E018 Characterising the earliest neurodegenerative changes in HD: multi-modal neuroimaging insights from the Huntington’s disease young adult study (HD-YAS)

<h3>Background</h3> HD-YAS aims to characterise the HD phenotype ~24 years from predicted disease onset in a unique cohort of gene expansion carriers (GECs), evaluated at two time-points ~4.5 years apart. <h3>Aims</h3> To characterise the earliest neurodegenerative changes with multi-modal MRI. <h3>Methods</h3> 154 participants were recruited: 131 at visit 1 (64 GECs, 67 controls) and 23 additional participants at visit 2 (9 GECs, 14 controls). &gt;90% of participants underwent 3T MRI, providing volume/atrophy, diffusion, structural-connectivity, and quantitative-MRI (multi-parameter mapping (MPMs)) metrics. These were assessed cross-sectionally over pre-defined regions-of-interest, using all datapoints and mixed effect regression with random participant effect. Longitudinal direct change analyses used linear regression of a single change measure per participant. <h3>Results</h3> Volumetrics: Cross-sectionally, GECs showed reductions in whole-brain, grey-matter, white-matter, caudate and putamen volumes compared with controls, which were associated with age, CAG, or their interaction (FDR&lt;0.15). Longitudinally, elevated atrophy rates were evident in all regions-of-interest (FDR&lt;0.02), and most prominent in the caudate and putamen (FDR&lt;1.2x10–9); rates were influenced by age, CAG or their interaction (FDR&lt;1.5x10–2). MPMs: Cross-sectionally, R1 was elevated in the putamen in GECs compared with controls (FDR=0.1); and associated with age and CAG (FDR=0.1), suggestive of increased iron levels. There was no evidence of differences in metrics sensitive to demyelination. There were no significant longitudinal findings. Structural connectivity: No significant findings. <h3>Conclusions</h3> Elevated atrophy rates, particularly striatal, are evident &gt;20 years prior to predicted symptom onset. Increased iron in the putamen may be a very early feature. Together with the absence of congruent myelin-contrast decreases, this is suggestive of increased levels of toxicity and neuronal loss.