Imaging Glucose Metabolism and Dopaminergic Dysfunction in Sheep (Ovis aries) Brain Using Positron Emission Tomography Imaging Reveals Abnormalities in OVT73 Huntington's Disease Sheep.

Abstract

Huntington's disease (HD) is a neurodegenerative disease that causes cognitive, movement, behavioral, and sleep disturbances, which over time result in progressive disability and eventually death. Clinical translation of novel therapeutics and imaging probes could be accelerated by additional testing in well-characterized large animal models of HD. The major goal of our preliminary cross-sectional study is to demonstrate the feasibility and utility of the unique transgenic sheep model of HD (OVT73) in positron emission tomography (PET) imaging. PET imaging studies were performed in healthy merino sheep (6 year old, n = 3) and OVT73 HD sheep (5.5 year old, n = 3, and 11 year old, n = 3). Region-of-interest and brain atlas labels were defined for regional analyses by using a sheep brain template. [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) was employed to compare the regional brain glucose metabolism and variations in FDG uptake between control and HD sheep. We also used [¹⁸F]fluoro-3,4-dihydroxyphenylalanine ([¹⁸F]FDOPA) to compare the extent of striatal dysfunction and evaluated the binding potential (BP_ND) in key brain regions between the groups. Compared with healthy controls and 11 year old HD sheep, the 5.5 year old HD sheep exhibited significantly increased [¹⁸F]FDG uptake in several cortical and subcortical brain regions (P < 0.05-0.01). No difference in [¹⁸F]FDG uptake was observed between healthy controls and 11 year old HD sheep. Analysis of the [¹⁸F]FDOPA BP_ND parametric maps revealed clusters of reduced binding potential in the 5.5 year old and 11 year old HD sheep compared to the 6 year old control sheep. In this first-of-its-kind study, we showed the usefulness and validity of HD sheep model in imaging cerebral glucose metabolism and dopamine uptake using PET imaging. The identification of discrete patterns of metabolic abnormality using [¹⁸F]FDG and decline of [¹⁸F]FDOPA uptake may provide a useful means of quantifying early HD-related changes in these models, particularly in the transition from presymptomatic to early symptomatic phases of HD.