HD in Focus
Imaging tools offer new ways of studying HD treatments. Day Three of SfN's annual science meeting.
Huntington's disease (HD) is a fatal, hereditary disorder that causes the nerve cells in the brain to degenerate. It destroys the mind, but the most visible symptoms are the abnormal, involuntary movements known as chorea—for the Greek word to dance.
These fragmented, jerky motions are a kind of dyskinesia that crops up in other diseases, too, though for different reasons. In Parkinson's disease it can be induced after prolonged treatment with levodopa. It can also be triggered by anti-psychotic drugs.
Being able to control the chorea would be huge for the neurodegenerative field—not just for HD but for other movement disorders—but the search for effective therapeutics has been a long and frustrating one. The only approved drug is Tetrabenazine, which is moderate, short-lived and associated with unpleasant side effects.
Lately, though, scientists have been making strides on the preclinical end. There are a number of mouse models being used to study HD, including the R6/2 transgenic model that mimics the rapid, early progression of disease and more refined methodologies are being employed to study these motor deficits and track the pathology of HD in ways that weren't possible a decade ago.
One of these approaches is an imaging tool that uses some of the same techniques as animation. Scientists angle a high-speed camera simultaneously from three dimensions to capture the HD mice on film and then analyze their movements with kinematic algorithms—a kind of geometry of mice in motion.
Charles River's Finland site, which focuses on diseases of the central nervous system (CNS), has been using this motion-capture computer-generated imagery for about three years in its modeling of HD. In fact, HD was the first disease the group focused on with kinematic analysis. Over time, it has documented subtle phenotypic changes with earlier and more sensitive detection compared to traditional movement analysis. Updates on some of their earliest results can be found here and here.
Last year, the team reported finding subtle gait and fine motor deficits as early as four weeks of age when the HD mice were still largely asymptomatic for HD. They have since identified, for the first time, highly significant dyskinesia-like changes in the fine motor movements of R6/2 mice at four and 10 weeks of age. The scientists presented their poster on Monday at the Society for Neuroscience meeting in Chicago, one of several on HD.
Outi Kontkanen, Director of Business Development at the Finnish site, said it took years to fine-tune the tool to the point where they could differentiate how the HD mice walked and waded differently in motion compared to normal mice. None of this is visible to the naked eye, of course, but with kinematic analysis the changes start coming into focus. The HD mice raised their hind paws unusually high when pushing forward and revved up the backward movement of their front paws during stride, almost as though they were hesitating or adding an extra practice kick. The trajectory of the front paws in relation to the ground was also higher.
Historically, these types of motor deficits have been extremely hard to evaluate in mice. "There simply have been no tools to do such an assessment," says Kontkanen.
Being able to capture these subtle pathological symptoms offers drug developers a potentially useful way of assessing whether compounds designed to treat the chorea actually helps in reducing the dyskinesia-like motor deficits in HD mice, says Kontkanen.
Another mouse study conducted by the Finnish group offered a different strategy for evaluating disease progression and new treatments for HD. The group used radioactive isotopes to track different proteins in two different brain regions of the Q175K1 HD mouse model at 9-10 months, and then imaged the brains with PET/CT scans and autoradioagraphy.
"In Huntington's the amount [density] of these receptors is reduced as the disease progresses," says neuroscientist Tuulia Huhtala, who presented the data at the SfN meeting on Monday. She said the group was able to show that density and gene expression levels of these targets had significantly declined by age 9-months compared to wild-type mice, which means that the nuclear imaging and molecular analysis—when combined with other behavioral strategies—might also be useful in showing whether new treatment interventions are working effectively.
SfN Postscript: About Those Walking Dead…
Teen-age boys won't pay attention if you tell them you study conscious deficit hypoactivity disorder, delusional impulse aggression and oscillating reactions. But what if you said you created hypothetical models of zombie brains? University of California-San Diego neuroscientist Bradley Voytek's used this example to illustrate why it's important for scientists to pull themselves out of the weeds, so to speak, and think about how they communicate what they do to the lay public and even to other scientists. Voytek, who studies the relationships between neural oscillations, cognition, and disease—and penned "Do Zombies Dream of Undead Sheep?A Neuroscientific View of the Zombie Brian" with Carnegie Mellon University professor Timothy Verstynen—was part of a panel discussion at the SfN meeting populated by Ph.D. scientists who all blog. Some do it professionally, for others it is extracurricular. Voytek became interested in blogging about six years ago because he felt it would help him do his job better. He also finds blogging an effective way to network with colleagues virtually and share ideas when he can't see them in person at science meetings. Here is a link to his blog, Oscillatory Thoughts.
How to cite:
McEnery, Regina. HD in Focus. Eureka blog. Oct 20, 2015. Available: https://eureka.criver.com/hd-in-focus/