Huntington’s disease (HD) is a polyglutamine disease for which no current cure exists. It is caused by a genetic error on the HTT gene responsible for the formation of polyglutamine tracts and eventually of the production of Huntingtin protein in the cytoplasm. In healthy individuals the polyglutamine chain consists of no more than 36 repeats. However, in individuals with more than 36 repeats the production of Huntingtin protein takes an altered form, the mutant Htt (mHtt) which is found to be associated with increased neuronal decay^1,2 and metalloprotein-bound iron⁴. While Magnetisation Transfer Imaging (MTI) has been linked to myelin loss³ and T2 relaxometry to iron content⁵, Chemical Exchange Saturation Transfer (CEST) MRI is shown to be sensitive to protein size and concentration⁶. In this study we compared relaxometry and MTI with CEST in order to assess whether the latter provides additional information about Huntington’s disease patients. Premanifest/ early Huntington’s patients (n=54) and healthy individuals (n=47) were recruited as part of the third visit of the TRACKON-HD study and scanned on identical 3T Philips MR scanners and identical receive head coils (8-channel) in Leiden (UMC) and Vancouver (UBC). The CEST/MTI protocol consisted of 3 seconds saturation (50% duty cycle, 50ms duration, FA= 1620o, 2μT B1rms), with a GRASE (GRadient And Spin Echo) readout (resolution 4mm3). Frequency offsets included 10ppm (MT) and 49 points from -6 to 6 ppm. A reference scan was also acquired without saturation. B0 field maps were also acquired for inhomogeneity correction. CEST was calculated as the asymmetry from 2-4 ppm while MTI was calculated as the ratio to the reference with no saturation. T1 maps were acquired using an inversion recovery protocol with 5 inversion times (TI): 200, 500, 1000, 2000 and 4000ms followed by a GRASE readout. T2 maps were acquired using a protocol of 12 multiple echoes (TE) and minimum TE=21ms, also followed by a GRASE readout. Region of Interest analysis was manually performed on each participant over four brain regions based on the literature1,2,7, including the putamen and globus pallidus, frontal lobe white matter, occipital lobe white matter and temporal lobe grey matter, as shown in figure 1. Statistical analysis was performed in Matlab using upaired ttest (95% confidence interval).Comparison between females and males (figure 2) revealed no significant differences (p>0.1) across healthy individuals nor between HD patients, therefore no groups were formed depending on the participants’ sex. ROI analysis revealed significant differences (p<0.001) in MTI between healthy controls and HD patients (figure 3d) which however strongly correlates (p<0.001) with T2 values (figure 3b and figure 4). CEST signal (figure 3a) showed significant alterations (p<0.05) in the putamen and globus pallidus region which did not correlate with any values of MT, T1 (figure 3c) or T2 (figure 3b). Changes in the CEST asymmetry could be indicative of alterations in the total protein structure or concentration in the corresponding regions for HD patients, independently from any measureable atrophy, or any changes to T1 and T2 relaxometry. The lack of MT changes in regions with CEST variation might indicate differences associated with mobile proteins, such as metabolites, instead of myelin loss. To our knowledge this work demonstrates for the first time that CEST might be used to provide additional information for HD patients. Nonetheless further longitudinal studies are essential in order to understand the origins of the CEST signal before is considered as a marker for disease progression or response to treatment.