Novel reference region model reveals increased microglial and reduced vascular binding of 11C(R)-PK11195 in patients with Alzheimer's disease
Novel reference region model reveals increased microglial and reduced vascular binding of 11C(R)-PK11195 in patients with Alzheimer's disease
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DOI：
10.2967/jnumed.108.050583
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发表时间：
2008-08-01
影响因子：
9.3
通讯作者：
Turkheimer, Federico E.
中科院分区：
文献类型：
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作者：
Tomasi, Giampaolo;Edison, Paul;Turkheimer, Federico E.
（11）C-（R）-PK 11195是一种PET自由基示踪剂，用于定量外周苯二氮卓类药物结合位点（PBBS）。PBBS是活化的小胶质细胞的一致标志物，并且（11）C-（R）-PK 11195已被用于成像患病脑和瘤形成中的小胶质细胞活性。然而，PBBS也在脑血管系统（内皮和平滑肌）中表达，并且据我们所知，没有证据表明病理性脑中血管PBBS的变化或这种变化对（11）C-（R）-PK 11195结合的定量有影响。为了研究这个问题，我们已经使用了一个修改的参考组织模型（SRTMV），占示踪血管活动在参考和靶组织，并将其应用于估计的结合潜力（BP）在一个队列的阿尔茨海默病（AD）患者。方法：共10例AD患者和10名年龄匹配的健康受试者接受了（11）C-（R）-PK 11195扫描。使用Hammersmith最大概率图谱提取11个感兴趣区域的时间-活性曲线。首先使用标准简化参考组织模型（SRTM）估计BP，其中参考组织使用监督选择算法计算。随后，我们应用了SRTMV，其使用针对靶（V B（T））和参考（V B（R））区域两者的额外线性项来对PBBS血管活动进行建模，其中考虑血管示踪剂活动（C（B）），而C（B）直接从图像中提取。Vb（R）固定为5%，并估计R（1）、k（2）、BP和Vb（T）。还通过免疫细胞化学对年轻人和老年人对照组和3例AD死后脑的单独队列进行血管系统中的PBBS密度评估。结果如下：在SRTM中加入血管成分增加了所有受试者的BP，但增加的量不同（对照组约为11.9%，AD患者为16.8%）。此外，使用SRTMV得出的对照组平均Vb（T）值为4.22%，但AD患者仅为2.87%。免疫组化显示，由于血管纤维化，AD中PBBS表达减少。结论：AD患者Vb（T）降低可解释为两种独立但同时存在的现象。AD脑内血管纤维化导致管腔尺寸减小和血容量减少。同时，纤维化过程决定了血管PBBS的损失，特别是在平滑肌中，如本文通过免疫化学记录的。在SRTM中纳入额外的血管组分有效地模拟了这2个并发过程，并且由于疾病队列中与血管系统结合的示踪剂减少，AD中的BP比对照中的BP更大。
(11)C-(R)-PK11195 is a PET radictracer for the quantification of peripheral benzodiazepine binding sites (PBBSs). The PBBS is a consistent marker of activated microglia, and (11)C-(R)-PK11195 has been used to image microglial activity in the diseased brain and in neoplasia. However, the PBBS is also expressed in the brain vasculature (endothelium and smooth muscles), and no evidence, to our knowledge, exists of a change in the vascular PBBS in pathologic brains or of such a change having an effect on the quantification of (11)C-(R)-PK11195 binding. To investigate this issue, we have used a modified reference-tissue model (SRTMV) that accounts for tracer vascular activity both in reference and target tissues and applied it for the estimation of binding potential (BP) in a cohort of patients with Alzheimer's disease (AD). Methods: A total of 10 patients with AD and 10 age-matched healthy subjects who underwent a (11)C-(R)-PK11195 scan were considered in the analysis. The time-activity curves of 11 regions of interest were extracted using the Hammersmith maximum probability atlas. BPs were first estimated using the standard simplified reference-tissue model (SRTM) with the reference tissue computed with a supervised selection algorithm. Subsequently, we applied an SRTMV that models PBBS vascular activity using an additional linear term for both target (Vb(T)) and reference (Vb(R)) regions accounting for vascular tracer activity (C(B)), whereas C(B) was extracted directly from the images. Vb(R) was fixed to 5%, and R(1), k(2), BP, and Vb(T) were estimated. PBBS density in the vasculature was also assessed by immunocytochemistry on a separate cohort of young and elderly controls and 3 AD postmortem brains. Results: The inclusion of a vascular component in the SRTM increased BPs in all subjects, but the amount of the increase was different (about 11.9% in controls and 16.8% in patients with AD). In addition, average Vb(T) values derived using the SRTMV were 4.22% for controls but only 2.87% in patients with AD. Immunochemistry showed reduced PBBS expression in AD due to vascular fibrosis. Conclusion: The reduction of Vb(T) in AD can be interpreted as a consequence of 2 independent but concurring phenomena. The vascular fibrosis in the AD brain causes the well-documented decrease of the size of lumens and the reduction of blood volume. At the same time, the fibrotic process determines the loss of vascular PBBS, particularly in smooth muscles, as here documented by immunochemistry. The inclusion of the additional vascular component in the SRTM effectively models these 2 concurrent processes and amplifies the BP in AD more than in controls because of the decrease in tracer binding to the vasculature in the disease cohort.