Study protocol for the iMarkHD study in individuals with 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 gene. Although the cause of HD is known, much remains unknown about mechanisms underlying clinical symptom development, disease progression, and specific clinical subtypes/endophenotypes. In the iMarkHD study, we aim to investigate four discrete molecular positron emission tomography (PET) tracers and magnetic resonance imaging (MRI) markers as biomarkers for disease and symptom progression. Following MRI optimization in five healthy volunteers (cohort 1), we aim to recruit 108 participants of whom 72 are people with HD (PwHD) and 36 healthy volunteers (cohort 2). Pending interim analysis, these numbers could increase to 96 PwHD and 48 healthy controls. Participants will complete a total of 10 study visits, consisting of a screening visit followed by a clinical and MRI visit and PET visits at baseline, year 1, and year 2. PET targets include the cannabinoid 1, histamine 3, and serotonin 2A receptors, and phosphodiesterase 10A, whereas MRI will be multimodal, including, but not limited to, the assessment of cerebral blood flow, functional connectivity, and brain iron. Recruitment is currently active and started in September 2022. By combining PET and multi-modal MRI assessments we expect to provide a comprehensive examination of the molecular, functional, and structural framework of HD progression. As such, the iMarkHD study will provide a solid base for the identification of treatment targets and novel outcome measures for future clinical trials.