The DigiGait Imaging System is the most widely published treadmill gait analysis system available for studies of animal models of neurodegeneration, such as amyotrophic lateral sclerosis [ALS]. Video 1 provides some indication of the power of the DigiGait instrumentation to describe gait disturbances, in this example reflected in the ability of the right hind limb of an SOD1 G93A mouse [~15 weeks old] to engage the treadmill belt (1).
The DigiGait software reports the step-to-step increase in paw placement angle variability. The appearance of this defect is not binary, but the result of a process, revealed by study of the animal much earlier in life and with great care, via challenging the animal to walk uphill at a faster speed. As in human life, the subtle symptoms of ALS in mice can be unmasked sooner with the proper diagnostic tools.
Clinical gait analysis is used frequently in the evaluation of patients with Parkinson’s disease [PD] and Huntington’s disease [HD]. For patients with PD, for example, in which gait changes are more plastic and responsive to medications, the assessment of gait is useful in the personalization of therapy (2). Gait analysis, however, is not routinely used in assessing patients with ALS, most likely because the course of the disease decidedly impairs the walking ability of patients diagnosed with lower-limb onset ALS. Subjects with ALS, moreover, do not typically present with gait disturbances much in advance of the ALS diagnosis. Although improved gait analysis of patients might provide earlier diagnosis, there are so many factors that affect gait that it is difficult to see that improved gait analysis of ALS patients would improve the current diagnostic delay of ~1 year (3). However, physiomarkers in animal models of neurodegenerative diseases are advancing understanding of the pathogenesis of PD, HD, and ALS. An increasing number of research groups are applying treadmill gait analysis to their rodent models of numerous movement disorders, including ALS, to use metrics of gait as harbingers of disease or indicators of therapeutic efficacy.
As in humans, the ALS motor function phenotype in mice is not at all overt presymptomatically. Clinically, patients retain their ability to walk in the community until after they lose ~45% of their predicted maximal muscle force of lower-extremity muscles (4). It should come as no surprise, then, that casual observations of the animals walking in their cages do not indicate that their muscles are weakened. The SOD1 G93A mouse model of ALS, moreover, does not display overt symptoms of hind limb weakness until after ~14 weeks of age. Gait, paradoxically, is supranormal presymptomatically in SOD1 G93A mice treadmill walking a comfortable speed, possibly due to compensatory changes occurring at the level of the motorneuron. Coarse methods of gait analysis do not indicate gait disturbances in this model until cursory examination of the animal’s’ health indicates its obvious morbid condition. Although a semi-automated assessment of overground walking recently indicated that gait disturbances occur in SOD1 G93A mice (5), the data are limited to a few strides at indeterminate walking speeds; this may explain, in part, the confusing tapestry of gait changes described. The investigators indicated their data to be noisy (5), which may undermine the ability of their approach to indicate a gait disturbance until after 12 weeks of age. It is not at all clear, for example, why the instrumentation, or the researchers, reported a ‘stand time’ metric expressed in millimeters; either a quirk in the software or a convention adopted by the investigators. [“Time” in gait analysis is usually measured and reported in seconds or milliseconds.] The investigators, nonetheless, indicated that “stand time” was increased in SOD1 G93A mice (5), presymptomatically, which is consistent with the supranormal gait reported by The Jackson Laboratory (6) and others (1,7) in SOD1 G93A mice just preceding the rapid capitulation to paresis, paralysis, and death.
Differences in walking speed between subjects is the most important confounder in the interpretation of gait differences, whether in the clinical gait assessment labs or preclinical animal vivaria. Athletes such as gold medalist track phenom Usain Bolt might exhibit “increased stand time” during running compared to his pursuers because the metabolic cost of walking and running is lower with longer strides and shorter cadence. Very often, data indicating shorter stride length is secondary to a slower walking speed of a subject. It is important, therefore, to compare posture and kinematics between subjects walking or running at comparable walking speeds.
The animation shown in Video 2 illustrates two mice, a wild-type mouse (top), and an SOD1 G93A mouse (bottom) at ~35 days of age. The stance width of the forelimbs is significantly narrower in SOD1 G93A mice than wild-type mice at 5-6 weeks of age. Not as they take a few hesitant steps through a tunnel, or across paper with poster paint on their paws, but as they run 20+ strides at a speed of 40 cm/s at an incline of 15 degrees. This is the earliest functionally meaningful phenotype identified in this model, and may reflect compensatory changes due to lower neuropathology.
1. Hampton TG and Amende I. Treadmill gait analysis characterizes gait alterations in Parkinson’s disease and amyotrophic lateral sclerosis mouse models. J Mot Behav. 2010 Jan-Feb;42(1):1-4. Link: http://www.tandfonline.com/doi/abs/10.1080/00222890903272025
2. Cancela J et al. Gait assessment in Parkinson’s disease patients through a network of wearable accelerometers in unsupervised environments. Conf Proc IEEE Eng Med Biol Soc. 2011 Aug;2011:2233-6. Link: http://ieeexplore.ieee.org/xpl/freeabs_all.jsp?arnumber=6090423
3. Cellura E et al. Factors affecting the diagnostic delay in amyotrophic lateral sclerosis. Clin Neurol Neurosurg. 2011 Dec 12. [Epub ahead of print] Link: http://www.sciencedirect.com/science/article/pii/S0303846711003921
4. Jette DU, et al. The relationship of lower-limb muscle force to walking ability in patients with amyotrophic lateral sclerosis. Phys Ther. 1999 Jul;79(7):672-81. Link: http://ptjournal.apta.org/content/79/7/672.long
5. Mead RJ et al. Optimised and rapid pre-clinical screening in the SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS). PLoS One. 2011;6(8):e23244. Epub 2011 Aug 18. Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158065/?tool=pubmed
6. Wooley CM, et al. Gait analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve. 2005 Jul;32(1):43-50. Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1350398/?tool=pubmed
7. Amende I, et al. Gait dynamics in mouse models of Parkinson’s disease and Huntington’s disease. J Neuroeng Rehabil. 2005 Jul 25;2:20. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201165/?tool=pubmed