To see a menu of other published PhysioFeature articles, please click here.
Gait Analysis for Early Phenotyping of Mouse Models of Amyotrophic
Lateral Sclerosis
Thomas G. Hampton;
Mouse Specifics, Inc., Boston, MA.
Abstract
Methods
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.
Video 1
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 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.
Video 2
Results
Discussion
References
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
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
