A Multi-Study Model-Based Evaluation of the Sequence of Imaging and Clinical Biomarker Changes in Huntington’s Disease
Year: 2021
Type: article
Abstract: Understanding the order and progression of change in biomarkers of neurodegeneration is essential to detect the effects of pharmacological interventions on these biomarkers. In Huntington’s disease (HD), motor, cognitive and MRI biomarkers are currently used in clinical trials of drug efficacy. Here for the first time we use directly compare data from three large observational studies of HD (total N = 532) using a probabilistic event-based model (EBM) to characterise the order in which motor, cognitive and MRI biomarkers become abnormal. We also investigate the impact of the genetic cause of HD, cytosine-adenine-guanine (CAG) repeat length, on progression through these stages. We find that EBM uncovers a broadly consistent order of events across all three studies; that EBM stage reflects clinical stage; and that EBM stage is related to age and genetic burden. Our findings indicate that measures of subcortical and white matter volume become abnormal prior to clinical and cognitive biomarkers. Importantly, CAG repeat length has a large impact on the timing of onset of each stage and progression through the stages, with a longer repeat length resulting in earlier onset and faster progression. Our results can be used to help design clinical trials of treatments for Huntington’s disease, influencing the choice of biomarkers and the recruitment of participants.
Source: Frontiers in Big Data
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,150
Funders: CHDI Foundation, Wellcome Trust, National Institute for Health and Care Research, European Commission, University College London Hospitals NHS Foundation Trust, Medical Research Council, Engineering and Physical Sciences Research Council, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke
Awards: Computational models for clinical trial design in Huntington's disease, Statistical disease modeling and clinimetrics to prepare for preventive trials in huntington disease, G1842620754, TREAT-HD: targeting neurodegeneration in Huntington's disease, G2810537366, G3018663809, Medical image computing for next-generation healthcare technology, Cognition and brain imaging in Huntingtons disease, G4266322423, Data-driven models for Progression Of Neurological Disease, G434337789, TREAT-HD: targeting neurodegeneration in Huntington's disease, G6868616705, G7329585684, G844244329, Preparing for preventive clinical trials in Huntington's disease, G902693135, G991456907, G993623663
OpenAlex ID: W3190128877