TRACK-HD Researchers Publish Fourth Multinational Huntington’s Disease Collaboration Study Findings in The Lancet Neurology

by Jude Gustafson, Department of Psychiatry, UI Health Care

Huntington’s disease (HD) is a slow-progressing neurological illness for which there is currently no treatment or cure. HD is one of few heritable diseases that inevitably follow a very basic, autosomal-dominant genetic pattern. This means that children of parents who have a mutation of the HD gene known as “CAG expansion” have a 50% chance of inheriting the gene, and inheriting the gene invariably predicts eventual development of the disease state. Overt symptoms usually arise in middle age, and over the course of about 15 years, manifest through gradual decline in motor function, cognitive faculty, and behavioral control, and eventually culminate in death.

The research strategy for HD is two-pronged: Some investigators are focused on finding an actual cure, or at the very least, treatments that will stave off symptoms or arrest development of the disease. Other researchers, such as the international TRACK-HD team, are in search of tools that can be used to detect the earliest signs of the disease and the most subtle indicators of disease progress, and ultimately, give clues as to whether a particular treatment is working.

With some clinical trials aiming to start as early as 2015, the goal of the TRACK-HD research team, which is headed by Sarah Tabrizi at University College of London in London, England, and includes Douglas Langbehn, MD, PhD, and Hans Johnson, PhD, of the UI Health Care Department of Psychiatry, was to identify the best clinical tools to assess HD treatments. In their recent study, they evaluated the effectiveness of a wide battery of HD tests including brain imaging, psychiatric assessment, cognition testing, and combined cognitive/motor evaluations. Optimal tools would be those capable of reliably and definitively measuring the most diminutive changes in brain function and structures in CAG mutation carriers prior to onset of clinical symptoms.

Study participants were involved in intense testing lasting an entire day. Great care was taken to accurately measure data, and in order to reduce inter-rater reliability problems, only a few skillfully trained experts administered testing at the four research sites in Europe and Canada. Computer scoring was used as much as possible to eliminate human error and subjectivity, and these methods helped ensure researchers could accurately pinpoint the most sensitive, useful tools for HD detection and evaluation.

Data from brain scans showed consistent deterioration of the basal ganglia—a relay station that handles neural communications among lower regions and the cerebral cortex, especially the frontal lobes. Perhaps the most critical finding was that significant detectable tissue loss in the cerebral cortex often begins one to two years prior to onset of overt HD symptoms. These earliest clues to disease onset will be the target of future therapies that aim to keep brain networks intact to avert the physical changes that precede other symptoms.

Motor tests, including a computerized finger-tapping exercise, measured both uniformity of movement and speed of tapping. Study data revealed that the length of time subjects keep their fingers removed from the testing pad between taps is an especially reliable, sensitive indicator of neural breakdown in the HD symptomatic evolution. Also ranking among the most sensitive measures of disease progress was an integrated cognitive and motor skills challenge requiring subjects to translate simple codes, then to respond to the coded messages in writing.

To reduce subject burden and minimize costs, it has generally been assumed that clinical trials in HD would not last longer than 24 months. Although the TRACK-HD team had solid baseline data at one year, and had also identified the most promising evaluation tools for subjects who had experienced HD onset by the end of the 24-month study, they wanted more data to draw more meaningful conclusions about subjects whose symptoms were still largely undetectable at the end of that study. Subsequently, a one-year extension was approved for follow-up research that helped affirm deductions from the original two-year study and further strengthened understanding and conclusions drawn about premanifest subjects. Data from the third year of testing suggested strongly that clinical trials of preventive therapies will require more time, with a minimum of three years for robust, reliable data.

Some of the most notable data from TRACK-HD studies thus far are those showing structural brain volume changes revealed in MRI. Tenaciously stretching even further for evidence of HD’s etiological underpinnings, TRACK-HD research colleagues, aim to publish more findings on premanifest HD research within the next year based on trials that utilize functional MRI imaging to reveal metabolic brain phenomena, as well as diffusion tensor tools that locate ever more subtly affected brain circuitry in pre-symptomatic subjects.

For more information, see the article, Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data on The Lancet Neurology web site.

Contacts

Doug Langbehn, MD, PhD, Professor of Psychiatry and Biostatistics, Department of Psychiatry
Hans Johnson, PhD, Assistant Professor of Psychiatry, Electrical and Computer Engineering, and Biomedical Engineering, Department of Psychiatry

For more information about HD research at the Carver College of Medicine, see the Huntington's Disease Society of America Center of Excellence web site.