Imaging Glucose\nMetabolism and Dopaminergic Dysfunction\nin Sheep (Ovis aries) Brain Using Positron\nEmission Tomography Imaging Reveals Abnormalities in OVT73 Huntington’s\nDisease Sheep

Huntington’s\ndisease (HD) is a neurodegenerative disease\nthat causes cognitive, movement, behavioral, and sleep disturbances,\nwhich over time result in progressive disability and eventually death.\nClinical translation of novel therapeutics and imaging probes could\nbe accelerated by additional testing in well-characterized large animal\nmodels of HD. The major goal of our preliminary cross-sectional study\nis to demonstrate the feasibility and utility of the unique transgenic\nsheep model of HD (OVT73) in positron emission tomography (PET) imaging.\nPET imaging studies were performed in healthy merino sheep (6 year\nold, <i>n</i> = 3) and OVT73 HD sheep (5.5 year old, <i>n</i> = 3, and 11 year old, <i>n</i> = 3). Region-of-interest\nand brain atlas labels were defined for regional analyses by using\na sheep brain template. [<sup>18</sup>F]fluorodeoxyglucose ([<sup>18</sup>F]FDG) was employed to compare the regional brain glucose\nmetabolism and variations in FDG uptake between control and HD sheep.\nWe also used [<sup>18</sup>F]fluoro-3,4-dihydroxyphenylalanine ([<sup>18</sup>F]FDOPA) to compare the extent of striatal dysfunction and\nevaluated the binding potential (BP<sub>ND</sub>) in key brain regions\nbetween the groups. Compared with healthy controls and 11 year old\nHD sheep, the 5.5 year old HD sheep exhibited significantly increased\n[<sup>18</sup>F]FDG uptake in several cortical and subcortical brain\nregions (<i>P</i> < 0.05–0.01). No difference\nin [<sup>18</sup>F]FDG uptake was observed between healthy controls\nand 11 year old HD sheep. Analysis of the [<sup>18</sup>F]FDOPA BP<sub>ND</sub> parametric maps revealed clusters of reduced binding potential\nin the 5.5 year old and 11 year old HD sheep compared to the 6 year\nold control sheep. In this first-of-its-kind study, we showed the\nusefulness and validity of HD sheep model in imaging cerebral glucose\nmetabolism and dopamine uptake using PET imaging. The identification\nof discrete patterns of metabolic abnormality using [<sup>18</sup>F]FDG and decline of [<sup>18</sup>F]FDOPA uptake may provide a useful\nmeans of quantifying early HD-related changes in these models, particularly\nin the transition from presymptomatic to early symptomatic phases\nof HD.