Huntington disease (HD) is an inherited neurodegenerative disorder with motor, cognitive, and psychiatric deficits [1]. White matter (WM) atrophy has been reported in diffusion MR studies of HD patients though what drove the changes is not clear [2-4]. Iron accumulation in HD patients’ brains has been shown in postmortem brain analysis [5]. Quantitative Susceptibility Mapping (QSM) is a novel method for estimation of magnetic susceptibility in tissue from phase change of 3D gradient-echo MRI [6-7]. QSM has been used to characterize microstructural change in white matter in developing mouse brain [8], e.g., demyelination, and iron accumulation in human HD patients [9]. In this study, we perform longitudinal QSM to characterize white matter pathology and iron deposition in the YAC128 mouse model of HD that expresses the full length human mutant huntingtin (mHTT) gene [10].The study was approved by the IACUC of Biomedical Sciences Institutes, Singapore. 11 WT mice (5 males, 6 female) and 14 YAC128 mice (7 males, 7 females) were used in this study. Imaging was conducted on a 7T MRI (ClinScan, Bruker BioSpin, Germany) with a 4 channel array coil. 3D Multi-echo gradient-echo images were acquired with the following parameters: TR=60ms, TE1/𝛥TE/TE6=6.26/7.77/45.11ms, FOV=27x27x18mm3, matrix size=192x192x128, and 6 repetitions. Total scan time was approximately 72 minutes. MR acquisitions were done at 9, 12, and 15 months of age. After each scan, 3-4 animals from each group were sacrificed for histological validation. The raw phase was processed by Laplacian-based phase unwrapping and V_SHARP background phase removal [7]. QSM maps were reconstructed using a two-level STAR-QSM algorithm [11] for reducing streaking artifacts. For group analysis, magnitude image was linearly registered to an in-house created T2-weighted fast spin echo-based anatomical template based on YAC128 and WT mice of 9 months old. The registered images were averaged to create age-specific template for further non-linear registration using FSL’s FNIRT [12]. The QSM maps were warped to the template and compared by t-test using SPM8 [13]. Regions-of-interest (ROIs) were chosen on the statistical maps.Voxel-wise comparison (Fig.1) showed YAC128 mice having decreased susceptibility in the cingulate cortex (Cg) and caudate putamen (CPu), but increased susceptibility in the corpus callosum (cc), dorsal subiculum (DS), globus palladius (GP), and inferior colliculus (IC) as early as 9 months old. ROI analysis (Fig. 2) suggested that increased susceptibility in DS, GP and IC may be due to iron deposition while the reduced negative susceptibility in cc may relate to demyelination.This study demonstrates the potential application of QSM to characterize tissue property changes which may reflect demyelination and iron accumulation in HD. The trend was not consistent in the voxel-wise statistical map, which might be due to the decreased sample size over time. The result is consistent with known pathology of YAC128 mice and HD patients. Further histological analysis is being performed to confirm the QSM findings.