Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington's disease.

INTRODUCTION: Strong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington's disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures. METHODS: This is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites' level and diffusion. Age and sex matched healthy subjects are included as a control group. DISCUSSION: Results from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.

Raising Awareness of Therapeutic Misconception and Optimism Around Clinical Trials in Huntington's Disease.

The Huntington's disease (HD) community is moving into an exciting time with Huntingtin lowering strategies entering human clinical trials. These upcoming targeted therapeutic approaches for this devastating disease with unmet medical needs, are believed to be a last resort for many patients and their families. Recently, patients with HD were shown to be at high risk for therapeutic misconception, mistaking research for actual treatment. It is important that investigators are aware of their patient's, as well as their own, vulnerability to therapeutic misconception. To limit therapeutic misconception, information should be provided on the rationale for clinical trials and the differences between clinical research and clinical care should be carefully discussed.