To access whole brain white matter alterations in developmental macaque brains with transgenic Huntington’s disease (HD). Three HD rhesus monkeys (male) were generated by lentiviral-mediated transgenesis as previously described ¹. Four age-matched wild-type non-transgenic rhesus macaques (2 males and 2 females) were used as control. Animals were scanned every 6 months from 6 months to 4 years old. During MRI scanning, they were anesthetized with ~1.0% isoflurane mixed with 100% O₂. Diffusion weighted images were acquired with a Siemens 8-channel phased-array volume coil and a dual spin-echo, echo planar imaging (EPI) sequence and the following imaging parameters: TE = 89 ms, TR = 5700 ms, voxel size = 1.3 mm × 1.3 mm × 1.3 mm, a single b-value of 1000 s/mm² with 30 diffusion encoding directions. T1-weighted images acquired with a 3D MPRAGE with inversion time = 950 ms were used for structural identification and constructing an anatomical macaque template for the DTI image registration. FA maps were nonlinearly registered to a population-specific FA template, and then skeletonised with TBSS toolbox (FMRIB, Oxford). The ages for the maximum FA were calculated by fitting with a Poisson regression model: FA = A*age*e^-B*age + C, where A, B and C are the parameters of the model ². After confirming normal distribution of the calculated ages by a one-sample Kolmogorov-Smirnov test, a two sample independent t-test was used to test the group difference within the skeletonized FA maps with FDR correction (q=0.05). The age for the maximum FA was averaged within the ROIs with group difference, and compared with independent t-tests with FDR correction (q= 0.05). Widespread differences in brain maturation are illustrated in Fig. 1. These areas include medial prefrontal cortex (mPFC), ventral lateral prefrontal cortex (vlPFC), dorsal premoter (dPMC) and primary motor cortex (PMC), somatosensory cortex (SSC), temporal cortex (TC), parietal cortex (PC) and visual cortex (VC), and also included caudate (CA), putamen (PU), thalamus (TH), corpus callosum (CC), brain stem (BS) and cerebrum (CB). Maximum FA in HD animals is much lower than that in control group (Fig. 2). In particular, white matter in HD animals degenerate much earlier than that in control animals (22.8±1.1 vs 50.9±1.5 months). In this work, spatial-temporal changes of white matter in HD monkey brains were examined using DTI. Abnormal white matter maturation and degeneration in the motor, sensory and cognitive brain areas are consistent with those seen in prodromal and symptomatic HD patients ^{3, 4}. Furthermore, progressive changes in affected brain areas were also aligned with symptom onset and associated with specific cognitive and motor behavioral changes as disease progress in the same HD monkeys reported previously ⁵. HD monkeys can potentially be used as preclinical large animal model to facilitate the development of novel biomarkers through noninvasive imaging.