Revealing the Timeline of Structural MRI Changes in Premanifest to Manifest Huntington Disease

Background and ObjectivesLongitudinal measurements of brain atrophy using structural MRI (sMRI) can provide powerful markers for tracking disease progression in neurodegenerative diseases. In this study, we use a disease progression model to learn individual-level disease times and hence reveal a new timeline of sMRI changes in Huntington disease (HD).MethodsWe use data from the 2 largest cohort imaging studies in HD-284 participants from TRACK-HD (100 control, 104 premanifest, and 80 manifest) and 159 participants from PREDICT-HD (36 control and 128 premanifest)-to train and test the model. We longitudinally register T1-weighted sMRI scans from 3 consecutive time points to reduce intraindividual variability and calculate regional brain volumes using an automated segmentation tool with rigorous manual quality control.ResultsOur model reveals, for the first time, the relative magnitude and timescale of subcortical and cortical atrophy changes in HD. We find that the largest (similar to 20% average change in magnitude) and earliest (similar to 2 years before average abnormality) changes occur in the subcortex (pallidum, putamen, and caudate), followed by a cascade of changes across other subcortical and cortical regions over a period of similar to 11 years. We also show that sMRI, when combined with our disease progression model, provides improved prediction of onset over the current best method (root mean square error = 4.5 years and maximum error = 7.9 years vs root mean square error = 6.6 years and maximum error = 18.2 years).DiscussionOur findings support the use of disease progression modeling to reveal new information from sMRI, which can potentially inform imaging marker selection for clinical trials.