In vivo synaptic and dopamine transporter imaging in Parkinson's disease

项目摘要/摘要 需要开发更好的生物标记物和更有效的治疗帕金森病(PD)是当务之急。 这项拟议的研究项目应用新的分子神经成像方法来直接研究突触。 以及帕金森病患者多巴胺转运体(DAT)的正电子发射断层扫描(PET)成像 开发了示踪剂，11C-UCB-J用于突触密度，18FE-PE2I用于DAT。 这项研究将对60名帕金森病患者进行详细的比较，每个患者20名，在不同的临床 阶段(Hoehn和Yahr阶段1-3)和11C-UCB-J(目标1)。我们假设会有一个地区性的 帕金森病患者大脑主要感兴趣区的突触缺陷模式将首先包括 皮质下核团，然后扩散到前额叶和运动皮质，早于 从尾端到嘴端的预测 进化 模特。 使用第一个目标中的受试者子集，15PD 处于疾病不同临床阶段的受试者将在两年后接受纵向变化检查。 (目标2)。我们预计示踪剂将对每个临床阶段的变化敏感，带有皮质突触 密度的降低在疾病过程的后期更加明显。我们还将研究这些更改 18FE-PE2I与11C-UCB-J结合的比较，给出了在不同阶段的敏感性的直接评估 疾病以及纵向(目标3)。探索性目标将使一部分受试者重复临床 从最初的PET扫描开始三年的检查，以调查突触密度和DAT是否 症状变化的预测(次级目标1)我们还研究了正常帕金森病患者和轻度帕金森病患者的认知功能。 认知障碍(PD-MCI)，观察皮质区域可能的差异(子目标2)。最后，我们会 在这一重要的发展中研究领域中调查身体优先与大脑优先的症状(子目标 3)。这项研究将总共持续四年。 帕金森病受试者将从耶鲁运动障碍诊所和当地的帕金森病支持小组招募。PD 受试者将获得临床诊断确认(例如，MDS-统一帕金森氏病评定量表)。全 科目将包括检查(包括心电和血液检查)，以确定研究资格。科目 有资格参加的人还将获得解剖磁共振成像，以进行联合注册(和部分体积校正) 和最高分辨率的人脑PET扫描仪，带有放射性示踪剂11C-UCB-J和18FE-PE2I。 本项目是研究新型PET显像剂治疗帕金森病的一项极具创新性的研究。这一点对于 有几个原因。首先，它结合了两种已被发现显著减少的尖端示踪剂 在警局。其次，这是通过包括更大的、更先进的临床技术来验证令人兴奋的初始工作的关键一步 一群人。第三，它检查了受试者内部的纵向随访期，提供了关于 这些标记物的灵敏度。最后，我们将探索这些生物标志物是否可以为特定的 临床要素。因此，这项工作将为下一代局部放电成像提供重要的指导。

Project abstract/summary The need to develop better biomarkers and more effective therapies in Parkinson's disease (PD) is a priority. This proposed research project applies novel molecular neuroimaging methods to directly investigate synapses and the dopamine transporter (DAT) in PD by using positron emission tomography (PET) imaging with newly developed tracers,11C-UCB-J for synaptic density and 18FE-PE2I for DAT. The study will perform a detailed comparison with 60 total PD subjects, 20 subjects each in different clinical stages (Hoehn and Yahr stages 1-3) with 11C-UCB-J (Aim 1). We hypothesize that there will be a regional pattern of synaptic deficits in PD patients in primary regions-of-interest in the brain that will first include subcortical nuclei and then spread to prefrontal and motor cortices, occurring in the cortex earlier than predicted from a caudal-to-rostral evolution model. Using a subset of subjects from the first aim, 15 PD subjects in different clinical stages of the disease will be examined two years later for longitudinal changes (Aim 2). We expect that the tracer will be sensitive to changes in each clinical stage, with cortical synaptic density decreases more pronounced later in the disease process. We will also examine these changes with 18FE-PE2I compared to 11C-UCB-J binding, giving direct evaluations of sensitivity in different stages of the disease as well as longitudinally (Aim 3). Exploratory aims will have a subset of subjects repeat clinical examinations three years from the initial PET scans to investigate whether synaptic density and DAT were predictive of symptom change (Sub-Aim 1.) We also study cognitively normal PD patients vs. PD with mild cognitive impairment (PD-MCI) to observe possible differences in cortical areas (Sub-Aim 2). Finally, we will investigate body-first vs. brain-first onset of symptoms in this important developing area of research (Sub-Aim 3). The study will last a total of four years. PD subjects will be recruited from the Yale Movement Disorders Clinic and local PD support groups. PD subjects will have clinical confirmation of diagnosis (e.g., MDS-Unified Parkinson's Disease Rating Scale). All subjects will include examinations (including ECG and blood work) to determine study eligibility. Subjects eligible to participate will also receive an anatomical MRI for co-registration (and partial volume corrections) and the highest resolution human brain PET scanner available with the radiotracers 11C-UCB-J and 18FE-PE2I. This project is a highly innovative study to investigate novel PET imaging agents in PD. This is important for several reasons. First, it combines two cutting edge tracers that have been found to be significantly decreased in PD. Secondly, it is a crucial step to validate exciting initial work by including larger, more clinical advanced cohorts. Thirdly, it examines longitudinal follow up periods within subjects, providing needed data on the sensitivity of these markers. Lastly, we will explore whether these biomarkers can be informative about specific clinical elements. Thus, this work will provide important guidance for the next generation of PD imaging.