Institute of Radiochemistry and Experimental Molecular Imaging, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937, Cologne, Germany.
Institute of Neuroscience and Medicine, Nuclear Chemistry (INM-5), Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428, Jülich, Germany.
Mol Neurobiol. 2022 Jun;59(6):3402-3413. doi: 10.1007/s12035-022-02793-8. Epub 2022 Mar 21.
Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [F]PI-2620 for tau deposition, [F]DPA-714 for TSPO expression associated with neuroinflammation, and [F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n = 8) and non-transgenic littermates (n = 8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients.
大脑葡萄糖代谢低下是阿尔茨海默病（AD）的典型标志，通常与持续的神经退行性变和神经元功能障碍有关。然而，其潜在的病理过程尚不完全清楚，并且在动物模型中的重现性也尚未得到很好的证实。本研究的目的是使用正电子发射断层扫描（PET）示踪剂[F]PI-2620 测量的葡萄糖代谢低下与 AD 病理生理学的各种分子靶点之间的区域相关性，[F]DPA-714 用于与神经炎症相关的 TSPO 表达，以及[F]UCB-H 用于突触密度，在转基因 tau 病小鼠模型中。使用上述示踪剂在小动物 PET 扫描仪中检查 7 个月大的 rTg4510 小鼠（n=8）和非转基因同窝小鼠（n=8）。rTg4510 小鼠的整个前脑均观察到代谢低下。tau 病理学、TSPO 表达增加和突触丢失在皮质和海马中均有共定位，与代谢低下相关。然而，在丘脑，代谢低下发生在没有 tau 相关病理学的情况下。因此，大脑代谢低下与两种区域不同的分子病理学形式有关：（1）包括突触退化和神经炎症的阿尔茨海默病型特征性神经病理学，与大脑皮质中的 tau 沉积共定位，（2）在没有 AD 病理生理学其他标志物的情况下，丘脑的病理变化，可能反映了下游或远程的适应过程，可能会影响功能连接。我们的研究证明了多示踪剂方法在小动物模型中探索复杂的 AD 病理机制相互作用的可行性。这些观察结果表明，多种空间异质性的病理机制可能导致 AD 小鼠模型中观察到的代谢低下，并促使未来进行纵向研究以及在人类患者中研究可能类似的病理机制。
