Departments of Neurology, Washington University, St Louis, MO.
Ann Neurol. 2013 Mar;73(3):390-6. doi: 10.1002/ana.23798. Epub 2013 Feb 19.
Molecular imaging and clinical endpoints are frequently discordant in Parkinson disease clinical trials, raising questions about validity of these imaging measures to reflect disease severity. We compared striatal uptake for 3 positron emission tomography (PET) tracers with in vitro measures of nigral cell counts and striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.
Sixteen macaques had magnetic resonance imaging and baseline PETs using 6-[18F]fluorodopa (FD), [11C]dihydrotetrabenazine (DTBZ), and 2beta-[11 C]carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). MPTP (0-0.31 mg/kg) infused unilaterally via the internal carotid artery produced stable hemiparkinsonism by 3 weeks. After 8 weeks, PETs were repeated and animals were euthanized for striatal dopamine measurements and unbiased counts of tyrosine hydroxylase-stained nigral cells.
Striatal uptake for each radiotracer (FD, DTBZ, CFT) correlated with stereologic nigral cell counts only for nigral loss<50% (r2=0.84, r2=0.86, r2=0.87, p<0.001 respectively; n=10). In contrast, striatal uptake correlated with striatal dopamine over the full range of dopamine depletion (r2=0.95, r2=0.94, r2=0.94, p<0.001; n=16). Interestingly, indices of striatal uptake of FD, DTBZ, and CFT correlated strongly with each other (r2=0.98, p<0.001).
Tracer uptake correlated with nigral neurons only when nigral loss was <50%. This along with previous work demonstrating that nigral cell counts correlate strongly with parkinsonism ratings may explain discordant results between neuroimaging and clinical endpoints. Furthermore, strong correlations among striatal uptake for these tracers support lack of differential regulation of decarboxylase activity (FD), vesicular monoamine transporter type 2 (DTBZ), and dopamine transporter (CFT) within 2 months after nigrostriatal injury.
在帕金森病临床试验中，分子成像和临床终点经常不一致，这引发了对这些成像测量反映疾病严重程度的有效性的质疑。我们比较了在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的猴子中，3 种正电子发射断层扫描（PET）示踪剂的纹状体摄取与体外黑质细胞计数和纹状体多巴胺的关系。
16 只猕猴进行了磁共振成像和基线 PET 检查，使用 6-[18F]氟多巴（FD）、[11C]二氢四苯并嗪（DTBZ）和 2β-[11C]碳甲氧基-3β-（4-氟苯基）托烷（CFT）。通过颈内动脉单侧输注 MPTP（0-0.31mg/kg），3 周后产生稳定的偏侧帕金森病。8 周后，重复 PET 检查，处死动物测量纹状体多巴胺，并对酪氨酸羟化酶染色的黑质细胞进行无偏计数。
每个放射性示踪剂（FD、DTBZ、CFT）的纹状体摄取仅与黑质损失<50%的立体学黑质细胞计数相关（r2=0.84、r2=0.86、r2=0.87，p<0.001；n=10）。相比之下，纹状体摄取与纹状体多巴胺在多巴胺耗竭的全范围内相关（r2=0.95、r2=0.94、r2=0.94，p<0.001；n=16）。有趣的是，FD、DTBZ 和 CFT 的纹状体摄取指数彼此之间高度相关（r2=0.98，p<0.001）。
当黑质损失<50%时，示踪剂摄取与黑质神经元相关。这与先前的研究表明，黑质细胞计数与帕金森病评分密切相关，这可能解释了神经影像学和临床终点之间的不一致结果。此外，这些示踪剂在纹状体摄取方面的强烈相关性支持在黑质纹状体损伤后 2 个月内，脱羧酶活性（FD）、囊泡单胺转运体 2（DTBZ）和多巴胺转运体（CFT）的调节没有差异。
