Project III: Cingulo-Opercular Task Control Network Cholinergic Dysfunction in PD

项目 III：PD 中的颊盖任务控制网络胆碱能功能障碍

• 批准号: 10493275
• 负责人: Roger L Albin
• 金额: $ 11.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493275
• 关键词: Anterior; Attention; Biological; Biological Markers; Biology; Brain; Clinical; Clinical Research; Clinical Trials; Cognitive; Cognitive deficits; Collaborations; Complex; Denervation; Development; Diffuse; Disease; Evaluation; Freezing; Functional disorder; Gait; Image; Impaired cognition; Impairment; Incidence; Intervention; Knowledge; Ligands; Magnetic Resonance Imaging; Malignant - descriptor; Measures; Motor; National Institute of Neurological Disorders and Stroke; Natural History; Neurotransmitters; Parkinson Disease; Phenotype; Positron-Emission Tomography; Prognosis; Recommendation; Refractory; Reporting; Research; Resources; Subgroup; System; Testing; Universities; Validation; acetylcholine transporter; basal forebrain; biomarker development; cholinergic; clinical care; cognitive function; cohort; disease heterogeneity; disease phenotype; disorder subtype; dopamine replacement therapy; improved; magnetic resonance imaging biomarker; motor disorder; personalized medicine; prospective; synucleinopathy; targeted treatment; therapy development

PROJECT III: SUMMARY/ABSTRACT Cognitive deficits are a morbid dopamine replacement therapy-refractory feature of Parkinson disease (PD). The pathophysiology of PD-related cognitive deficits is complex, likely involving interacting and variable impairments of several brain systems, particularly in early to moderate disease. Incidence and natural history of PD cognitive deficits is heterogeneous. Understanding the pathophysiologies of PD cognitive impairments is essential for development of personalized therapies. PD heterogeneity is a major obstacle to effective clinical research. Identifying PD subgroups will enhance discovery of useful interventions through subgroup specific or stratified clinical trials, identify biomarkers, improve prognosis assessment in clinical care, and assist etiopathogenic research. Some of the “highest priority recommendations” of the NINDS PD 2014 Research Report call for research to understand the pathophysiology of cognitive impairments and for PD subgroup identification. The U-M Udall Center established a deeply phenotyped PD cohort imaged with the vesicular acetylcholine transporter PET ligand [18F]FEOBV, revealing heterogeneous cholinergic deficits. Cholinergic terminal deficits in Cingulo-Opercular Task Control network (COTC) nodes – Anterior Cingulate and Insular Cortices (AC-I) – correlate with both domain specific and global cognitive deficits. An important component of the Attentional-Motor Interface (AMI; Overall Component), the COTC subserves tonic attention, coordinating network activities across different cognitive domains. Preliminary analysis suggests that early COTC node (AC- I) cholinergic deficits are a subgroup defining-feature in PD, predicting more rapid cognitive decline. The central hypothesis of Project III is that early COTC node (AC-I) cholinergic denervation contributes significantly to cognitive impairment in early to moderate PD and identifies a PD subgroup with accelerated cognitive decline. In addition to our established Udall subject cohort, we have access to a separate cohort of incident PD subjects through collaboration with the University of Groningen, deeply phenotyped and imaged with [18F]FEOBV PET, for rigorous experimental replication and validation of our primary hypothesis. We will correlate early COTC node (AC-I) cholinergic denervation with domain-specific and general measures of cognitive function. In a prospective analyses, we will determine if early COTC node (AC-I) cholinergic denervation predicts more rapid cognitive decline. In an integrated analysis with Project I, we will determine if COTC node (AC-I) cholinergic denervation is associated with Freezing of Gait (FoG). In exploratory analyses, we will assess if more accessible MRI or other measures correlate with COTC node (AC-I) cholinergic denervation, identifying potential, accessible biomarkers of COTC node (AC-I) cholinergic denervation. Project III will identify an important substrate of PD cognitive impairment and identify a PD subgroup with a more aggressive natural history - a “malignant hypocholinergic disease phenotype.” These results will identify potential targets for therapeutic interventions and biomarker development.

项目三：摘要/摘要 认知缺陷是一种病态的多巴胺替代疗法--帕金森病(PD)的顽固特征。 帕金森病相关认知障碍的病理生理学是复杂的，可能涉及相互作用和变量 几个大脑系统的损伤，特别是在早期到中度疾病中。发病率和自然历史 帕金森病的认知缺陷是异质性的。了解帕金森病认知障碍的病理生理学 对个性化治疗的发展至关重要。帕金森病的异质性是临床有效的主要障碍 研究。识别帕金森病亚组将通过亚组特异性或 分层临床试验，识别生物标记物，改善临床护理的预后评估，并协助 病因研究。NINDS PD 2014研究报告中的一些“最优先的建议” 报告呼吁研究以了解认知障碍和帕金森病亚组的病理生理学 身份证明。U-M Udall中心建立了一个与水泡一起成像的深表型PD队列 乙酰胆碱转运体PET配体[18F]FEOBV，揭示异质性胆碱能缺陷。胆碱能 扣带回-顶叶任务控制网络(COTC)节点的终末缺陷--前扣带回和岛状 大脑皮层(AC-I)--与特定领域和整体认知缺陷相关。的一个重要组成部分 注意-运动接口(AMI；整体组件)，COTC辅助紧张性注意，协调 跨不同认知域的网络活动。初步分析认为，早期COTC结节(AC- I)胆碱能缺陷是帕金森病患者的一个亚群特征，预示着认知功能的快速下降。中环 项目III的假设是，早期COTC结节(AC-I)胆碱能去神经显著有助于 早期至中度帕金森病患者的认知损害，并确定认知功能减退加速的帕金森病亚组。 除了我们已建立的Udall主题队列外，我们还可以访问事件PD主题的单独队列 通过与格罗宁根大学的合作，用[18F]FEOBV PET进行了深入的表型和成像， 对我们的主要假设进行严格的实验复制和验证。我们将把早期的COTC关联起来 结节(AC-I)胆碱能去神经与特定领域和一般的认知功能测量。在一个 前瞻性分析，我们将确定早期COTC结节(AC-I)胆碱能神经失神经是否预示着更快 认知能力下降。在与项目I的综合分析中，我们将确定COTC结节(AC-I)胆碱能 失神经与步态冻结(雾)有关。在探索性分析中，我们将评估是否更容易获得 MRI或其他措施与COTC结节(AC-I)胆碱能去神经相关，识别电位， 可获得的COTC结节(AC-I)胆碱能失神经的生物标志物。项目III将确定一个重要的 帕金森病认知损害的基础，并确定有更具侵袭性自然病史的帕金森病亚组-a “恶性低胆碱能疾病表型。”这些结果将确定潜在的治疗靶点 干预措施和生物标记物开发。