Childhood to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease (ChANGE-HD) study protocol: A Prospective Longitudinal Neurodevelopmental Study of Huntington’s Disease

Although adult Huntington’s disease (HD) studies have significantly advanced our understanding of the course of degeneration, they may underrepresent critical neurodevelopmental aspects of the disease. Significant gaps remain in understanding how mutant huntingtin affects early neurodevelopment, its long-term impact, as well as potential implications for treatment outcomes. The Childhood to Adult Neurodevelopment in Gene-Expanded Huntington’s Disease ( ChANGE-HD; NCT01951588 ) study aims to evaluate brain structure and function in premanifest, at-risk children and young adults, and explore HD’s developmental origins. Here, we introduce the ChANGE-HD study protocol, which will investigate and integrate the neurodevelopmental and neurodegenerative aspects of HD. The ChANGE-HD study is a prospective, multi-site observational trial with an accelerated longitudinal design. Four hundred participants aged 6-30 years who are at risk for HD will be recruited and asked to return for multiple visits (if possible). At each visit, cognitive, motor, behavioral, blood, and MRI data are collected. ChANGE-HD represents the first prospective multi-site study to systematically document brain structure and function during the premanifest phase of HD in children and young adults. Data collection is ongoing with first results anticipated in 2026-2027. The ChANGE-HD approach is likely to provide novel pathophysiological insights and guide the development of therapeutic strategies tailored to both the developmental and degenerative phases of the disease.