plane ROM, as well as increased total support, initial double support, and joint moments compared to subjects with the lowest scores.

Discussion

This study describes lab-based three-dimensional video motion analysis in PSP. Patients with PSP have increased anteroposterior sway, slower gait velocity, wider stance, and lower cadence. The gait stability ratio and Romberg ratio was high consistent with postural imbalance and increased reliance on vision for stability, experienced by PSP patients. Motion analysis metrics correlated with clinical scales reflecting that they are a marker of disease severity. Another important finding was that we were able to detect a difference between the two least clinically impaired subjects by gait analysis. Velocity was different among these patients suggesting that this may be a variable that can detect subtle changes early in the disease course and over time, however longitudinal studies will be needed to confirm this. Gait velocity has been previously reported as an important marker of neurodegenerative disease.^36–38 These findings suggest that laboratory-based motion analysis may offer an objective method for quantifying gait and balance impairment in PSP. Our study is unique in that we report all motion variables: spatial-temporal, postural sway, and joint kinematics in a lab-based setting.

There is one previous study of laboratory-based motion analysis in PSP, however it does not report kinetic and kinematic data.³⁹ Our findings are consistent with previous studies which were done using body worn devices or a gait belt, however lab-based video motion analysis offers a higher degree of precision. A study of static postural sway reported findings similar to ours, in that PSP primarily differed from PD in increased AP sway¹⁷. All forms of parkinsonism are reported as having a bradykinetic gait with smaller stride length and speed, however patients with PSP may have a higher initial acceleration¹⁴. Patients with PSP have also been reported as having a deficit in their ability to correct the forward center of gravity displacement at gait initiation^40,39 and impaired perception of surface tilt³⁰ which may be a common fall mechanisms. Patients with PSP tend to spend more time in double support phases of the gait cycle which was confirmed in our study¹⁸. Dynamic platform tilt induced instability shows different postural control strategies in PD and PSP, and this has yet to be replicated in larger cohorts²¹. Postural control abnormalities have been demonstrated in other small cohorts but with variable methodology ^41,42.

Motion analysis offers an avenue to detect changes in gait in balance which may be missed on clinical exam. Possible applications in PSP may include early diagnosis, as evidenced by previous work done in PD. The Baltimore study of aging reported gait changes in patients with PD before onset of typical clinical symptoms of PD^43,44. Prior studies of postural instability in Parkinson’s disease using single point axial accelerometer show smaller anticipatory postural adjustments in PD compared to controls²⁴. These accelerometer based sway measurements have been noted to change more significantly in PD over a year as compared to little if any change in clinical scales^13,15. While exploratory, the differences in gait velocity among patients with similar clinical disease severity in our cohort, may point to the potential of gait metrics as being able to detect early or mild gait impairment. This will need to be replicated in larger longitudinal studies and compared with other disease groups.

In our study gait parameters correlated with disease severity. Although patients in this cohort underwent cross-sectional motion analysis only, patients at different stages of disease demonstrated variable extent of abnormalities in motion parameters. Gait analysis may be a potential physiological biomarker reflecting clinical change over time. Application of such physiological biomarkers will be important in future clinical trials of disease modifying therapy and treatment targeted towards gait and balance. Patients with a disease onset characterized by speech/language disorders who later developed motor symptoms had the most severe gait impairment and over all longer disease duration, along with another patient clinically diagnosed as PSP-P who had a disease duration of 12 years at exam. The study is not powered to detect any meaningful differences between PSP phenotypes, it may be an important aspect to address in larger longitudinal studies.

In summary, this study describes comprehensive lab-based three-dimensional video motion analysis in a PSP cohort. This is the first study that includes motion parameters in a range of PSP phenotypes and includes kinetic, kinematic, postural sway and spatial-temporal gait metrics. This is an essential first step to gain a broad objective understanding of gait and balance impairment in PSP. While motion analysis labs are not present at every center, a high degree of reproducibility exists between labs⁴⁵ and the accurate data obtained in labs can be used to validate motion sensing devices that capture a more limited number of motion metrics.

This study has important limitations. The sample size is small with limited statistical significance in some parameters that were studied. This is meant to be an introduction to the motion profile in PSP using three-dimension video motion analysis, and larger cohorts will be needed to assess the heterogeneity of gait impairment across the PSP spectrum. Not all PSP phenotypes were represented in adequate numbers to draw conclusions about differences between phenotypes. This study shows the correlation between clinical scales and gait metrics however it is not powered to assess if one is superior to another, and that would require longitudinal assessment in larger cohorts. Due to the cross-sectional nature extensive comparison between gait analysis versus clinical scales cannot be made. Neuropathological confirmation of diagnosis is not available. Future directions following this preliminary work would be to analyze gait impairment in a larger cohort of PSP, capturing the entire clinical spectrum of PSP, comparison between phenotypes, longitudinal assessment to analyze change over time and investigating neuroanatomical corelates of the noted gait abnormalities.

Highlights.

• Progressive supranuclear palsy can lead to various clinical phenotypes, most of which are eventually associated with severe gait and balance impairment.

• Clinical examination alone may not detect subtle abnormalities.

• Objective motion analysis in PSP is a tool to quantify gait and balance abnormalities with possible applications in diagnosis, monitoring progression and assessing response to therapy.

• Laboratory based three-dimensional video motion capture is an accurate and detailed way of assessing locomotion and balance which shows meaningful abnormalities in PSP.