Preparing for preventive clinical trials: the Predict-HD study.

BACKGROUND The optimal design and outcome measures for preventive clinical trials in neurodegenerative diseases are unknown. OBJECTIVE To examine measures that may be associated with disease in the largest cohort ever recruited of prediagnosed individuals carrying the gene expansion for Huntington disease (HD). DESIGN The Predict-HD study is a multicenter observational research study in progress at 17 sites in the United States, 4 in Canada, and 3 in Australia. SETTING Genetics and HD outpatient clinics. PARTICIPANTS Five hundred five at-risk individuals who had previously undergone elective DNA analyses for the CAG expansion in the HD gene (predictive testing) and did not currently have a clinical diagnosis of HD. MAIN OUTCOME MEASURES Basal ganglia volumes on magnetic resonance images, estimated probability of diagnosis (based on CAG repeat length), performances on 21 standardized cognitive tasks, total scores on 3 scales of psychiatric distress, and motor diagnosis based on the Unified Huntington's Disease Rating Scale. RESULTS Several variables showed progressive decline as the diagnostic ratings advanced toward manifest disease. Estimated probability of diagnosis was associated with Unified Huntington's Disease Rating Scale prediagnostic stages and varied from 15% in persons with no motor abnormalities to nearly 40% in those with abnormalities suggestive of probable disease. Striatal volumes, cognitive performances, and even psychiatric ratings declined significantly with motor manifestations of disease. CONCLUSIONS The documentation of biological and refined clinical markers suggests several clinical end points for preventive clinical trials. Longitudinal study is critical to further validate possible markers for prediagnosed HD.