E012 Differential cortical layer vulnerability in Huntington’s disease gene expansion carriers revealed by quantitative 7T MRI at 600µm isotropic resolution

<h3>Background</h3> Selective atrophy occurs in layer 3 (L3) and L5 of the primary motor cortex, and L3, L4 and L6 of the primary visual cortex in advanced Huntington’s Disease (HD).(1,2) However, the distribution and extent of cortical layer pathology in HD gene expansion carriers (GEC) is unknown. <h3>Aims</h3> To detect cortical layer pathology in GEC by comparison with healthy controls. <h3>Methods</h3> Using 7-Tesla (7T) MRI at 600µm isotropic resolution, we employed a whole brain voxel-wise analysis in GEC approximately 15 years from estimated onset (n=16) and matched controls (n=18). Cortical brain regions showing significant group differences in quantitative MRI (qMRI) were divided into 8 equi-volume layers and layer-wise group level comparisons were explored. The von Economo (VE) atlas was used to estimate histological layers. <h3>Results</h3> Significant group differences were observed in striatal but not cortical volume (figure 1). Voxel based quantification analyses revealed clusters with lower proton density in the left frontal eye field (LFEF) and right visual area 6 (RV6) (figure 2). The largest effects were found in L4 for both (LFEF: FDR=0.08, Hedges’ d=0.95; RV6: FDR=0.009, Hedges’ d=1.26). For histological layers, left frontalis agranularis had the largest effect in layer III (FDR=0.025, Hedges’ d=1.15), and in right area peristriata (ROA), layer V (FDR=0.0002, Hedges’ d=1.7)(figure 3). <h3>Conclusions</h3> In this first demonstration of differential cortical layer vulnerability in GEC, the results from ROA layer V is consistent with post-mortem studies.(3) Differences with qMRI but not with volumetric MRI support a novel role for 7T qMRI in cortical pathology examination in GEC. <h3>References</h3> Thu DCV, Oorschot DE, Tippett LJ, <i>et al</i>. Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington’s disease. <i>Brain.</i> 2010;<b>133</b>(4):1094–110. Macdonald V, Halliday G. Pyramidal cell loss in motor cortices in Huntington’s disease. <i>Neurobiol Dis</i>. 2002;<b>10</b>(3). Pressl C, Mätlik K, Kus L, <i>et al</i>. Selective vulnerability of layer 5a corticostriatal neurons in Huntington’s disease. <i>Neuron</i>. 2024 Mar 20;<b>112</b>(6):924–941.e10. doi: 10.1016/j.neuron.2023.12.009.