Veronese Mattia, Zanotti-Fregonara Paolo, Rizzo Gaia, Bertoldo Alessandra, Innis Robert B, Turkheimer Federico E
Department of Neuroimaging, IoPPN, King's College London, London, UK.
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA; INCIA UMR-CNRS 5287, Université de Bordeaux, Bordeaux, France.
Neuroimage. 2016 Apr 15;130:1-12. doi: 10.1016/j.neuroimage.2016.01.058. Epub 2016 Feb 2.
PET studies allow in vivo imaging of the density of brain receptor species. The PET signal, however, is the sum of the fraction of radioligand that is specifically bound to the target receptor and the non-displaceable fraction (i.e. the non-specifically bound radioligand plus the free ligand in tissue). Therefore, measuring the non-displaceable fraction, which is generally assumed to be constant across the brain, is a necessary step to obtain regional estimates of the specific fractions. The nondisplaceable binding can be directly measured if a reference region, i.e. a region devoid of any specific binding, is available. Many receptors are however widely expressed across the brain, and a true reference region is rarely available. In these cases, the nonspecific binding can be obtained after competitive pharmacological blockade, which is often contraindicated in humans. In this work we introduce the genomic plot for estimating the nondisplaceable fraction using baseline scans only. The genomic plot is a transformation of the Lassen graphical method in which the brain maps of mRNA transcripts of the target receptor obtained from the Allen brain atlas are used as a surrogate measure of the specific binding. Thus, the genomic plot allows the calculation of the specific and nondisplaceable components of radioligand uptake without the need of pharmacological blockade. We first assessed the statistical properties of the method with computer simulations. Then we sought ground-truth validation using human PET datasets of seven different neuroreceptor radioligands, where nonspecific fractions were either obtained separately using drug displacement or available from a true reference region. The population nondisplaceable fractions estimated by the genomic plot were very close to those measured by actual human blocking studies (mean relative difference between 2% and 7%). However, these estimates were valid only when mRNA expressions were predictive of protein levels (i.e. there were no significant post-transcriptional changes). This condition can be readily established a priori by assessing the correlation between PET and mRNA expression.
正电子发射断层扫描（PET）研究能够对脑内受体种类的密度进行活体成像。然而，PET信号是与靶受体特异性结合的放射性配体部分和不可置换部分（即组织中非特异性结合的放射性配体加上游离配体）的总和。因此，测量通常假定在脑内恒定的不可置换部分，是获得特异性部分区域估计值的必要步骤。如果有一个参考区域，即一个没有任何特异性结合的区域，就可以直接测量不可置换结合。然而，许多受体在脑内广泛表达，真正的参考区域很少见。在这些情况下，可以通过竞争性药理阻断来获得非特异性结合，但这在人体中往往是禁忌的。在这项工作中，我们引入了基因组图，仅使用基线扫描来估计不可置换部分。基因组图是对拉森图形法的一种变换，其中从艾伦脑图谱获得的靶受体mRNA转录本的脑图谱被用作特异性结合的替代指标。因此，基因组图无需药理阻断就能计算放射性配体摄取的特异性和不可置换成分。我们首先通过计算机模拟评估了该方法的统计特性。然后，我们使用七种不同神经受体放射性配体的人体PET数据集寻求真值验证，其中非特异性部分要么通过药物置换单独获得，要么从真正的参考区域获得。通过基因组图估计的总体不可置换部分与实际人体阻断研究测量的结果非常接近（平均相对差异在2%至7%之间）。然而，这些估计仅在mRNA表达能够预测蛋白质水平时才有效（即不存在显著的转录后变化）。通过评估PET与mRNA表达之间的相关性，可以很容易地预先确定这种情况是否成立。
