Neuroimaging of PDE10A

PDE10A 的神经影像学

• 批准号: 9975921
• 负责人: JOEL Synes PERLMUTTER
• 金额: $ 61.53万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975921
• 关键词: Acute; Agonist; Autopsy; Behavior; Binding Sites; Biological Markers; Blinded; Brain; Carbidopa; Chemicals; Chronic; Clinical Research; Confusion; Contralateral; Corpus striatum structure; DRD2 gene; Data; Disease; Disease Progression; Dopamine; Dopamine Receptor; Dopaminergic Agents; Dose; Drug Exposure; Dystonia; Enzymes; Failure; Family; Functional disorder; Human; Huntington Disease; Immunohistochemistry; In Vitro; Injury; Intracarotid; Investigation; Kinetics; Levodopa; Ligands; Measures; Mediating; Mental disorders; Molecular; Monkeys; Motor; Neurons; Neurotransmitters; Normal Pressure Hydrocephalus; Parkinson Disease; Parkinsonian Disorders; Pathology; Pathway interactions; Pharmaceutical Preparations; Positron-Emission Tomography; Property; Psychotic Disorders; Quantitative Autoradiography; Schizophrenia; Side; Signal Transduction; Synapses; Tissues; Tracer; Translating; base; behavior in vitro; brain pathway; dopaminergic neuron; enzyme activity; human imaging; imaging study; in vivo; molecular imaging; motor behavior; nervous system disorder; neuroimaging; nigrostriatal pathway; nonhuman primate; nonhuman tissue; novel therapeutics; phosphoric diester hydrolase; postsynaptic; pramipexol; presynaptic; prevent; radioligand; receptor; uptake; vesicular monoamine transporter

ABSTRACT Multiple neurologic and psychiatric disorders including Parkinson disease (PD), Huntingon disease (HD), dystonia and schizophrenia involve dopaminergic (DA) pathways as part of pathophysiology or treatment. Changes in function of nigrostriatal pathways may reflect either presynaptic or postsynaptic effects. Most previous studies focused on presynaptic changes. This proposal focuses on phosphodiesterases (PDEs) that control signal transduction of both families of DA receptors (D1-like and D2-like). PDE10A, the PDE subtype restricted to striatal medium spiny neurons (MSNs) and is expressed in direct (mosty D1-mediated) and indirect pathway neurons (mostly D2-mediated). PET ligands for PDE10A could facilitate study of pathophysiology, disease progression or target engagement for diseases with striatal pathologies such as PD or HD. However, the interactions among presynaptic nigrostriatal neurons, DA receptors, behavior and PDE10A remain unknown. Failure to understand these relationships led to confusion about interpretation of clinical studies using presynaptic molecular DA biomarkers. Molecular imaging measures also may be altered by either acute or chronic drug exposures, thus investigation of those potential effects also will permit unabmiguous interpretation of human studies. This proposal will help prevent such confusion by directly determining the effects of nigrostriatal injury on striatal PDE10A, comparing with presynaptic measures, D1-like and D2-like DA receptors, other striatal neurotransmitters and motor behavior in nonhuman primates (NHPs). We will leverage previously collected tissues from NHPs that have been treated with varying doses of intracarotid (ic) MPTP that causes graded degrees of nigrostriatal injury. We also will study new NHPs to determine the relationships between in vivo PET measures of PDE10A with other presynaptic and postsynaptic biomarkers. We will use two different PET radioligands for PDE10A that have different tracer kinetic properties. Finally, we will determine the effects of acute or chronic drugs on in vivo PDE10A in striatum since drug effects can be a major confound in human imaging studies, particularly of dopaminergic pathways. These proposed studies will permit unambiguous interpretation of PDE10A PET radioligands to investigate relevant pathophysiologies or provide measures of target engagement of new therapies for PD, HD and possibly psychosis.

摘要 多种神经和精神疾病，包括帕金森病（PD）、亨廷顿病（HD）， 肌张力障碍和精神分裂症涉及多巴胺能（DA）途径作为病理生理学或治疗的一部分。 黑质纹状体通路功能的变化可能反映突触前或突触后效应。最 以往的研究主要集中在突触前的变化。该提案的重点是磷酸二酯酶（PDE）， 控制两个DA受体家族（D1样和D2样）的信号转导。PDE10A，PDE亚型 仅限于纹状体中型多刺神经元（MSN），并以直接（大多数D1介导）和间接 通路神经元（主要是D2介导的）。PDE10A的PET配体可以促进病理生理学的研究， 疾病进展或具有纹状体病理学的疾病（如PD或HD）的靶点接合。然而，在这方面， 突触前黑质纹状体神经元、DA受体、行为和PDE10A之间的相互作用仍然存在 未知不理解这些关系导致了临床研究解释的混乱 使用突触前DA分子生物标记。分子影像学测量也可能被急性或慢性炎症改变。 或慢性药物暴露，因此，对这些潜在影响的调查也将允许 人类研究的解释。这项建议将有助于防止这种混乱，直接确定 黑质纹状体损伤对纹状体PDE 10A的影响，与突触前测量、D1样和D2样DA比较 受体，其他纹状体神经递质和非人灵长类动物（NHP）的运动行为。 我们将利用先前从NHP收集的组织，这些组织已经用不同剂量的 颈动脉内（ic）MPTP，导致黑质纹状体损伤的分级程度。我们还将研究新的NHP， 确定PDE10A的体内PET测量与其他突触前和突触后 生物标志物。我们将使用两种不同的PET放射性配体用于PDE10A，其具有不同的示踪剂动力学性质。 最后，我们将确定急性或慢性药物对纹状体中PDE10A的影响，因为药物作用 可能是人体成像研究中的主要混淆因素，特别是多巴胺能通路。这些拟议 研究将允许明确解释PDE 10A PET放射性配体，以研究相关的 病理生理学或提供PD、HD新疗法的靶向参与的测量， 精神病