Fluid and Imaging Biomarkers in Huntington’s Disease

Abstract

Growing interest in earlier and mechanism-targeted interventions for Huntington’s disease (HD) has brought focus on biomarkers capable of informing trial design and regulatory pathways. This review discusses recent advances in fluid and neuroimaging biomarkers since the introduction of the HD-Integrated Staging System (HD-ISS), focusing on candidates with the most relevant evidence for regulatory applications. Neurofilament light (NfL) has become a versatile biomarker for prognostic enrichment and safety monitoring. Mutant huntingtin (mHTT) and somatic expansion ratio (SER) provide mechanistic evidence of target engagement. HD-YAS showed SER predicts striatal atrophy over multi-year intervals, but its short-term sensitivity remains uncertain. Structural MRI remains the most sensitive imaging marker of progression, whilst PET and diffusion imaging offer mechanistic insight but limited temporal sensitivity. The most advanced biomarkers now span neuronal injury, target engagement and neurodegeneration. Moving toward qualified endpoints will require harmonised methods, improved analytical validation and stronger evidence linking biomarker change to clinical benefit.