A12 Identification of the key role of white matter in the pathogenesis of huntington’s disease

Purpose Pathogenesis of Huntington’s Disease (HD) is complex and progressive. Subtle changes seem to occur in the brain of gene carriers far from the onset of symptoms.1 There is a need of early, functional biomarkers, for pathogenesis understanding and treatment evaluation. White matter seems to be affected early and independently from striatal degeneration.2 Here we present a longitudinal MRI study on the CAG140 mouse model of HD for assessing white matter integrity over the life of this very progressive mouse model. Methods We scanned a cohort of 11 heterozygous CAG140 mice and 11 WT littermates, with 5 timepoints between 2.5 and 18 months of age. Structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging were acquired at each timepoint. Results Our results show early defects of diffusion properties in the anterior part of the corpus callosum (CC) at 5 months of age, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months). At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST too, as well as the pallidum (-21.0%). MT imaging showed reduced signal in the septum (-21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Figure 1 summarizes these results as variation maps between CAG140 and WT mice. Discussion Axonal projection data from Allen Connectivity Atlas3 is shown in figure 2 compared with our results. It illustrates the existence of a vulnerable network composed of the striatum and motor cortex in the CAG140 mouse model. Alterations of the diffusion properties and glutamate concentration in the anterior CC seem to point out the importance of white matter, in particular of cortico-striatal tracts, in this vulnerability. Our results, in line with literature, show the key role of white matter alteration in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD. References Tabrizi SJ, et al. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009;8:791–801. Casella C, Lipp I, Rosser A, Jones DK, Metzler-Baddeley CA. Critical review of white matter changes in Huntington’s disease. Movement Disorders 2020;35:1302–1311. Oh SW, et al. A mesoscale connectome of the mouse brain. Nature 2014;508:207–214.