‘Ambitious’ study investigates use of PET imaging biomarkers for Huntington's disease 

Huntington’s disease (HD) is still often defined by the onset of motor symptoms, inversely associated with the size of the CAG repeat expansion in the huntingtin (HTT) gene. In recent years, the way in which we stage HD has been improved and we have begun moving away from just relying on HTT CAG repeat length. For example, in the HD-ISS staging system, magnetic resonance imaging (MRI) has been introduced as a measure to differentiate the earliest stages of disease before motor onset. This recognises that subclinical changes and pathological processes precede the initiation of clinical symptoms, but much remains unknown about the mechanisms underlying the development of symptoms and disease progression. A need exists for easily obtainable, reliable, and robust biomarkers for the development and evaluation of future disease-modifying treatments. 

Here, the iMarkHD study, taking place at King’s College London in collaboration with sites across the UK, forms an essential link. Our study looks beyond brain volume reduction, and in addition to multimodal MRI imaging, includes four different positron emission tomography (PET) ligands, providing useful information about the functional organisation of brain changes. Targets for PET imaging include serotonin 2A, cannabinoid 1, and histamine 3 receptors, as well as phosphodiesterase 10A enzyme. All targets have shown potential as biomarkers for HD in previous smaller-scale or animal studies, and in the iMarkHD study we determine their usefulness as biomarkers for disease and symptom progression. The study is a longitudinal observational study with yearly follow-up for two years, where participants additionally undergo extensive clinical phenotyping. We aim to recruit 72 individuals with HD at different stages of the disease and 36 healthy volunteers, which probably makes this the most ambitious PET study so far in the HD field.  

Although our findings will not replace HTT gene testing in the diagnosis of HD, they could provide novel outcome measures for therapeutic trials. In fact, our recent interim analysis showed clear reduction in binding ratios and distribution volume of the PET tracers in individuals with HD already at an early premotor stage. To be able to use PET imaging in clinical practice further investments are needed, given the current high costs of PET scanning.  

The interim findings were presented at this year’s EHDN congress in Strasbourg, where we were able to show our results in a dedicated session on new observational studies. This was very well received and attracted many questions from the audience, including questions about the utility of PET markers as outcomes for early interventional trials. Also, among our participants, there is great enthusiasm despite the burden of frequent scans. We have received excellent feedback, and the opportunity to contribute to a study looking beyond traditional outcomes in HD was often mentioned, as well as the support and knowledge of our wonderful iMarkHD team. We are excited to continue our successful collaboration with participants and our network of referral sites across the UK and hope to be able to present our baseline results in early 2025 while continuing to collect longitudinal data.