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

Abstract

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. © 2022 International Parkinson and Movement Disorder Society.

In Vivo Cerebral Imaging of Mutant Huntingtin Aggregates Using11C-CHDI-180R PET in a Nonhuman Primate Model of Huntington Disease

“…Immunohistochemical studies using monoclonal antibodies for (m)HTT in this model have verified the formation of EM48-and 2B4-positive mHTT aggregates in these same brain regions (16,17). Furthermore, this macaque model shows working memory impairment and motor dysfunction (chorea, dystonia, tremor, incoordination) and develops structural and functional corticostriatal changes including mild atrophy, increased white matter diffusivity, reduced cerebral glucose metabolism, and altered striatal D 2/3 receptor density (17,18).…”

Alterations of fractional anisotropy throughout cortico-basal ganglia gray matter in a macaque model of Huntington’s Disease

“…striatal atrophy via T1-and T2-weighted MRI, alterations in white matter microstructure via DTI) ( Weiss et al, 2022 ). Recent positron emission tomography (PET) studies in this same cohort of animals revealed signatures of ongoing cortico-basal ganglia neurodegenerative processes, including reduced glucose utilization (F18-Fluorodeoxyglucose PET) and reduced D2/D3 receptor binding (F18-Fallypride PET) ( Weiss et al, 2023 ). Here, we continue to expand on the available set of biomarkers in this model by establishing that characteristics of gray matter diffusion are also altered early on and progress in severity over time.…”