Imaging of cholinergic systems in PD

PD 胆碱能系统成像

• 批准号: 9130289
• 负责人: Nicolaas Ida Bohnen
• 金额: $ 42.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9130289
• 关键词: Acetylcholinesterase; Binding; Biodistribution; Biological Markers; Brain Stem; Brain region; Cell Nucleus; Cerebellar vermis structure; Cerebrum; Cholinesterases; Clinical; Cohort Studies; Complex; Corpus striatum structure; Coupling; Data; Dementia; Denervation; Development; Disease Progression; Dopa; Dopamine; Elements; Enzymes; Equilibrium; Evolution; Functional disorder; Gait; Gait abnormality; Gait speed; Goals; Heterogeneity; Human; Image; Impairment; Lead; Ligands; Modeling; Musculoskeletal Equilibrium; National Institute of Neurological Disorders and Stroke; Nerve; Nerve Degeneration; Parkinson Disease; Pathway interactions; Patients; Pattern; Positron-Emission Tomography; Posture; Process; Progressive Supranuclear Palsy; Recommendation; Regulation; Reporting; Research; Resistance; Role; Sensory Process; Structure; System; Testing; Thalamic structure; Translating; Work; abstracting; acetylcholine transporter; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cholinergic neuron; cohort; density; directed attention; equilibration disorder; falls; fluoroethoxy-benzovesamicol; follow-up; monoamine; motor deficit; nerve supply; new therapeutic target; non-demented; novel; patient stratification; prospective; research study; tool; uptake

Project II: Summary/Abstract Dopamine-resistant gait and postural dysfunctions represent a critical unmet need in Parkinson disease (PD). Evidence is accumulating that cholinergic system dysfunction contributes significantly to gait and balance impairment. The cholinergic system is implicated in mobility functions in PD because of loss of cholinergic basal forebrain (BF) neurons directing attention and degeneration of cholinergic neurons in the pedunculopontine nucleus (PPN) complex. Although mobility functions require intrinsic coupling between locomotor and postural functions, our work points to dissociable and additive motor deficits characterized by specific associations with BF vs. PPN cholinergic degenerations. Our recent work shows that slowing of gait speed appears to be a good correlate of BF cholinergic degeneration in patients with mild to moderate PD. We have also data suggesting that cholinergic thalamic denervation, reflecting PPN cholinergic afferent degeneration, is associated with falls and postural dysfunction in PD. These results implicate PPN degeneration as a significant mechanistic factor contributing to impaired postural control in PD. Progressive mobility impairments likely reflect cumulative effects of multisystem degenerations in PD. The goal of this project is to study the different contributions of cholinergic projection system degenerations to PD gait and postural dysfunctions. Together with the other Projects in this Udall Center proposal, this study will contribute to testing of the “3-Hit” model of gait and balance dysfunction in PD (detailed in "Overview"). This model posits that serial degeneration of nigrostriatal (first “hit”) and BF/PPN cholinergic systems (second and third “hits”, resp.) are responsible for the typically inexorable progression of dopamine-resistant gait and postural dysfunction in PD. We hypothesize that BF and PPN deficits contribute to dissociable and additive components of PD gait and postural dysfunction. Our center developed a novel vesicular acetylcholine transporter (VAChT) PET ligand, fluoroethoxy-benzovesamicol ([18F]FEOBV), which enables a more accurate assessment of cholinergic nerve terminal integrity compared to previously used cholinesterase-based ligands. Most notably, [18F]FEOBV will allow quantitative assessment of cholinergic terminals in the cerebellar vermis, which originates in the PPN. The spinocerebellum is important in the regulation of postural control through the processing of propioceptive information. Identification of pathway specific deficits may lead to novel therapeutic targets for treatment of gait and balance disorders in PD. This proposal is directly responsive to the NINDS PD 2014 Research Report "highest priority recommendations" including 1) developing biomarkers for dopa-resistant features of PD, in particular gait and balance problems (Clinical Rec. #2); 2) characterizing mechanisms that underlie the heterogeneity in clinical presentation and rates of PD progression (Clinical Rec. #3); and 3) development of patient stratification tools to define more homogenous cohorts of PD subjects (Translational Rec. #1).

项目II：摘要/摘要 多巴胺的聚集和姿势功能障碍代表了帕金森病的至关重要的需求 （PD）。有证据表明胆碱能系统功能障碍对步态和 平衡损害。胆碱能系统与PD的迁移率有关 胆碱能碱性前脑（BF）神经元指导胆碱能神经元的注意力和变性 花梗核（PPN）复合物。尽管移动功能需要固有的耦合 运动和姿势功能，我们的工作指向可解散和添加电动机定义为 与BF与PPN胆碱能退化的特定关联。我们最近的工作表明步态放缓 在轻度到中度PD患者中，速度似乎是BF胆碱能变性的良好相关性。 我们还拥有数据表明胆碱能丘脑神经神经，反映了PPN胆碱能影响 变性与PD的跌倒和姿势功能障碍有关。这些结果暗示PPN 退化是导致PD姿势控制受损的重要机械因素。进步 流动性障碍可能反映了PD多系统变性的累积影响。 该项目的目的是研究胆碱能投影系统退化的不同贡献 PD步态和姿势功能障碍。与这个Udall中心提案中的其他项目一起， 研究将有助于测试PD中收集和平衡功能障碍的“ 3击”模型（详细介绍 “概述”）。该模型认为nigrostriatal（第一个“命中”）和BF/PPN胆碱能的系列变性 系统（第二和第三个“命中”，分别是）负责通常是不可避免的进展 PD中耐多巴胺的步态和姿势功能障碍。我们假设BF和PPN定义了贡献 PD步态和姿势功能障碍的可分离和添加成分。我们的中心开发了一本小说 囊泡乙酰胆碱转运蛋白（VACHT）宠物配体，氟乙氧基 - 苯佐奶酪（[18f] feOBV） 与先前使用的 基于胆碱酯酶的配体。最值得注意的是，[18F] FEOBV将允许对胆碱能的定量评估 小脑vermis中的末端，起源于PPN。脊椎小脑在 通过处理propibo感知信息来调节姿势控制。识别途径 具体的定义可能会导致新的热目标治疗AIT和PD平衡疾病。这 提案直接响应Ninds PD 2014研究报告“最高优先级建议” 包括1）开发用于PD抗DOPA特征的生物标志物，特别是攻击和平衡 问题（临床记录＃2）; 2）表征临床异质性基础的机制 PD进展的呈现和速率（临床记录＃3）； 3）患者分层的发展 定义更均匀的PD受试者队列的工具（转化rec。＃1）。