Background and objective Controversy exists regarding the feasibility of preventive clinical trials in prodromal Huntington disease (HD). A primary limitation is a lack of outcome measures for persons with the gene mutation who have not yet been diagnosed with HD. Many longitudinal studies of cognitive decline in prodromal HD have not stratified samples based on disease progression, thereby obscuring differences between symptomatic and nonsymptomatic individuals.

Methods Prodromal participants from PREDICT-HD were stratified by disease progression into one of three groups: those having a High, Medium, or Low probability of motor manifestation within the next 5 years. Data from a total of N=1299 participants with up to 5950 data points were subjected to linear mixed effects regression on 29 longitudinal cognitive variables, controlling for age, education, depression, and gender.

Results Performance of the three prodromal HD groups was characterised by insidious and significant cognitive decline over time. Twenty-one variables from 19 distinct cognitive tasks revealed evidence of a disease progression gradient, meaning that the rate of deterioration varied as a function of progression level, with faster deterioration associated with greater disease progression. Nineteen measures showed significant longitudinal change in the High group, nine showed significant change in the Medium group and four showed significant cognitive decline in the Low group.

Conclusions Results indicate that clinical trials may be conducted in prodromal HD using the outcome measures and methods specified. The findings may help inform interventions in HD as well as other neurodegenerative disorders.