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

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2024-11-06 Epub Date: 2024-10-17 DOI:10.1021/acschemneuro.4c00561
Georgia K Williams, Jordy Akkermans, Matt Lawson, Patryk Syta, Steven Staelens, Mohit H Adhikari, A Jennifer Morton, Björn Nitzsche, Johannes Boltze, Chris Christou, Daniele Bertoglio, Muneer Ahamed
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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 (BPND) 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 BPND 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.

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利用正电子发射断层扫描成像技术对绵羊(Ovis aries)大脑的葡萄糖代谢和多巴胺能功能障碍进行成像,发现 OVT73 亨廷顿氏病绵羊的异常。
亨廷顿氏病(Huntington's disease,HD)是一种神经退行性疾病,会引起认知、运动、行为和睡眠障碍,随着时间的推移会导致进行性残疾并最终死亡。通过在特征明确的大型 HD 动物模型中进行更多测试,可以加速新型疗法和成像探针的临床转化。我们的初步横断面研究的主要目标是证明独特的 HD 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。正电子发射断层成像研究在健康美利奴羊(6 岁,n = 3)和 OVT73 HD 羊(5.5 岁,n = 3 和 11 岁,n = 3)中进行。使用绵羊大脑模板为区域分析定义了感兴趣区和大脑图谱标签。我们使用[18F]氟脱氧葡萄糖([18F]FDG)来比较对照组和 HD 羊的区域脑糖代谢和 FDG 摄取的变化。我们还使用[18F]氟-3,4-二羟基苯丙氨酸([18F]FDOPA)比较了两组绵羊纹状体功能障碍的程度,并评估了两组绵羊主要脑区的结合电位(BPND)。与健康对照组和11岁的HD绵羊相比,5.5岁的HD绵羊在几个皮层和皮层下脑区的[18F]FDG摄取量明显增加(P < 0.05-0.01)。健康对照组和 11 岁 HD 羊的[18F]FDG 摄取量没有差异。对[18F]FDOPA BPND参数图的分析表明,与6岁的对照组绵羊相比,5.5岁和11岁的HD绵羊的结合潜力降低。在这项首创性研究中,我们利用 PET 成像技术展示了 HD 羊模型在脑葡萄糖代谢和多巴胺摄取成像中的实用性和有效性。利用[18F]FDG和[18F]FDOPA摄取量的下降识别代谢异常的离散模式,可为量化这些模型中与HD相关的早期变化提供有用的方法,尤其是在HD从症状前阶段向症状早期阶段过渡的过程中。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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