Preparing for Preventive Clinical Trials

Abstract

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.

Verbal episodic memory declines prior to diagnosis in Huntington's disease

“…The current study examines memory in pre-HD gene carriers both with and without minor neurological signs, and with a sample large enough to provide adequate power for examining several covariates or individual difference factors that may help account for variability in memory performance in pre-HD. This study is part of the Predict-HD project (Paulsen et al, 2006a), an ongoing longitudinal study aimed at identifying cognitive, neurological, and psychiatric markers that track disease progression in early HD. Consistent with the broader goals of Predict-HD, the current study provides a focused look at memory function in pre-HD and examines the sensitivity of a common measure of memory for detecting subtle declines early in the disease.…”

Automatic detection of preclinical neurodegeneration

“…13 Because machine-learning techniques can potentially be used in large, multicenter treatment trials, 14,15 we sought to explore SVM performance on images from several centers. Encouraging SVM performance with HD will support the strategy of using a similar approach to identify a preclinical phase in other neurodegenerative disorders, such as AD.…”

“…A cohort of 96 PSCs and 95 control subjects enrolled in the PREDICT-HD study 15 were included. PREDICT-HD is an international multicenter study to discover biologic and refined clinical predictors of disease progression in PSCs.…”

“…Exclusion criteria for both PSCs and controls included evidence of unstable illness, alcohol or drug abuse, a history of special educational needs, and a history of other CNS diseases or events. 15 All T1-weighted anatomic brain MRI scans were checked for artifacts using a semiautomatic quality control procedure at the time of acquisition.…”

“…16 This is a robust model for age of disease diagnosis based on data from almost 3,000 gene carriers. As in previous work on the PREDICT-HD data, 15 we used the algorithm to estimate the probability of developing unequivocal signs of HD in the next 5 years. PSCs were classified into three equally sized subgroups with 1) less than 10%, 2) 10% to 33%, and 3) more than 33% probability of clinical manifestation in 5 years.…”