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

帕金森病的体内突触和多巴胺转运蛋白成像

• 批准号: 10521681
• 负责人: DAVID A MATUSKEY
• 金额: $ 68.92万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521681
• 关键词: Adult; Affect; Anatomy; Animal Model; Area; Binding; Biological Markers; Blood; Bradykinesia; Brain; Brain Diseases; Brain scan; Cell Nucleus; Characteristics; Clinic; Clinical; Cognitive; Cytoplasm; Data; Detection; Diagnosis; Diagnostic; Diagnostic Imaging; Disease; Disease Progression; Dopamine; Electrocardiogram; Elements; Eligibility Determination; Evaluation; Evolution; Functional disorder; Gene Mutation; Human; Image; Individual; Investigation; LRRK2 gene; Lewy Bodies; Location; Magnetic Resonance Imaging; Measures; Methods; Modeling; Molecular; Motor; Motor Cortex; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Movement Disorders; Muscle Rigidity; Neurodegenerative Disorders; Parkinson Disease; Pathologic; Pathology; Patients; Pattern; Positron-Emission Tomography; Prefrontal Cortex; Process; Proteins; Research; Research Project Grants; Resolution; Scanning; Sensory; Sleep; Substantia nigra structure; Support Groups; Symptoms; Synapses; Tracer; Tremor; Ventral Striatum; Work; alpha synuclein; body density; clinical examination; cognitive function; cohort; density; dopamine transporter; early onset; effective therapy; follow-up; illness length; imaging agent; imaging approach; imaging biomarker; in vivo; innovation; interest; mild cognitive impairment; molecular imaging; neuroimaging; neuropsychiatry; next generation; nigrostriatal system; non-motor symptom; novel; presynaptic; protein aggregation; radiotracer; recruit

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.

项目摘要/概要 开发更好的生物标志物和更有效的帕金森病（PD）治疗方法是当务之急。 这项拟议中的研究项目应用新的分子神经影像学方法直接调查突触 应用正电子发射断层扫描（PET）技术， 用11 C-UCB-J标记突触密度，用18FE-PE 2 I标记DAT。 本研究将对总共60例PD受试者进行详细比较，不同临床试验中各20例受试者 阶段（Hoehn和Yahr阶段1-3）与11 C-UCB-J（Aim 1）。我们假设会有一个区域性的 PD患者大脑主要感兴趣区域的突触缺陷模式，首先包括 皮层下核团，然后扩散到前额叶和运动皮层，发生在皮层早于 从尾部到喙部 进化 模型 使用来自第一个目标的受试者子集，15 PD 两年后将检查处于疾病不同临床阶段的受试者的纵向变化 (Aim 2）的情况。我们期望示踪剂对每个临床阶段的变化都很敏感，皮质突触 密度在疾病过程的后期降低得更明显。我们还将研究这些变化， 18FE-PE 2 I与11 C-UCB-J结合的比较，直接评价了不同阶段的敏感性。 疾病以及纵向（目标3）。探索性目的将使一部分受试者重复临床试验 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 预测症状变化（子目标1.）我们还研究了认知正常的PD患者与轻度PD患者， 认知障碍（PD-MCI），以观察皮质区的可能差异（子目标2）。最后我们将 在这一重要的发展中研究领域中，研究身体先出现症状与大脑先出现症状（子目标 3）。这项研究将持续四年。 PD受试者将从耶鲁运动障碍诊所和当地PD支持小组招募。PD 受试者将具有诊断的临床确认（例如，MDS-统一帕金森病评定量表）。所有 受试者将接受检查（包括ECG和血液检查），以确定研究资格。科目 有资格参与的患者还将接受解剖MRI以进行配准（和部分容积校正） 以及最高分辨率的人脑PET扫描仪，可使用放射性示踪剂11 C-UCB-J和18FE-PE 2 I。 该项目是一项高度创新的研究，旨在研究PD中的新型PET显像剂。这是非常重要的 有几个原因。首先，它结合了两个切割边缘示踪剂，已被发现显着减少 在警局其次，这是通过包括更大的、更先进的临床研究来验证令人兴奋的初步工作的关键一步。 同伙第三，它检查了受试者的纵向随访期， 这些标记的敏感性。最后，我们将探讨这些生物标志物是否可以提供关于特定的 临床元素因此，这项工作将为下一代PD成像提供重要指导。