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Normal values as well as determining factors for the six-minute walk test are available in healthy adults, but less is known about individuals with Parkinson disease (PD). The purpose of this study was to create a PD-specific reference equation and identify unique factors associated with six-minute walk distance (6MWD). Eighty individuals (66.3 ± 9.8 yrs) with mild to moderate PD underwent a neurologic examination (UPDRS) and completed a small battery of tests to assess their balance confidence, fall risk, mobility, and balance. 6MWD was 394.1 ± 98.4 m (95% confidence interval: 370.0 – 418.1). Stepwise multiple regression analysis demonstrated the timed up-and-go test (TUG), one-leg stance test (OLS), and gender to be significant independent contributors to 6MWD and accounted for 56.6% of the variance. The resulting PD-specific regression equation is as follows: 6MWDpred = 543.06 + (− 10.83*TUG) + (2.04*OLS) + (−44.44*Gender). (For gender: 0 = female, 1 = male). Future interpretation of 6MWD in individuals with PD may be enhanced if expressed as a percentage of the predicted value utilizing this reference equation.
Assessment of functional exercise capacity via the six-minute walk test is widely used in clinical settings, often as an outcome measurement for evaluating an intervention . Reference equations for six-minute walk distance (6MWD) are available [2–3], yet were developed using data from healthy older adults. Utilizing these equations for individuals with motor impairment, such as those with Parkinson disease (PD), may not be appropriate. For example, Garber & Friedman  reported 6MWD in individuals with PD that were 42% of that predicted by one such reference equation , suggesting that there are factors unique to PD that are not considered in these existing equations. Canning et al , as well as work from our laboratory , have identified certain variables that explain large portions of variance in 6MWD and therefore contribute to the observed reduced distances. These variables broadly comprise measures of Parkinsonian symptoms and functional mobility (i.e. Berg Balance Score, Timed up-and-go), which are distinct from the variables contained in the reference equations for healthy adults (e.g. anthropometrics, age and gender) [2–3].
Given noted features of PD such as reduced stride length and hypokinesia, 6MWD is reduced in those with PD as compared to healthy adults [5,7]. While such a patient-control comparison may be of interest, it may be of additional utility to compare ‘patients to patients’. The latter may be useful in understanding the extent of functional exercise capacity in relation to individuals that share the same neurological disorder. Considering the unique factors associated with 6MWD in PD [5–6], it would be valuable to develop predictions that are specific to those with PD. As a result, the following comprise the objectives of this study: 1) determine 6MWD in a large sample of individuals with PD, 2) compare measured 6MWD with predicted 6MWD from existing reference equations, and 3) identify factors contributing to 6MWD and develop a PD-specific reference equation. Parts of our results have been reported previously (e.g. demographics, performance scores) , but the objective and analysis of this report is distinct.
Eighty individuals with idiopathic PD  were recruited from the Washington University Movement Disorders Clinic. Subjects were excluded if they had other neurological deficits or serious medical issues, and/or were unable to independently ambulate. Demographics are provided in Table 1. All eligible subjects provided their written informed consent following a health screening and study briefing. Experimental testing was approved by the Human Research Protection Office at the Washington University School of Medicine.
The following data were recorded; 1) anthropometric variables, 2) the Unified Parkinson’s Disease Rating Scale (UPDRS) , 3) Hoehn and Yahr (HY) scale , 4) the Activities-specific Balance Confidence scale , 5) the freezing of gait (FOG) questionnaire , 6) one leg stance (OLS) test , 7) the timed up-and-go (TUG) , and 8) the six-minute walk test .
OLS is used to assess balance by having an individual stand on only their preferred leg, and their single best time, out of three attempts, was used for analysis. The TUG is a basic test of functional mobility whereby the individual rises from a chair, walks 3 m, and then returns to sit in the chair. Similarly, we used their single best time, out of three attempts. For the six-minute walk test, subjects were asked to walk as far as they could down a 30.5 m corridor for six minutes. They were advised that they were able to slow down or rest if needed. Spotters were available to supervise the execution of turns at the ends of the corridor. To determine whether subjects also experienced any akinetic blocks or freezing of gait, they also completed the FOG questionnaire.
The UPDRS motor subsection, administered by a single Movement Disorders Specialist, was also used for the Postural Instability and Gait Disorder (PIGD) subscale which was calculated by adding items 27–30 from the UPDRS and is thought to represent clinical mobility . The same clinician also rated the clinical disability of each subject according to the Hoehn & Yahr scale. Scores range from 0–5, with ‘0’ indicating no signs of the disease, and a score of ‘5’ reserved for those who are wheelchair bound or unable to independently move. A score of 2–3 is generally considered mild to moderate in disease severity and presents with bilateral symptoms and postural instability in some cases.
Collectively, these data were hypothesized to capture the variance in 6MWD. It should be noted that height records were not recorded in 38 of our 80 subjects. However, we did have records of subjects’ leg length which has been used previously to estimate height . Using the full data sets (i.e. known heights) from our 42 subjects, we estimated leg length to be 52% of total height and then applied this parameter to the 38 subjects in which height was not directly recorded. (See results for additional discussion).
All statistical analyses were performed using SPSS (Chicago, IL) v17.0 software. Pearson correlation coefficients were calculated and a stepwise multiple regression was used to determine independent variables explaining the variance in 6MWD. An additional forced entry regression using variables identified in previous literature, e.g. age, height, weight, and gender) [2–3], was also performed for comparison purposes. Variables were allowed to enter the model at the 5% level of significance. Data were checked and met the assumptions of regression (i.e. normality, multicollinearity, homoscedasticity, etc.) and are presented as mean ± SD.
Considerable variability was noted in the 6MWD (range: 152.7–613.6 m) for individuals with PD (mean age 66 y, HY of 2.3), with an average distance of 394.1 m. Some of this variability may be accounted for through univariate correlation analysis demonstrating gender, age, HY stage, UPDRS, TUG, PIGD, FOG, and OLS to be significantly correlated with 6MWD (r = −.67 to 0.48; p < 0.05). Coefficients are presented in Table 1. As seen in Table 1, height is not significantly correlated to 6MWD (r = 0.20; p = .22) for the entire sample. We additionally ran a correlation for those subjects (n = 42) in which height was not estimated, and also did not find a significant relationship (r = 0.17, p = .48).
We chose six variables with the largest significant univariate correlations to enter into our stepwise multiple regression (i.e. 16 cases per variable). PIGD, OLS, TUG, FOG, HY, and gender were entered into our stepwise multiple regressions and TUG, OLS, and gender were identified as significant (p < 0.01) independent contributors to 6MWD, explaining approximately 56.6% of the variance. The largest portion was explained by TUG, explaining 44.7%, followed by OLS time (7.8%), and gender (4.0%). For predicting 6MWD, our regression equation includes the following: 6MWDpred = 543.06 + (−10.83*TUG) + (2.04*OLS) + (−44.44*Gender). (For gender: 0 = female, 1 = male).
Using predictor variables derived from healthy adults [2–3], we performed a forced entry regression analysis and were only able to explain 17.8% of the variance in 6MWD in our sample with PD compared to 56.6% which was explained using a stepwise technique. In addition, we input our data into the existing equations for healthy individuals using their published coefficients and found them to significantly overestimate mean 6MWD by 57.9% on average (range: 143.2–254.2 m). To further confirm the appropriateness of our estimated height data, we also separately analyzed those subjects (n = 42) with full data sets and found a very similar 58.9% overestimation of 6MWD to that observed. With the exception of gender, no variables were common amongst previously reported equations and those found in the present study. A comparison of observed distance, predicted distance based on our equation, and predicted distances based on two existing equations, developed from healthy populations (ages 40–85 yrs), are presented in Figure 1B.
To illustrate the agreement between our observed scores and predicted scores, a Bland-Altman plot is presented in Figure 1A. The mean ± sd of the differences is −4.53 ± 114.25, and therefore mean ± 2sd are (−233.04, 223.98). From the plot, only 5/80 (6.2%) points exceed the ± 2sd demarcations. Although the difference between mean 6MWD for observed (394.06) and predicted (389.54) is small, figure 1A further illustrates the variability in 6MWD in those with PD.
Our main finding demonstrates that for individuals with PD, the variance in 6MWD is not accounted for through anthropometrics, gender and age as seen in healthy adults. Therefore, utilizing previously published reference equations to predict 6MWD is not appropriate for individuals with PD, a finding that is supported by earlier work . These equations [2–3] were able to explain between 38–66% of the variance in 6MWD through height, age, weight, and gender in healthy adults. Yet when we forced the entry of these variables (e.g. age, height, weight, gender), only 17.8% of the variance in 6MWD was explained. However, we report a PD-specific regression equation that identifies increased fall risk, balance, and gender as independent contributors to 6MWD, explaining approximately 56.6% of the variance. Our findings support those of Canning et al.  that underscore the importance of identifying physical impairments associated with functional exercise capacity (i.e. 6MWD) that may be directly targeted for future rehabilitation.
It has been suggested previously that interpretation of 6MWD is enhanced when expressed as a percentage of predicted values as opposed to a single arbitrary distance . However, this suggestion assumed that 6MWD reference equations were developed with the population of interest which was previously not applicable to individuals with PD. Utilizing the reference equation of the present study, future investigations may be able to interpret 6MWD in individuals with PD as a percentage of that predicted. For example, we may consider an abnormal 6MWD as that which is below the 95% confidence interval. In our sample this would be a distance of less than 370 m, which was found for 29 out of 80 subjects. On average, this equated to a 6MWD that was approximately 40% less than that predicted. Such a criterion may be useful for interpreting functional exercise capacity in individuals with PD. Therefore, we believe this PD-specific reference equation may be of utility to clinicians in order to gauge where their patients are performing relative to what is expected. In addition, clinicians may be able to provide realistic therapy goals of attaining a certain percent of predicted 6MWD based on the PD-specific equation which are more reasonable than those derived from healthy older adults [2–3].
Caution is advised when interpreting these results for several reasons. First, our cross-sectional design may be prone to selection bias and may overestimate 6MWD in those with more advanced PD. Based upon our average HY stage, the majority of this sample is mild to moderate in their disease progression. Despite this, our subject characteristics exhibited quite a range (see Table 1) in many of our assessments. Further, this is the largest sample of individuals with PD (N = 80) to date reporting 6MWD. A second potential limitation due to our study design is stability or test-retest reliability of the six-minute walk test. Although this is of greater concern for those studies utilizing 6MWD as an outcome measurement [7,18], the reliability of this test in persons with PD is strong and has been supported in two separate studies (ICC = 0.95, 0.96) [19–20]. Lastly, the six-minute walk test is most frequently used in pulmonary and cardiac settings. As there remains a substantial portion of variance (i.e. 43.4%) left unexplained, we cannot account for the influence of motivation as well as preferred walking speed that may have contributed noise to this data. In addition, it is likely that more sophisticated cardiopulmonary assessments may provide additional insight for individuals with PD and this is an area worthy of additional research. However, the advantage of the variables included in the reference equation of the present study is the absence of sophisticated technology needed to collect such data.
Performance of the six-minute walk test is variable in individuals with PD as evidenced by the range in 6MWD (i.e. 315–560 m) [4–5, 7,17–20] and is illustrated in Figure 1A. A portion of this variability may be explained through measures of fall risk (e.g. TUG), balance (e.g. OLS) as well as gender. This differs from healthy adults in which anthropometrics and age are of greater importance. As a result, utilizing regression equations intended for healthy adults, results in inflated 6MWD estimates for individuals with PD (See Figure 1B). Despite this, a considerable amount of variability remains to be explained in 6MWD. Canning and colleagues  previously reported that hypokinesia accounted for a large portion of variance in 6MWD in those with PD. These authors quantified hypokinesia as the walking velocity recorded while walking as fast as possible over an 8-m walkway. Unfortunately, we were unable to perform similar measurements to quantify hyopkinetic walking which may have accounted for a portion of our unexplained variance. However, we suspect that the inclusion of the TUG in the present study provides some utility in describing hypokinesia.
The PD-specific reference equation presented herein aims to circumvent those previous limitations and provide researchers and clinicians the opportunity to interpret their observed 6MWD in comparison to predicted values. Additional research is necessary to confirm the appropriateness of this equation in other samples and/or identify other factors to help explain a greater amount of variability in 6MWD.
Authors would like to thank Madeleine Hackney for subject recruitment. The project described was supported by Grant Number T32HD007434 from the National Institute of Child Health and Human Development. Additional support was provided by 1K01HD048437. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHHD or NIH.
Financial Support: The project described was supported by Grant Number T32HD007434 from the National Institute of Child Health and Human Development. Additional support was provided by 1K01HD048437. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NICHHD or NIH.