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Challenges—and progress—in diagnosing and translating CNS disease from mouse to men
Some conditions are easy to diagnose. Swab someone’s cheek or draw their blood and you can detect HIV antibodies within weeks of infection.
Not so for some of the more lethal diseases of the Central Nervous System (CNS). Getting a disease diagnosed from early on, and intervening with therapies that might improve the course of a degenerative condition like Alzheimer’s is challenging. By the time a diagnosis is made—in part by evaluating a person’s fine motor and cognitive skills—the CNS disease is often so widespread that the therapeutic window—and the chances for conducting clinical trials that might lead to a positive outcome—have narrowed considerably, if not closed altogether.
Translating CNS disease from mice to men is also tricky. Animal disease models--especially transgenic disease models for a specific defect—have brought lots of new information to the field of Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease, including new insights into the mechanisms driving disease pathogenesis. Yet, although these disease models recapitulate almost all of the pathogenic features of the human disease, and have led to the testing of many promising drug candidates in clinical trials, the drugs ultimately have not been shown to work in humans.
Fortunately, this challenging research scenario could be easing a bit thanks to the wonders of applied preclinical CNS research. Scientists have been exploring 3D analysis of fine motor movement that enables researchers to more accurately model and measure subtle movement and coordination in rodents with CNS damage. This approach is currently being used in rodent studies to model a number of CNS disease ranging from Parkinson’s disease and ALS to Huntington’s disease, to detect disease-like symptoms earlier, with greater precision, and enhanced sensitivity to traditionally applied analyses.
In diseases such as Huntington’s—where a mutant protein triggers brain cell death, loss of motor and cognitive skills and eventually death--clinicians already analyze fine motor skills, such as the rate and rhythm of finger-tapping, to make an early diagnosis . Scientists have also used robotic therapy devices to measure functional motor recovery process in recovering stroke patients; the device uses five different measures of movement smoothness—a characteristic of coordinated human movement that improve in stroke patients as they start to recover—to assess coordination. (see Footnote 1).
The exact same readouts used in these clinical studies can’t be used for mice, naturally, but a fairly close analysis of kinematic movement—the geometry of pure motion—is achievable in mice using the fine motor kinematic analysis and specific algorithms. If this sounds a bit like the motion-capture computer-generated imagery that relies on live action to create an animation you wouldn’t be that far off. Kinematics is concerned with temporal aspects of motion, such as positions, angles, velocities, and accelerations of body segments and joints during motion.
The automated, high-precision kinematic movement analysis can be utilized to detect subtle phenotype changes, with earlier and more sensitive detection compared to traditional movement analysis (see Footnote 2). This allows the investigation of rats and mice as they walk on a ladder or beam, over ground, walking, wading and swimming.
Movements of relevant body parts, such as different limb joints, trunk and tail can be recorded using a high-speed camera from the bottom and both sides simultaneously (see Figure 1). This allows correlation of all body parts to establish a complete profile of the animal's motor abilities. The analysis is applicable not only to study of fine motor defect development in rodent models of CNS and other motor-impairrment diseases, but also may offer a sensitive tool to investigate efficacy of therapeutic approaches or to study subtle motor skill changes that are similar to human CNS disease (see Figure 2).
Fine movement kinematic analysis of a mouse, shown above in Figure 1, and the correlate in human diagnosis and evaluation, shown below in Figure 2.
CNS scientists at Charles River Discovery Research Services work to provide as much translatable information as possible for behavioral testing, imaging and biomarkers. Fine motor kinematic analysis in animal models for the first time brings a translatable assay for motor testing. Bringing the pre-clinical and clinical studies methodologically closer offers better opportunities for lead drug candidates to break through in the clinical studies.
And hopefully bring some hope to the millions of patients and families dealing with these dreaded diseases.
If you are interested in learning more about how researchers are studying movement in animals with CNS disease, sign up for The Source . It’s free and you will find an excellent webinar housed there about this very subject titled “The MotoRater: CNS Fine Motor Kinematics Revolutionized”.
Rohrer B, Fasoli S, Krebs HI, Hughes R, Volpe B, Frontera WR, Stein J, Hogan N. Movement smoothness changes during stroke recovery. The Journal of Neuroscience, 2002 Sep 15;22(18):8297-304.
Zörner B, Filli L, Starkey ML, Gonzenbach R, Kasper H, Röthlisberger M, Bolliger M, Schwab ME. Profiling locomotor recovery: comprehensive quantification of impairments after CNS damage in rodents. Nature Methods, 2010 Sep;7(9):701-8.
Toni Ahtoniemi obtained his PhD in 2008 on central nervous system related disease models. After working four years in the preclinical drug development sector, Toni joined Charles River Discovery Research Services in 2012. He is a project manager at Charles River’s Finland site and has a focus on helping clients accelerate their drug development process. In his free time Toni likes to pack his parachute and go skydiving over the beautiful Finnish Lakeland.