Abstract

There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington’s disease is a 32-site, international, observational study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7–12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.

Highlights

  • (PREDICT-Huntington’s Disease (HD); NS040068) has examined early indicators of chiatric, and imaging correlates of emerging disease

  • Significant limitations to preventive clinical trials for HD include a lack of knowledge of the natural history of the disease and a dearth of outcome measures sensitive to disease changes in the earliest, or premanifest, stages of the disease

  • Findings show longitudinal change in 36 of 39 measures examined over a 10-year natural observation study in premanifest HD

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Summary

Introduction

(PREDICT-HD; NS040068) has examined early indicators of chiatric, and imaging correlates of emerging disease Only one other study has examined multiple phenotypic and biologic markers of change over time together in premanifest HD (Tabrizi et al, 2012, 2013). Conclusions from this group suggest imaging measures are useful for indexing change, but “decline in cognitive, quantitative motor, or oculomotor measures were limited at this stage” (Tabrizi et al, 2012). Graphical analysis is used to illustrate the course of premanifest HD

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