E03 Uncovering the temporal sequence of regional brain volume and neural connectivity changes in huntington’s disease

Background Huntington Disease (HD) is a neurodegenerative disorder that can be characterised by magnetic resonance imaging (MRI) measurements of brain volume loss and neural connectivity changes. We recently developed a probabilistic disease progression model to uncover the most likely temporal sequence of structural MRI changes occurring during HD progression. However, there is currently less information regarding the ordering of neural connectivity changes and whether these precede or follow brain volume loss. Aims Here we aim to expand our previous model by including neural connectivity markers to uncover a new temporal sequence of events occurring in the HD brain. This model is the first of its kind, providing insight into HD disease mechanisms and progression, and potentially guiding future treatments by determining the most optimal stage for intervention. Method We apply the event-based model (EBM), a machine learning method for uncovering sequences of events, to cross-sectional MRI data from both genotype-confirmed HD patients and healthy controls (HC) from the Track-On HD cohort. We first performed a data-driven analysis to select nine statistically significant structural and connectivity markers with high effect sizes between the HC and HD groups. These markers were input into the EBM to uncover the most likely sequence of events and stage individuals along this sequence. Results The EBM revealed a sequence of events beginning with the atrophy of structural markers: putamen, striatum, globus, caudate and white matter, followed by the degeneration of four neural connections: left posterior parietal cortex (PPC) to right PPC, right PPC to left PPC, left dorsolateral prefrontal cortex (DLPFC) to left medial frontal gyrus and left DLPFC to right supramarginal gyrus. These findings align with clinical knowledge of HD progression, and provide the first data-driven confirmation that brain volume loss precedes connectivity changes in HD.