Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
Prostate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial... Show moreProstate cancer (PCa) is frequently treated with radiotherapy. However, depending on the aggressiveness of the disease, the risk of recurrence can be up to 35% within five years of the initial treatment. Patients with localised recurrent PCa are candidates for curative (i.e. salvage) treatment. To overcome the toxicity associated with whole-gland approaches, focal salvage treatments target the index lesion while sparing the surrounding tissue. The studies described in this thesis elaborate on the use of quantitative multi-parametric MRI (mp-MRI) for the detection and localisation of locally recurrent PCa after radiotherapy. Pre-treatment radiomic imaging features were found to have potential to improve recurrence-risk prediction models for high-risk PCa patients treated with radiotherapy. In this thesis, the mp-MRI properties of irradiated benign tissue and recurrent tumour were characterised, with access to pathological samples. These findings can be used as a foundation to establish guidelines (which are currently absent) on how to assess and score MRI scans after radiotherapy. Improving radiological knowledge in the recurrent setting can lead to improved staging and result in better patient selection for salvage treatments. Lastly, this thesis provides evidence on how best to define the region to target, leading to a refinement of focal salvage strategies. Show less
