POSTMORTEM VALIDATION OF BIOMARKERS FOR IMAGING PARKINSON DISEASE

 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。迫切需要一种可靠的成像生物标志物来监测疾病进展和治疗效果。神经影像学生物标志物有可能提供PD进展的无偏测量，如黑质纹状体多巴胺能神经元的损失所示。我们之前评估了MPTP治疗猴中黑质纹状体神经元突触前标记物的三种不同PET示踪剂：[11C]DTBZ（囊泡单胺转运蛋白2型[VMAT 2]标记物），[11C]CFT（多巴胺转运[DAT]标记物）和[18 F]FD（主要反映大脑脱羧酶活性和储存）并且证明了这些中的每一种的纹状体摄取与黑质纹状体神经元的数量线性相关，但是仅当黑质纹状体神经元的损失不超过50%时。相反，这些示踪剂中的每一种都与用高效液相色谱法测量的纹状体多巴胺线性相关。我们最近发现，直接PET测量中脑摄取DTBZ或CFT确实与黑质细胞损失相关。然而，突触前神经元的变化与影响该通路功能的其他措施的关系仍不清楚。我们最近还报道，除皮质突触核蛋白病外，伴有β淀粉样蛋白病理的PD患者从PD运动发作或痴呆发作时起，进展至死亡的速度更快。这就提出了一个问题，即β淀粉样蛋白患者是否有不同的病理变化，导致这种更快的进展。在这个R 01中，我们将利用以前收集的人脑组织，以确定突触后多巴胺能标记物和相关的递质系统和黑质纹状体神经元的损失之间的关系。我们建议对VMAT 2、DAT、多巴胺受体进行定量放射自显影测量，（D1、D2、D3和D4）、胆碱能标志物囊泡乙酰胆碱转运蛋白（VAChT）和外周苯二氮卓受体（PBR），使用病理学良好表征的对照和PD脑（n=120，8组每组15人，男性和女性认知健康对照，无或有淀粉样蛋白-β（tau阴性），仅具有突触核蛋白病理学的PD和具有突触核蛋白加淀粉样蛋白-β的PD）。将系统分析这些生物标志物的纹状体（尾状核、壳核和丘脑核）和纹状体外（黑质、苍白球、丘脑和皮质）分布，以与雄性和雌性组的PD疾病持续时间和严重程度相关。然后，我们将确定哪种受体和放射性配体与多巴胺能神经元损失、多巴胺损失或运动评级具有最佳相关性。这项研究将为进一步验证 PD进展的神经影像学生物标志物。本研究对进一步了解帕金森病中多巴胺受体亚型在多巴胺传递和PBR调节中的功能作用具有重要意义。这将是第一项使用大型和病理学特征良好的PD和健康对照病例人群的综合研究。我们在进行D2和D2受体、神经炎症的定量放射自显影以及评估突触前和突触后多巴胺D2和D3受体方面处于独特的地位。这将是第一次交叉验证和有效的比较与这些生物标志物的系统性措施在相同的主题。

 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. A reliable imaging biomarker is urgently needed to monitor disease progression and therapy efficacy. Neuroimaging biomarkers have potential to provide unbiased measurements of PD progression, as indicated by loss of nigrostriatal dopaminergic neurons. We previously evaluated three different PET tracers for presynaptic markers of nigrostriatal neurons in MPTP-treated monkeys: [11C]DTBZ (a vesicular monoamine transporter type 2 [VMAT2] marker), [11C]CFT (a dopamine transport [DAT] marker) and [18F]FD (primarily reflects cerebral decarboxylase activity and storage) and demonstrated that striatal uptake of each of these linearly correlates with the number of nigrostriatal neurons but only when the loss of nigrostriatal neurons does not exceed 50%. In contrast, each of these tracers does linearly correlate with striatal dopamine as measured with high performance liquid chromatography. We recently found that direct PET measures of midbrain uptake of DTBZ or CFT does correlate with nigral cell loss. Yet, the relationship of changes in presynaptic neurons with other measures that affect function of this pathway remains unclear. We also recently reported that PD patients with amyloid-beta pathology in addition to cortical synucleinopathy have faster progression to death from either time of PD motor onset or time of dementia onset. This raises questions about whether those with amyloid-beta have different pathologic changes underlying this faster progression. In this R01, we will leverage human brain tissues collected previously, to determine the relationship between postsynaptic dopaminergic markers and related transmitter systems and the loss of nigrostriatal neurons. We propose to conduct quantitative autoradiography measures of the VMAT2, DAT, dopamine receptors (D1, D2, D3 and D4), cholinergic marker vesicular acetylcholine transporter (VAChT) and the peripheral benzodiazepine receptor (PBR) using pathologically well characterized control and PD brains (n=120, 15 each group for 8 groups, male and female cognitively healthy controls without or with amyloid-beta (tau negative), PD with only synuclein pathology and PD with synuclein plus amyloid-beta). Striatal (caudate, putamen and nucleus accumbens) and extra-striatal (substantia nigra, globus pallidus, thalamus and cortex) distribution of these biomarkers will be analyzed systematically to correlate with the PD disease duration and severity for both male and female groups. We then will determine which receptor and radioligand will have the best correlation with the dopaminergic neuron loss, dopamine loss or motor ratings. This study will provide a critical step for further validation of a neuroimaging biomarker of PD progression in clinic. The studies proposed in this grant have great potential on extending our understanding of the functional roles of dopamine receptor subtypes on dopamine transmission and PBR regulation in the PD. This will be the first comprehensive study using a large and pathologically well characterized population of PD and healthy control cases. We are in a unique position to conduct quantitative autoradiography of D2 and D2 receptors, neuroinflammation and evaluate the pre- and postsynaptic dopamine D2 and D3 receptors. This will be the first cross validation and valid comparisons with systematic measures of these biomarkers in the same subjects.