Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany.
Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.
Neuroimage. 2024 Aug 15;297:120748. doi: 10.1016/j.neuroimage.2024.120748. Epub 2024 Jul 26.
β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies.
Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13-16 months) were examined three times by Aβ-PET ([F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30-60 min p.i. standardized uptake value ratios (SUVR) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining.
All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆=20.4 % ± 2.9 %, ∆=18.4 % ± 4.5 %, ∆=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)=83.0 %, DC=69.3 %, DC=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (z=11.5 ± 1.6; z=5.3 ± 1.3; z=3.4 ± 0.6) and effect sizes (d=8.5, d=4.5, d=4.1). However, correlations at the individual mouse level were still strong between scanners (r=0.96, r=0.91, r=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028).
Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.
β-淀粉样蛋白（Aβ）小动物 PET 有助于量化阿尔茨海默病（AD）小鼠模型中的纤维状淀粉样蛋白病变。因此，该方法作为临床前药物试验中的监测工具越来越受到关注。在这方面，不同扫描仪在多个地点的数据的协调将允许建立大型合作队列，并可能有助于不同治疗方法的疗效比较。因此，我们旨在通过对头对头比较三种不同的最先进的小动物 PET 扫描仪来确定 Aβ-PET 定量的一致性水平，这有助于为未来的多中心研究铺平道路。
在 5±2 周的时间内，使用 Aβ-PET([F]florbetaben)对转基因 APPPS1(n=9)和野生型(WT)(n=8)小鼠进行三次检查，年龄范围为 13-16 个月) 使用西门子 Inveon DPET、MedisonanoScan PET/MR 和 MedisonanoScan PET/CT 进行检查，采用协调的重建协议。计算皮质与白质 30-60 分钟 p.i.的标准化摄取比值(SUVR)，以比较 APPPS1 与 WT 小鼠的结合差异、效应大小(Cohen's d)和 z 分数值。计算不同扫描仪之间个体 SUVR 一致性的相关系数(Pearson's r)。使用体素分析来确定空间病理模式的一致性。为了验证 PET 成像与组织学金标准的相关性，将个体 SUVR 值与 methoxy-X04 染色的面积占有率进行相关分析。
所有三种小动物 PET 扫描仪在 APPPS1 和 WT 小鼠之间产生了可比的组间差异(∆=20.4%±2.9%，∆=18.4%±4.5%，∆=18.1%±3.3%)。体素分析证实了空间模式的高度一致性(Dice 系数(DC)=83.0%，DC=69.3%，DC=81.9%)。三个扫描仪组水平方差的差异导致了不同的 z 分数(z=11.5±1.6；z=5.3±1.3；z=3.4±0.6)和效应大小(d=8.5，d=4.5，d=4.1)。然而，在个体小鼠水平上，扫描仪之间的相关性仍然很强(r=0.96，r=0.91，r=0.87；所有 p≤0.0001)。甲氧-X04 染色在所有三台 PET 机联合使用时具有显著相关性(r=0.76，p<0.0001)，在个体水平上也具有相关性(PET：r=0.81，p=0.026；PET/MR：r=0.89，p=0.0074；PET/CT：r=0.93，p=0.0028)。
我们对三种不同扫描仪采集的标准化小动物 Aβ-PET 的比较证实了在临床前 AD 研究中向多中心方法发展的可能性。图像采集和分析方法的调整实现了数据集之间的总体可比性。然而，不同扫描仪的灵敏度和特异性方差的差异可能会限制个体小鼠水平的数据解释，并值得进行方法优化。
