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: 10282007
• 负责人: Roger L Albin
• 金额: $ 10.68万
• 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/10282007
• 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III：摘要/摘要 认知缺陷是帕金森氏病（PD）的病态多巴胺替代治疗疗法特征。 PD相关认知缺陷的病理生理很复杂，可能涉及相互作用和可变 几种大脑系统的损害，特别是在中度疾病的早期至中度疾病。发病率和自然史 PD认知缺陷是异质的。了解PD认知障碍的病理生理是 对于开发个性化疗法至关重要。 PD异质性是有效临床的主要障碍 研究。识别PD亚组将通过特定于亚组或 分层临床试验，识别生物标志物，改善临床护理中的预后评估并协助 疗法研究。 Ninds PD 2014研究的一些“最高优先建议” 报告呼吁进行研究，以了解认知障碍的病理生理学和PD亚组 鉴别。 U-M UDALL中心建立了与囊泡的深层表型PD队列 乙酰胆碱转运蛋白宠物配体[18F] FEOBV，揭示了异质性胆碱能缺乏。胆碱能 终端定义在cingulo-obercular任务控制网络（COTC）节点 - 前扣带回和岛屿 皮质（AC-I） - 与域特异性和全局认知缺陷均相关。一个重要组成部分 注意运动界面（AMI；整体组件），COTC繁殖补品，协调一致 跨不同认知领域的网络活动。初步分析表明早期COTC节点（ac- i）胆碱能定义是PD中定义功能的亚组，预测认知能力下降。中央 项目III的假设是早期COTC节点（AC-I）胆碱能神经保护作用显着贡献 早期至中度PD的认知障碍，并鉴定出具有加速认知能力下降的PD亚组。 除了我们已建立的UDALL主题队列外，我们还可以访问单独的事件PD主题 通过与格罗宁根大学的合作，与[18f] feobv宠物进行了深刻的表现和成像， 用于严格的实验复制和验证我们的主要假设。我们将与早期的COTC相关联 淋巴结（AC-I）胆碱能神经保护，具有域特异性和一般认知功能的度量。在 前瞻性分析，我们将确定早期COTC节点（AC-I）胆碱能神经预测是否更快 认知能力下降。在与项目I的综合分析中，我们将确定COTC节点（AC-I）是否胆碱能 改造与步态冻结有关（FOG）。在探索性分析中，我们将评估是否更可访问 MRI或其他措施与COTC淋巴结（AC-I）胆碱能神经关联，确定潜力， COTC节点（AC-I）胆碱能神经神经的可访问生物标志物。第三项目将确定重要的 PD认知障碍的底物并确定具有更具侵略性自然史的PD亚组 - A “恶性降压素能疾病表型。”这些结果将确定治疗的潜在目标 干预和生物标志物的发展。