We report our findings on direct comparisons of commonly used outcome measures in FOG clinical trials. The study was designed to determine: 1) the specificity of each marker for FOG and 2) responsiveness of each marker to an intervention. In addition, we investigated whether adding a dual task or calculating dual task interference changed the biometric properties of each marker or should be considered as a separate marker. The goal of our study was to provide objective data regarding the utility of each of these markers for clinical trials or behavioral association studies in order to assist investigators in choosing the appropriate marker for the scientific question being asked. The findings of our study can inform future clinical trials investigating the effectiveness of novel interventions for FOG and can help interpret previous trials that have reported changes in these surrogate markers.
All of the surrogate markers studied were able to differentiate between ON and OFF indicating the responsiveness to levodopa challenge with and without a dual task. However, none of the markers studied were able to distinguish between the PD control group and the FOG group when ON medications. These were two very similar groups (with very similar UPDRS scores) who only differed by the fact that the FOG group had the underlying propensity for FOG behavior when in the OFF state. These findings imply that these markers are not specific for FOG, however, the rigorous design of this study comparing very similar groups should be taken into account when interpreting this finding. These markers may be used in clinical trials to study the magnitude of response to an intervention, however, may not to represent a change in FOG severity itself. Turn duration and step CV in the dual task condition showed a strong trend toward significance when comparing the ON-FOG group and the PD-control. Therefore, dual task turn duration and step CV should not be ruled out as a proxies for FOG severity in crossectional studies or imaging-behavioral associations investigating the relationship of a specific finding to FOG, or as an outcome in clinical trials of a therapeutic intervention. Similar markers like stride time variability have been shown to correlate with overall disease severity and have also been shown to be greater in patients with PD and FOG as compared to PD alone[26, 27].
Turn duration is a very simple metric to obtain, and has been utilized effectively in clinical trials for FOG in the past. Our finding that adding the dual task to multiple surrogate markers improves the biometric properties of the marker informs this and future studies when selecting markers of this condition. Curtze et al found that turning measurements were the strongest correlates of disease severity as measured by the UPDRS, in a large PD cohort with similar disease duration, although this study did not look at FOG. It is important to note that although some patients may experience a FOG episode during turning (particularly the severe FOG level), in this setup (using a large turning space and a cone) is designed to minimize - not precipitate - a FOG episode, and each parameter’s value is an average of at least two trials in each condition. Therefore, these results are independent of whether or not a FOG episode is triggered and differ from studies of the turn condition designed to trigger a freezing episode and then quantify each episode individually. By understanding the biometric properties of markers of FOG severity that do not depend on eliciting a FOG episode we can remove the inherent variability of the episode, presumably allowing a more consistent and representative assessment of FOG severity. Furthermore, such a marker is inherently simple to capture, and can be repeated in one session, making it ideal for same day dose finding studies or early stage neuromodulation clinical trials. However, this comes at the cost of specificity for FOG, for most of the parameters derived from this approach.
Study limitations include our inability to determine which condition (ON or OFF) best indicates severity, since we were comparing each marker in the ON and OFF states. However, other studies have assessed turn measurements and have found the OFF condition to be superior. We were powered to determine a difference between PD-controls and freezers, but not between ON and OFF freezers, or ON freezers and PD-controls. Small sample size is also a limitation, and should be taken into consideration when interpreting p-values, especially trends. Therefore, non-significant differences or strong trends should not be discarded. Also due to the design we could not compare each marker’s ability to differentiate between severity levels with the nFOGQ. This is due to the fact that retrospective subjective questionnaires, when administered, provide an overall assessment of severity over a period of time (usually weeks) and cannot be administered reliably to predict severity in the ON and OFF state. There was a small difference in age between the control and FOG groups (67.2 years for the control, and 64.3 years for the FOG group) and a significant difference in disease duration (5.2 years control, 10.2 years FOG group). The disease duration difference is to be expected as FOG occurs later in the disease course. Finally, this is not a validation study of any one surrogate marker, but our findings help identify most appropriate markers to answer future scientific questions or to be used in clinical trials and should lead to future validation studies of such.
Based on the findings of this comparative study of surrogate markers of FOG severity, we conclude that: 1) objective gait assessment can be a useful outcome measure in clinical trials and behavioral association studies, 2) dual task turn duration and dual task step CV are most specific for FOG of the markers compared, and 3) velocity, step/stride length and dual task turn duration are responsive to levodopa challenge. Further validation studies of these surrogate markers are warranted for their use as outcome measures in clinical trials.