Preclinical, Imaging, and Research Laboratories (PIRL), South Australian Health and Medical Research Institute (SAHMRI), Gilles Plains, Adelaide 5086, Australia.
National Imaging Facility, SAHMRI, Adelaide 5000, Australia.
ACS Chem Neurosci. 2024 Nov 6;15(21):4082-4091. doi: 10.1021/acschemneuro.4c00561. Epub 2024 Oct 17.
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, = 3) and OVT73 HD sheep (5.5 year old, = 3, and 11 year old, = 3). Region-of-interest and brain atlas labels were defined for regional analyses by using a sheep brain template. [F]fluorodeoxyglucose ([F]FDG) was employed to compare the regional brain glucose metabolism and variations in FDG uptake between control and HD sheep. We also used [F]fluoro-3,4-dihydroxyphenylalanine ([F]FDOPA) to compare the extent of striatal dysfunction and evaluated the binding potential (BP) 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 [F]FDG uptake in several cortical and subcortical brain regions ( < 0.05-0.01). No difference in [F]FDG uptake was observed between healthy controls and 11 year old HD sheep. Analysis of the [F]FDOPA BP 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 [F]FDG and decline of [F]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.
亨廷顿病 (HD) 是一种神经退行性疾病，会导致认知、运动、行为和睡眠障碍，随着时间的推移会导致进行性残疾，最终导致死亡。通过在具有良好特征的大型 HD 动物模型中进行额外的测试，可以加速新型治疗药物和成像探针的临床转化。我们初步横断面研究的主要目标是证明 HD 的独特转基因绵羊模型 (OVT73) 在正电子发射断层扫描 (PET) 成像中的可行性和实用性。在健康的美利奴绵羊 (6 岁，n = 3) 和 OVT73 HD 绵羊 (5.5 岁，n = 3 和 11 岁，n = 3) 中进行了 PET 成像研究。使用绵羊脑模板为区域分析定义了感兴趣区和脑图谱标签。[F]氟脱氧葡萄糖 ([F]FDG) 用于比较对照组和 HD 绵羊之间的区域性脑葡萄糖代谢和 FDG 摄取的变化。我们还使用[F]氟-3,4-二羟基苯丙氨酸 ([F]FDOPA) 来比较纹状体功能障碍的程度，并评估两组之间关键脑区的结合潜能 (BP)。与健康对照组和 11 岁的 HD 绵羊相比，5.5 岁的 HD 绵羊在几个皮质和皮质下脑区的[F]FDG 摄取显著增加 ( < 0.05-0.01)。健康对照组和 11 岁的 HD 绵羊之间的[F]FDG 摄取没有差异。[F]FDOPA BP 参数图的分析显示，与 6 岁的对照组绵羊相比，5.5 岁和 11 岁的 HD 绵羊的结合潜能降低。在这项首例研究中，我们展示了使用 PET 成像研究大脑葡萄糖代谢和多巴胺摄取的 HD 绵羊模型的有用性和有效性。使用[F]FDG 检测到离散的代谢异常模式，以及[F]FDOPA 摄取的下降，可能为在这些模型中定量检测与 HD 相关的早期变化提供了一种有用的方法，特别是在从无症状前阶段到 HD 的早期症状阶段的过渡期间。
