Project I: Evolution of cholinergic deficits within multisensory, cognitive, and motor integration brain regions and development of PIGD features in PwP

项目 I：多感觉、认知和运动整合脑区胆碱能缺陷的演变以及 PwP 中 PIGD 特征的发展

• 批准号: 10493260
• 负责人: Nicolaas Ida Bohnen
• 金额: $ 30.84万
• 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/10493260
• 关键词: Anterior; Attention; Auditory; Binding; Brain; Brain region; Clinical; Cognitive; Complement; Corpus striatum structure; Data; Development; Diffuse; Disease Progression; Equilibrium; Etiology; Evolution; Exhibits; Failure; Freezing; Functional disorder; Funding; Gait; Gait abnormality; Geniculate body structure; Goals; Grant; Impairment; Incidence; Insula of Reil; Interneurons; Intervention Studies; Lateral Geniculate Body; Ligands; Link; Medial; Modeling; Motor; National Institute of Neurological Disorders and Stroke; Parkinson Disease; Participant; Patients; Persons; Phenotype; Play; Positron-Emission Tomography; Prefrontal Cortex; Prospective cohort study; Recommendation; Refractory; Reporting; Research; Research Project Grants; Risk; Role; Sampling; Signal Transduction; Site; Structure; System; Testing; Thalamic structure; Visual; Visuospatial; Work; acetylcholine transporter; base; catalyst; caudate nucleus; cholinergic; cohort; density; disability; entorhinal cortex; equilibration disorder; falls; follow up assessment; follow-up; in vivo; information processing; insight; multisensory; nerve supply; neural circuit; novel; novel therapeutic intervention; posture instability; pre-clinical; recruit; way finding

PROJECT I: SUMMARY/ABSTRACT Postural instability and gait difficulty (PIGD) motor features are common in Parkinson disease (PD), and a significant cause of treatment-refractory disability. Accumulating evidence implicates cholinergic systems dysfunctions as significant contributors to gait and balance impairment. During the initial funding period, we established the vesicular acetylcholine transporter (VAChT) ligand [18F]FEOBV, which uniquely assesses cholinergic terminal density in high density regions such as the striatum. Our recent cross- sectional findings suggest that PwP participants with isolated falls and those with freezing of gait (FoG) status share common cholinergic deficits in the thalamus (lateral geniculate nucleus [LGN]) and striatum (caudate) with more extensive striatal, limbic, and prefrontal VAChT reductions in PwP with FoG. Consistent with Project II preclinical data indicating a critical role for striatal cholinergic interneurons (SChI) in integration of attentional and motor functions, these data suggest that SChI deficits are a common denominator in the etiology of falls and FoG. These results emphasize the need to understand PIGD, falls, and FoG as products of cholinergic projection dysfunctions within the framework of failing Attentional-Motor Integration (AMI) combined with failures of additional multisensory and cognitive integration. Episodic mobility disturbances (falls, FoG) are typically preceded by insidiously developing non- episodic PIGD features. We have novel preliminary data that cholinergic deficits of the medial geniculate nucleus (MGN) and the entorhinal cortex (ERC) are robustly associated with non-episodic PIGD deficits, These results imply a significant role of impaired sensorimotor integration underlying non-episodic PIGD motor features in PwP. The overarching goal of this project is to investigate the evolution of cholinergic deficits within multisensory, cognitive and motor integration brain regions and development of PIGD features in PwP. We hypothesize that this progresses from the MGN and ERC, then LGN and caudate nucleus, and then more diffuse striatal, limbic and cortical (prefrontal followed by anterior cingulum and insula) cholinergic deficits. To assess our hypotheses, we propose to perform a prospective cohort study with [18F]FEOBV brain PET at baseline and 2-year follow-up in PD subjects at risk of conversion to non-episodic and episodic (falls and FoG) PIGD motor features. Novel insights in cholinergic changes underlying incident development of PIGD may inform new therapeutic interventions to treat these debilitating motor complications. Project I is highly integrated thematically with Project II and the Catalyst Research Project, complementary to Project III, and will interact extensively with all Cores. Our work is based on a unique, deeply phenotyped cohort of PD participants developed in the prior funding cycle allowing us to recruit an enriched sample of patients likely to convert to fall and FoG status, allowing longitudinal within-subject assessments.

项目一：总结/摘要 姿势不稳和步态困难 (PIGD) 运动特征在帕金森病 (PD) 中很常见， 以及治疗难治性残疾的一个重要原因。越来越多的证据表明胆碱能 系统功能障碍是步态和平衡障碍的重要原因。在初始融资期间 在此期间，我们建立了囊泡乙酰胆碱转运蛋白（VAChT）配体[18F]FEOBV，它具有独特的 评估高密度区域（例如纹状体）的胆碱能终末密度。我们最近的交叉 部分研究结果表明，单独跌倒的 PwP 参与者和步态冻结 (FoG) 的参与者 丘脑（外侧膝状核 [LGN]）和纹状体都有共同的胆碱能缺陷 （尾状核）伴随着 FoG 的 PwP 中更广泛的纹状体、边缘和前额叶 VAChT 减少。持续的 项目 II 的临床前数据表明纹状体胆碱能中间神经元 (SChI) 在 注意力和运动功能的整合，这些数据表明 SChI 缺陷是一种常见的 跌倒和 FoG 病因学的分母。这些结果强调需要了解 PIGD、跌倒、 和 FoG 作为注意力运动失败框架内胆碱能投射功能障碍的产物 整合（AMI）与额外的多感官和认知整合的失败相结合。 阵发性活动障碍（跌倒、FoG）通常会在不知不觉中出现非运动障碍。 情景式 PIGD 特征。我们有新的初步数据表明内侧膝状体的胆碱能缺陷 核（MGN）和内嗅皮层（ERC）与非发作性 PIGD 缺陷密切相关， 这些结果表明感觉运动整合受损在非发作性 PIGD 中发挥着重要作用 PwP 中的电机功能。该项目的总体目标是研究胆碱能的进化 多感觉、认知和运动整合大脑区域的缺陷以及发育 PwP 中的 PIGD 功能。我们假设这从 MGN 和 ERC 开始，然后是 LGN 和 尾状核，然后是更弥漫的纹状体、边缘和皮质（前额叶，然后是前扣带回） 和岛）胆碱能缺陷。为了评估我们的假设，我们建议进行前瞻性队列研究 对有转化风险的 PD 受试者进行基线 [18F]FEOBV 脑部 PET 和 2 年随访研究 非发作性和发作性（跌倒和 FoG）PIGD 运动特征。关于胆碱能变化的新见解 PIGD 的潜在事件发展可能会为治疗这些疾病提供新的治疗干预措施 使人衰弱的运动并发症。项目 I 在主题上与项目 II 和 Catalyst 高度集成 研究项目是项目 III 的补充，并将与所有核心进行广泛的互动。我们的工作是 基于在之前的资助周期中开发的独特的、深度表型的 PD 参与者队列 使我们能够招募可能转变为跌倒和 FoG 状态的丰富患者样本，从而使 纵向受试者内评估。