Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study

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.

Keywords: Huntington disease; PREDICT-HD; clinical trials; natural history; neurodegenerative disorders; outcome measures; premanifest.

Figure 1

Plots of key outcome variables for preventive clinical trials. Empirical individual curves (thin lines) and fitted spline curves (thick lines) of key variables plotted over CAP_D (CAG-corrected age). Dashed lines indicate individuals who converted in the study. TMS indicates total motor score; TFC, total functional capacity; SDMT, Symbol Digit Modalities Test; Smell-ID, University of Pennsylvania Smell Identification Test (UPSIT); Obsess-Comp, obsessive-compulsive; CS Fluid, cerebral spinal fluid.

Figure 2

Data-derived model of premanifest Huntington disease. Scaled fitted spline curves of key variables plotted over CAP_D (CAG-corrected age). Blue colors indicate variables that decrease and red colors indicate variables that increase. Vertical axis is in standard deviation (SD) units. TMS indicates total motor score; CSF, cerebral spinal fluid; DYS, dysrhythmia; O–C, obsessive–compulsive; SDMT, Symbol Digit Modalities Test; SMELL, University of Pennsylvania Smell Identification Test (UPSIT); TFC, total functional capacity.