VALIDATION OF NEUROIMAGING BIOMARKERS FOR NIGROSTRAITAL NEURONS

描述（由申请人提供）：帕金森病（PD）在北美影响超过100万人，没有任何治疗方法被证明可以减缓其进展。为了开发和测试减缓疾病进展的新干预措施，我们必须验证反映可逆或可改变病理过程的生物标志物。越来越多的证据表明，黑质纹状体多巴胺能神经元的不同部分选择性易感性；因此，反映病理过程不同方面的生物标志物可能对开发这些新疗法至关重要。我们在前3年的初步研究已经阐明了神经成像生物标志物如何反映黑质纹状体神经元的潜在病理过程。在给予不同剂量的单侧颈动脉内MPTP两个月后，我们对非人灵长类动物的神经影像学测量与体外测量进行了数据比较，结果表明纹状体摄取[18F]FD（主要反映脱羧酶活性）、[11C]CFT（一种多巴胺转运标志物，DAT）和[11C]DTBZ（一种囊泡单胺转运蛋白2型）反映纹状体多巴胺含量，但如果黑质神经元的损失不超过50%，则只反映黑质DA细胞体。我们还通过体外定量放射自显影证明，随着黑质纹状体神经元数量的减少，DAT和VMAT2突触前位点没有差异调节。纹状体摄取FD、DTBZ和CFT的PET测量也随着黑质纹状体神经元数量的减少而发生几乎相同的变化。我们的研究结果显示，在MPTP后2个月，终端场（纹状体DA和PET测量）比黑质细胞体损失更大。我们也有初步数据表明，基于核磁共振的中脑平均扩散率测量与黑质纹状体多巴胺能神经元的体视学计数相关。一些初步研究表明，概率道追踪可能能够量化黑质纹状体轴突。总之，这些发现为这次更新中提出的研究奠定了基础。我们将验证这些新验证的神经成像生物标志物可以检测黑质纹状体多巴胺能神经元不同成分的时间依赖性变化的假设，并通过体外测量验证这些措施，包括黑质中酪氨酸羟化酶（TH）免疫染色的细胞体计数，TH染色的纹状体纤维，DAT免疫染色的纹状体纤维，纹状体多巴胺含量，纹状体DAT和VMAT2位点的定量放射自显影和使用有效评定量表的运动行为的临床评定。此外，我们将验证急性或慢性左旋多巴或多巴胺激动剂普拉克索可能改变选定的神经成像生物标志物的假设。该研究将为PD的相关病理部位的靶向治疗提供重要工具。

DESCRIPTION (provided by applicant): Parkinson disease (PD) affects more than one million people in North America, and no treatment has been proven to slow progression. To develop and test new interventions to slow disease progression, we must have validated biomarkers that reflect reversible or modifiable pathologic processes. Increasing evidence suggests selective vulnerability to different parts of nigrostriatal dopaminergic neurons; thus biomarkers that reflec different aspects of pathologic processes may be critical to develop these new therapies. Our initial studies in the first 3 years of this proposal have clarified how neuroimaging biomarkers reflect underlying pathologic processes of nigrostriatal neurons. We have data comparing neuroimaging measures with in vitro measures in nonhuman primates two months after giving different doses of unilateral intracarotid MPTP indicating that striatal uptake of [18F]FD (primarily reflecting decarboxylase activity), [11C]CFT (a dopamine transport marker, DAT) and [11C]DTBZ (a vesicular monoamine transporter type 2) reflect striatal dopamine content but only reflect nigral DA cell bodies if the loss of nigral neurons does not exceed 50%. We also demonstrated with in vitro quantitative autoradiography that DAT and VMAT2 presynaptic sites do not differentially regulate as the number nigrostriatal neurons decreases. PET measures of striatal uptake of FD, DTBZ and CFT also change nearly identifically as the number of nigrostriatal neurons decreases. Our results reveal that terminal fields (striatal DA and the PET measures) have greater loss than nigral cell bodies at 2 months post MPTP. We also have preliminary data that MR-based measures of midbrain mean diffusivity correlate with stereologic counts of nigrostriatal dopaminergic neurons. Some initial studies suggest that probablistic tract tracing may be able to quantify nigrostriatal axons. Together these findings set the stage for the studies proposed in this renewal. We will test the hypothesis that these newly validated neuroimaging biomarkers can detect time-dependent changes in different components of nigrostriatal dopaminergic neurons and validate these measures against in vitro measures including stereologic counts of tyrosine hydroxylase (TH) immunostained cell bodies in nigral, TH-stained striatal fibers, DAT immunostained striatal fibers, striatal dopamine content, quantitative autoradiography of DAT and VMAT2 sites in striatum and clinical ratings of motor behaviors using validated rating scales. In addition, we will test the hypothesis that acute or chronic administration of levodopa or the dopamine agonist pramipexole may alter selected neuroimaging biomarkers. This study will provide the critical tools for targeting the relevant pathologic sites for testing new therapies for PD.