Study Identifies Potential Huntington's Disease Biomarkers

Emma Hitt, PhD

December 02, 2010

December 2, 2010 — In patients with Huntington's disease (HD), a 12-month follow-up study suggests early biomarkers may be able to detect disease changes over time, long before symptoms appear.

Sarah Tabrizi, MD, with the University College London's Institute of Neurology, in the United Kingdom, and colleagues reported their findings in the December 2 issue of Lancet Neurology.

Quantitative imaging showed the greatest differentiation across the spectrum of disease, but functional measures and cognitive and motor impairment could be detected before symptoms of HD were manifest, they found.

"We show longitudinal change over 12 months in generalized and regional brain volume, cognition, and quantitative motor tasks in individuals many years from predicted disease onset and show the feasibility of obtaining quantifiable endpoints for future trials," Dr. Tabrizi and colleagues conclude.

TRACK-HD Measures Biomarkers Over Time

According to the researchers, treatment early in HD may be key to the optimal effectiveness of disease-modifying therapies, yet "sensitive and reliable biomarkers of disease progression" need to be established to test them, they write.

The TRACK-HD study was designed to detect biomarkers potentially relevant to HD, comparing a range of HD assessments, including advanced brain imaging (3T magnetic resonance imaging [MRI]), cognitive, quantitative motor, and oculomotor tests. The current study represents 12-month follow-up of a study initiated in 2009.

A total of 346 individuals from the 4 TRACK-HD sites in Canada, France, the Netherlands, and the United Kingdom completed the follow-up. Of those, 116 were premanifest individuals carrying the mutant HTT gene (pre-HD), 114 were patients with early HD, and 116 were well-characterized age- and sex-matched controls.

The researchers determined which changes in whole-brain volume, impaired motor and oculomotor tasks, and cognitive dysfunction were most sensitive to disease changes in a year and therefore provided the best means of assessment in future clinical trials of potential treatments.

Quantitative Imaging Techniques Best Predictor

Quantitative imaging techniques offered the strongest and most consistent detection of disease progression, showing statistically significant associations with indicators of disease pathology and measures of disease severity in both pre-HD and early HD individuals.

Whole-brain and regional atrophy rates were 0.2% and 1.37% higher, respectively, in pre-HD and 0.6% and 2.86% higher, respectively, in early HD patients during the 12-month period compared with controls. Furthermore, gray and white matter atrophy was increased even in subjects furthest from the predicted clinical onset of disease.

Additionally, pre-HD and early HD patients demonstrated a decline in both cognitive and motor function, whereas pre-HD patients also exhibited deterioration of oculomotor function.

"These data add significantly, as they are the first data over short periods of time (1 year), in both pre-manifest HD gene carriers and those with early-stage disease alongside a large control group," Dr. Tabrizi told Medscape Medical News. "Several imaging, cognitive, and motor measures have been proposed as suitable candidates for tracking disease progression, but the majority of studies to date have relied on cross-sectional data to infer utility," she added.

HD a Model for Other Diseases

According to Dr. Tabrizi, HD can be thought of as a model neurodegenerative disorder because it is monogenic and fully penetrant and htt gene expansion carriers can be identified with precision many years before symptom onset.

"As such, it can serve as a paradigm for studying other neurodegenerative conditions," she said. "Our longitudinal findings from TRACK-HD have key relevance therefore for informing early intervention strategies for other neurodegenerative disorders for which no highly predictive tests for the premanifest disease stages are available," she said.

According to editorialist, Justo García de Yébenes, MD, "clinical trials in presymptomatic people have been delayed...because it was difficult to focus on useful clinical endpoints."

In light of these findings, "we expect to see some of these neuroprotection trials done in asymptomatic mutation carriers of HD in the following years," concludes Dr. de Yébenes, who is director of the Neurodegenerative Diseases Unit at the Hospital Ramón y Cajal, in Madrid, Spain.

The study was funded by the CHDI/HighQ Foundation Inc, a not-for-profit organization dedicated to finding treatments for HD. The study authors have disclosed no relevant financial relationships.

Lancet Neurol. Published online December 2, 2010.

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