MediCity/PET Preclinical Laboratory, University of Turku, Turku PET Centre, Turku, Finland.
J Nucl Med. 2013 Aug;54(8):1434-41. doi: 10.2967/jnumed.112.110163. Epub 2013 Jul 5.
Follow-up of β-amyloid (Aβ) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer (11)C-Pittsburgh compound B ((11)C-PIB) to detect changes over time in Aβ deposition in the brains of living mice representing the APP23, Tg2576, and APP(swe)-PS1(dE9) transgenic mouse models of AD.
Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 7-9, 12, 15, and 18-22 mo of age. Regional (11)C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-to-free ratios in the late washout phase (40-60 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate (11)C-PIB binding to Aβ deposits. Additionally, the presence of Aβ deposits was evaluated in vitro using staining with thioflavin-S and Aβ1-40, Aβ1-16, and AβN3(pE) immunohistochemistry.
Neocortical (11)C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Aβ deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 ± 0.03 (n = 3) and 1.34 (n = 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7- to 12-mo-old) and old (15- to 22-mo-old) APP23 mice. Binding of (11)C-PIB to Aβ-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in (11)C-PIB retention were observed in aging Tg2576 or APP(swe)-PS1(dE9) mice in vivo, although in the latter, extensive Aβ deposition was already observed at 9 mo of age with immunohistochemistry.
The results suggest that (11)C-PIB binding to Aβ deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Aβ plaques. Longitudinal in vivo (11)C-PIB uptake studies are possible in APP23 mice.
评估临床应用的 PET 示踪剂 [(11)C]PIB（11）-匹兹堡化合物 B）是否能够检测到阿尔茨海默病（AD）转基因小鼠模型中 β-淀粉样蛋白（Aβ）沉积的随时间变化。
在 7-9、12、15 和 18-22 月龄时，用 60 分钟的动态 PET 扫描对来自每个转基因品系的小鼠进行成像。使用小脑参考输入的 Logan 图形分析定量区域（11）-PIB 保留作为分布容积比，作为 60 分钟扫描期间额皮质（FC）和小脑（CB）之间的放射性摄取比，以及晚期洗脱期（40-60 分钟）的结合与游离比。在最后一次成像后进行离体放射性自显影实验，以验证（11）-PIB 与 Aβ 沉积物的结合。此外，使用硫黄素-S 和 Aβ1-40、Aβ1-16 和 AβN3（pE）免疫组织化学染色体外评估 Aβ 沉积物的存在。
在有大量硫黄素-S 阳性 Aβ 沉积物的老年 APP23 小鼠中，新皮质（11）-PIB 保留明显增加。在 12 个月时，FC 的 Logan 分布容积比为 1.03 和 0.93（n=2），分别增加至 1.38±0.03（n=3）和 1.34（n=1）在 18 和 21 个月时。在年轻（7-12 月龄）和老年（15-22 月龄）APP23 小鼠之间，FC 的结合与游离比也观察到增加。（11）-PIB 与富含 Aβ 的皮质区域的结合在 APP23 脑切片的离体放射自显影图中也很明显。相比之下，在体内衰老的 Tg2576 或 APP（swe）-PS1（dE9）小鼠中未观察到（11）-PIB 保留的增加，尽管在后一种情况下，用免疫组织化学法已经在 9 月龄时观察到广泛的 Aβ 沉积。
结果表明，（11）-PIB 与转基因小鼠脑内 Aβ 沉积物的结合高度依赖于 AD 模型及其 Aβ 斑块的结构。在 APP23 小鼠中可以进行纵向体内（11）-PIB 摄取研究。
