目的:在临床前研究中,使用[18F]氟脱氧葡萄糖(FDG)作为神经变性的生物标志物,可能由于免疫细胞对葡萄糖的摄取增强而引起偏倚.在这项研究中,我们试图在两种代表阿尔茨海默病(AD)病理标志的小鼠模型中研究突触小泡糖蛋白2A(SV2A)PET和[18F]UCB-H作为神经退行性过程的替代临床前生物标志物。
方法:总共29个PS2APP,年龄为4.4至19.8个月的20只P301S和12只野生型小鼠在注射后0-60分钟接受动态[18F]UCB-HSV2A-PET扫描(14.7±1.5MBq)。皮质示踪剂摄取的定量,小脑和脑干目标区域是通过从图像衍生输入函数(IDIF)计算相对分布体积(VT)来实现的。在转基因和野生型小鼠之间的所有靶区域比较[18F]UCB-H结合。在小鼠的亚组中进行额外的静态扫描以比较[18F]FDG和[18F]GE180(作为小胶质细胞活化的替代的18kDa转运蛋白示踪剂)标准化摄取值(SUV)与[18F]UCB-H结合在不同年龄。在最后的扫描之后,用突触标记进行免疫组织化学染色,以验证PET结果的金标准.
结果:与野生型对照相比,[18F]在8月龄P301S转基因小鼠中所有靶区域中的UCB-H结合显著降低(颞叶:p=0.014;小脑:p=0.0018;脑干:p=0.0014)。在13个月大(颞叶:p=0.0080;小脑:p=0.006)和19个月大(颞叶:p=0.0042;小脑:p=0.011)PS2APP转基因小鼠与野生型小鼠相比,而脑干显示[18F]UCB-H结合没有明显改变。死后小鼠脑组织的免疫组织化学分析证实了SV2APET发现。使用Pearson相关系数对[18F]UCB-H和[18F]FDG进行的相关分析显示,在PS2APP小鼠模型中存在显着的负相关(R=-0.26,p=0.018)。探索性分析进一步强调小胶质细胞激活是这种反比关系的潜在原因,因为[18F]FDG和[18F]GE180定量在该队列中呈正相关(R=0.36,p=0.0076).
结论:[18F]UCB-H可靠地描述了PS2APP和P301S转基因小鼠的进行性突触丢失,作为临床前研究中评估神经变性的生物标志物,有可能成为[18F]FDG更可靠的替代药物。
In preclinical research, the use of [18F]Fluorodesoxyglucose (FDG) as a biomarker for neurodegeneration may induce bias due to enhanced glucose uptake by immune cells. In this study, we sought to investigate synaptic vesicle glycoprotein 2A (
SV2A) PET with [18F]UCB-H as an alternative preclinical biomarker for neurodegenerative processes in two mouse models representing the pathological hallmarks of Alzheimer\'s disease (AD).
A total of 29 PS2APP, 20 P301S and 12 wild-type mice aged 4.4 to 19.8 months received a dynamic [18F]UCB-H
SV2A-PET scan (14.7 ± 1.5 MBq) 0-60 min post injection. Quantification of tracer uptake in cortical, cerebellar and brainstem target regions was implemented by calculating relative volumes of distribution (VT) from an image-derived-input-function (IDIF). [18F]UCB-H binding was compared across all target regions between transgenic and wild-type mice. Additional static scans were performed in a subset of mice to compare [18F]FDG and [18F]GE180 (18 kDa translocator protein tracer as a surrogate for microglial activation) standardized uptake values (SUV) with [18F]UCB-H binding at different ages. Following the final scan, a subset of mouse brains was immunohistochemically stained with synaptic markers for gold standard validation of the PET results.
[18F]UCB-H binding in all target regions was significantly reduced in 8-months old P301S transgenic mice when compared to wild-type controls (temporal lobe: p = 0.014; cerebellum: p = 0.0018; brainstem: p = 0.0014). Significantly lower
SV2A tracer uptake was also observed in 13-months (temporal lobe: p = 0.0080; cerebellum: p = 0.006) and 19-months old (temporal lobe: p = 0.0042; cerebellum: p = 0.011) PS2APP transgenic versus wild-type mice, whereas the brainstem revealed no significantly altered [18F]UCB-H binding. Immunohistochemical analyses of post-mortem mouse brain tissue confirmed the
SV2A PET findings. Correlational analyses of [18F]UCB-H and [18F]FDG using Pearson\'s correlation coefficient revealed a significant negative association in the PS2APP mouse model (R = -0.26, p = 0.018). Exploratory analyses further stressed microglial activation as a potential reason for this inverse relationship, since [18F]FDG and [18F]GE180 quantification were positively correlated in this cohort (R = 0.36, p = 0.0076).
[18F]UCB-H reliably depicts progressive synaptic loss in PS2APP and P301S transgenic mice, potentially qualifying as a more reliable alternative to [18F]FDG as a biomarker for assessment of neurodegeneration in preclinical research.