Ooms Maarten, Rietjens Roma, Rangarajan Janaki Raman, Vunckx Kathleen, Valdeolivas Sara, Maes Frederik, Himmelreich Uwe, Fernandez-Ruiz Javier, Bormans Guy, Van Laere Koen, Casteels Cindy
Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium; MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium.
MoSAIC-Molecular Small Animal Imaging Centre, KU Leuven, Leuven, Belgium; Division of Nuclear Medicine, Department of Imaging and Pathology, KU Leuven and University Hospital Leuven, Leuven, Belgium.
Neurobiol Aging. 2014 Dec;35(12):2858-2869. doi: 10.1016/j.neurobiolaging.2014.06.010. Epub 2014 Jun 16.
Several lines of evidence imply early alterations in endocannabinoid and phosphodiesterase 10A (PDE10A) signaling in Huntington disease (HD). Using [(18)F]MK-9470 and [(18)F]JNJ42259152 small-animal positron emission tomography (PET), we investigated for the first time cerebral changes in type 1 cannabinoid (CB1) receptor binding and PDE10A levels in vivo in presymptomatic, early symptomatic, and late symptomatic HD (R6/2) mice, in relation to glucose metabolism ([(18)F]FDG PET), brain morphology (magnetic resonance imaging) and motor function. Ten R6/2 and 16 wild-type (WT) mice were investigated at 3 different time points between the age of 4 and 13 weeks. Parametric CB1 receptor and PDE10A images were anatomically standardized to Paxinos space and analyzed voxelwise. Volumetric microMRI imaging was performed to assess HD pathology. In R6/2 mice, CB1 receptor binding was decreased in comparison with WT in a cluster comprising the bilateral caudate-putamen, globus pallidus, and thalamic nucleus at week 5 (-8.1% ± 2.6%, p = 1.7 × 10(-5)). Longitudinal follow-up showed further progressive decline compared with controls in a cluster comprising the bilateral hippocampus, caudate-putamen, globus pallidus, superior colliculus, thalamic nucleus, and cerebellum (late vs. presymptomatic age: -13.7% ± 3.1% for R6/2 and +1.5% ± 4.0% for WT, p = 1.9 × 10(-5)). In R6/2 mice, PDE10A binding potential also decreased over time to reach significance at early and late symptomatic HD (late vs. presymptomatic age: -79.1% ± 1.9% for R6/2 and +2.1% ± 2.7% for WT, p = 1.5 × 10(-4)). The observed changes in CB1 receptor and PDE10A binding were correlated to anomalies exhibited by R6/2 animals in motor function, whereas no correlation was found with magnetic resonance imaging-based striatal volume. Our findings point to early regional dysfunctions in endocannabinoid and PDE10A signaling, involving the caudate-putamen and lateral globus pallidus, which may play a role in the progression of the disease in R6/2 animals. PET quantification of in vivo CB1 and/or PDE10A binding may thus be useful early biomarkers for HD. Our results also provide evidence of subtle motor deficits at earlier stages than previously described.
多项证据表明，亨廷顿舞蹈病（HD）患者体内内源性大麻素和磷酸二酯酶10A（PDE10A）信号通路存在早期改变。我们使用[¹⁸F]MK-9470和[¹⁸F]JNJ42259152小动物正电子发射断层扫描（PET）技术，首次对症状前、早期症状期和晚期症状期HD（R6/2）小鼠体内1型大麻素（CB1）受体结合和PDE10A水平的脑内变化进行了研究，并与葡萄糖代谢（[¹⁸F]FDG PET）、脑形态（磁共振成像）和运动功能进行了关联分析。在4至13周龄之间的3个不同时间点，对10只R6/2小鼠和16只野生型（WT）小鼠进行了研究。将参数化的CB1受体和PDE10A图像进行解剖学标准化，使其与帕西诺斯脑图谱空间相对应，并进行体素分析。采用容积式显微MRI成像评估HD病理状况。在R6/2小鼠中，与WT相比，在第5周时，双侧尾状核-壳核、苍白球和丘脑核组成的一个簇中，CB1受体结合减少（-8.1%±2.6%，p = 1.7×10⁻⁵）。纵向随访显示，与对照组相比，在双侧海马、尾状核-壳核、苍白球、上丘、丘脑核和小脑组成的一个簇中，CB1受体结合进一步逐渐下降（晚期与症状前期年龄相比：R6/2小鼠为-13.7%±3.1%，WT小鼠为+1.5%±4.0%，p = 1.9×10⁻⁵）。在R6/2小鼠中，PDE10A结合潜能也随时间下降，在早期和晚期症状期HD时达到显著水平（晚期与症状前期年龄相比：R6/2小鼠为-79.1%±1.9%，WT小鼠为+2.1%±2.7%，p = 1.5×10⁻⁴）。观察到的CB1受体和PDE10A结合变化与R6/2动物运动功能异常相关，而与基于磁共振成像的纹状体体积无相关性。我们的研究结果表明，内源性大麻素和PDE10A信号通路早期存在区域性功能障碍，涉及尾状核-壳核和外侧苍白球，这可能在R6/2动物疾病进展中起作用。因此，PET定量检测体内CB1和/或PDE10A结合可能是HD有用的早期生物标志物。我们的结果还提供了比先前描述更早阶段存在细微运动缺陷的证据。
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