Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany.
German Center for Neurodegenerative Diseases Munich, Munich, Germany.
J Nucl Med. 2022 Jan;63(1):117-124. doi: 10.2967/jnumed.120.261858. Epub 2021 May 20.
β-amyloid (Aβ) PET is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and nonfibrillar Aβ components to the in vivo Aβ PET signal remain unclear. Thus, we obtained 2 murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ PET signal in vivo. We investigated groups of and APPPS1 mice at 3, 6, and 12 mo of age by longitudinal F-florbetaben Aβ PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group-level intermodality regression models using age- and genotype-matched sets of fibrillar and nonfibrillar Aβ data (predictors) and Aβ PET results (outcome) for both Aβ mouse models. An independent group of double-hit APPPS1 mice with dysfunctional microglia due to knockout of triggering receptor expression on myeloid cells 2 (Trem2) served for validation and evaluation of translational impact. Neither fibrillar nor nonfibrillar Aβ content alone sufficed to explain the Aβ PET findings in either AD model. However, a regression model compiling fibrillar and nonfibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ PET signal ( < 0.001). Fibrillar Aβ burden had a 16-fold higher contribution to the Aβ PET signal than nonfibrillar Aβ. However, given the relatively greater abundance of nonfibrillar Aβ, we estimate that nonfibrillar Aβ produced 79% ± 25% of the net in vivo Aβ PET signal in mice and 25% ± 12% in APPPS1 mice. Corresponding results in separate groups of APPPS1/Trem2 and APPPS1/Trem2 mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ PET signal. Taken together, the in vivo Aβ PET signal derives from the composite of fibrillar and nonfibrillar Aβ plaque components. Although fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of nonfibrillar Aβ plaque in AD-model mice contributes importantly to the PET signal.
β-淀粉样蛋白（Aβ）PET 是定量疑似阿尔茨海默病（AD）患者和转基因 AD 小鼠模型脑内淀粉样蛋白的重要工具。尽管 Aβ PET 与金标准免疫组织化学评估具有极好的相关性，但纤维状和非纤维状 Aβ 成分对体内 Aβ PET 信号的相对贡献仍不清楚。因此，我们获得了两种具有不同 Aβ 斑块组成的小鼠脑淀粉样变性模型，并通过 Aβ PET 进行免疫组织化学分析进行回归分析，以确定体内 Aβ PET 信号的生化贡献。我们通过纵向 F-氟比苯丙胺 Aβ PET 以及纤维状和总 Aβ 负荷的免疫组织化学分析，研究了 3、6 和 12 月龄的 和 APPPS1 小鼠组。然后，我们使用年龄和基因型匹配的纤维状和非纤维状 Aβ 数据（预测因子）和 Aβ PET 结果（结果）为两种 Aβ 小鼠模型应用组级的模态间回归模型。一组由于髓样细胞触发受体表达 2（Trem2）缺失而功能失调的 APPPS1 双打击小鼠用于验证和评估转化影响。单独的 APPPS1/Trem2 小鼠组由于 Trem2 缺失导致纤维状 Aβ 负荷增加，而非纤维状 Aβ 负荷减少，而非纤维状 Aβ 对 Aβ PET 信号的贡献也相应减少。在 APPPS1/Trem2 小鼠中，Aβ PET 信号的 79%±25%归因于非纤维状 Aβ，25%±12%归因于纤维状 Aβ。在 APPPS1/Trem2 小鼠中，Aβ PET 信号的 79%±25%归因于非纤维状 Aβ，25%±12%归因于纤维状 Aβ。APPPS1/Trem2 小鼠的单独分组验证了计算出的回归因子，并表明由于 Trem2 缺失导致的纤维状改变会影响 Aβ PET 信号。总之，体内 Aβ PET 信号源自纤维状和非纤维状 Aβ 斑块成分的组合。尽管纤维状 Aβ 固有地具有更高的 PET 示踪剂结合，但 AD 模型小鼠中非纤维状 Aβ 斑块的丰度对 PET 信号的贡献更为重要。
