Overhoff Felix, Brendel Matthias, Jaworska Anna, Korzhova Viktoria, Delker Andreas, Probst Federico, Focke Carola, Gildehaus Franz-Josef, Carlsen Janette, Baumann Karlheinz, Haass Christian, Bartenstein Peter, Herms Jochen, Rominger Axel
Department of Nuclear Medicine, Ludwig-Maximilians-University of Munich Munich, Germany.
DZNE-German Center for Neurodegenerative DiseasesMunich, Germany; Laboratory of Neurodegeneration, International Institute of Molecular and Cell BiologyWarsaw, Poland.
Front Neurosci. 2016 Feb 29;10:45. doi: 10.3389/fnins.2016.00045. eCollection 2016.
Preclinical PET studies of β-amyloid (Aβ) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Aβ-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Aβ burden (N = 40) were investigated by [(18)F]-florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (κ). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX∕REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all κ≥0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX∕REF. All SUVRCTX∕REF methods performed better than SUVCTX both with regard to longitudinal stability (d≥1.21 vs. d = 0.23) and histological gold standard agreement (R≥0.66 vs. R≥0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R mean = 0.75) was slightly superior to the brainstem (R mean = 0.74) and the cerebellum (R mean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Aβ-PET scans. Intracerebral reference regions lacking Aβ pathology serve for precise longitudinal in vivo quantification of [(18)F]-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria.
β-淀粉样蛋白（Aβ）积聚的临床前正电子发射断层扫描（PET）研究日益重要，但研究地点之间的比较需要标准化和优化的定量方法。因此，我们旨在在一个大型转基因小鼠数据集中系统评估：（1）一种用于脑空间归一化的自动化算法的影响，以及（2）不同参考区域对Aβ-PET的强度缩放方法。通过[¹⁸F] - 氟比他班PET研究了6周纵向观察期的PS2APP小鼠（N = 37）以及另一组组织学评估的Aβ负荷范围较窄的PS2APP小鼠（N = 40）。在应用自动化脑空间归一化之前，由三名不同训练水平的阅片者进行手动空间归一化，并通过Fleiss Kappa（κ）评估阅片者间的一致性。对于该方法，研究了不同病理阶段模板的影响。使用四个不同的脑摄取归一化参考区域来计算相对于原始额叶皮质标准化摄取值（SUVCTX）的额叶皮质标准化摄取值比率（SUVRCTX∕REF）。基于纵向稳定性（Cohen's d）并参考金标准组织病理学定量（Pearson's R）对结果进行比较。应用自动化脑空间归一化导致不同阅片者之间几乎完全一致（所有κ≥0.99），与组织学的相关性保持不变或有所改善。基于不适当病理阶段的模板导致SUVRCTX∕REF出现高达2.9%的系统偏差。就纵向稳定性（d≥1.21对比d = 0.23）和与组织学金标准的一致性（R≥0.66对比R≥0.31）而言，所有SUVRCTX∕REF方法均比SUVCTX表现更好。体素分析表明，全局平均缩放导致生理上不合理的纵向下降。后脑白质参考区域（R均值 = 0.75）略优于脑干（R均值 = 0.74）和小脑（R均值 = 0.73）。使用参考区域模板进行自动化脑归一化是一种避免临床前Aβ-PET扫描阅片者间变异性的出色方法。缺乏Aβ病理的脑内参考区域可用于[¹⁸F] - 氟比他班PET的精确纵向体内定量。考虑质量标准综合情况时，后脑白质参考区域表现最佳。
