VALIDATION OF NEUROIMAGING BIOMARKERS FOR NIGROSTRAITAL NEURONS

描述（由申请人提供）：帕金森病（PD）影响北美超过100万人，并且没有治疗被证明可以减缓进展。为了开发和测试新的干预措施来减缓疾病进展，我们必须有经过验证的生物标志物来反映可逆或可改变的病理过程。越来越多的证据表明，选择性的弱点，黑质纹状体多巴胺能神经元的不同部分，因此，生物标志物，反映病理过程的不同方面可能是至关重要的，以开发这些新的疗法。我们在这项提议的前3年的初步研究已经阐明了神经影像学生物标志物如何反映黑质纹状体神经元的潜在病理过程。我们有数据比较非人灵长类动物在给予不同剂量的单侧颈动脉内MPTP后两个月的神经影像学测量与体外测量，表明纹状体摄取[18 F]FD（主要反映脱羧酶活性），[11 C]CFT（多巴胺转运标记，DAT）和[11 C]DTBZ（囊泡单胺转运蛋白2型）反映纹状体多巴胺含量，但仅反映黑质DA细胞体，如果黑质神经元的损失不超过50%。我们还表明，在体外定量放射自显影DAT和VMAT2突触前位点不差异调节黑质纹状体神经元的数量减少。随着黑质纹状体神经元数量的减少，纹状体摄取FD、DTBZ和CFT的PET测量值也发生几乎相同的变化。我们的研究结果表明，终端领域（纹状体DA和PET措施）有更大的损失比黑质细胞体在MPTP后2个月。我们也有初步的数据，基于MR的措施中脑平均扩散与黑质纹状体多巴胺能神经元的体视学计数。一些初步的研究表明，概率束跟踪可能能够量化黑质纹状体轴突。这些发现为本次更新中提出的研究奠定了基础。我们将测试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的不同组分中的时间依赖性变化的假设，并验证这些措施对体外措施，包括黑质中酪氨酸羟化酶（TH）免疫染色细胞体视学计数，TH染色纹状体纤维，DAT免疫染色纹状体纤维，纹状体多巴胺含量，纹状体中DAT和VMAT2位点的定量放射自显影和使用经验证的评定量表的运动行为的临床评定。此外，我们将检验左旋多巴或多巴胺激动剂普拉克索的急性或慢性给药可能改变选定的神经影像学生物标志物的假设。本研究将为靶向相关病理部位提供关键工具，以测试PD的新疗法。 公共卫生相关性：帕金森病（PD）在北美影响着100多万人，没有任何治疗方法被证明可以减缓病情进展。为了开发这种治疗方法，有必要对疾病进展的各种时间依赖性成分进行客观测量。本申请提出开发和验证这种神经成像生物标志物，并确定急性或慢性施用的常用药物是否影响这些生物标志物测量。这些生物标志物的开发和验证是靶向和测试帕金森病新疗法的关键步骤。

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. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) affects more than one million people in North America, and no treatment has been proven to slow progression. To develop such a treatment, it is necessary to have an objective measure of the various time-dependent components of disease progression. This application proposes to develop and validate such neuroimaging biomarkers and determine whether commonly used medications either acutely or chronically administered affects these biomarker measures. Development and validation of such biomarkers are critical steps for targeting and testing new therapies for Parkinson disease.