Reduced D₂/D₃ Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease

Background: Dopamine system dysfunction and altered glucose metabolism are implicated in Huntington's disease (HD), a neurological disease caused by mutant huntingtin (mHTT) expression. Objective: The aim was to characterize alterations in cerebral dopamine D₂/D₃ receptor density and glucose utilization in a newly developed AAV-mediated NHP model of HD that expresses mHTT throughout numerous brain regions. Methods: Positron emission tomography (PET) imaging was performed using [¹⁸F]fallypride to quantify D₂/D₃ receptor density and 2-[¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) to measure cerebral glucose utilization in these HD macaques. Results: Compared to controls, HD macaques showed significantly reduced dopamine D₂/D₃ receptor densities in basal ganglia (P < 0.05). In addition, HD macaques displayed significant glucose hypometabolism throughout the cortico-basal ganglia network (P < 0.05). Conclusions: [¹⁸F]Fallypride and [¹⁸F]FDG are PET imaging biomarkers of mHTT-mediated disease progression that can be used as noninvasive outcome measures in future therapeutic studies with this AAV-mediated HD macaque model.