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: 10672414
• 负责人: Nicolaas Ida Bohnen
• 金额: $ 31.74万
• 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/10672414
• 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; 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; 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; 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I：摘要/摘要 姿势不稳定和步态难度（PIGD）运动特征在帕金森病（PD）中很常见， 以及造成治疗难治性残疾的重要原因。积累的证据暗示胆碱能 系统功能障碍是步态和平衡障碍的重要促进者。在最初的资金期间 时期，我们建立了囊泡乙酰胆碱转运蛋白（VACHT）配体[18F] FeOBV，它是唯一的 评估高密度区域（例如纹状体）中的胆碱能末端密度。我们最近的交叉 部分发现表明，具有孤立跌倒的PWP参与者和步态冻结的参与者（FOG） 状态在丘脑（侧向核核[LGN]）和纹状体中具有共同的胆碱能缺陷 （尾状）具有更广泛的纹状体，边缘和前额叶VACHT降低的PWP中的雾气。持续的 使用项目II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缺陷是常见的 瀑布和雾的病因中的分母。这些结果强调需要了解猪，跌倒， 和雾为胆碱能投影功能障碍的产物，在注意力运动失败的框架内 集成（AMI）结合了其他多感官和认知整合的失败。 发作性迁移率扰动（瀑布，雾）通常是在暗中发展的非 情节猪特征。我们有新的初步数据，可以使内侧遗传的胆碱能缺陷 细胞核（MGN）和内嗅皮层（ERC）与非剧本PIGD缺陷牢固相关， 这些结果表明，非疾病的障碍物积分受损的重要作用 PWP中的电机功能。该项目的总体目标是调查胆碱能的演变 多感官，认知和运动整合大脑区域的缺陷以及 PWP中的PIGD特征。我们假设这是从MGN和ERC，然后是LGN和 尾状核，然后是更多弥漫性纹状体，边缘和皮质（前额叶，然后是前扣带 和岛状）胆碱能缺陷。为了评估我们的假设，我们建议执行前瞻性队列 在基线时使用[18F] FeOBV脑宠物的研究和PD受试者的2年随访，有可能转换为 非剧本和情节性（瀑布和雾）猪运动特征。胆碱能变化的新见解 PIGD的基本事件发展可能会为新的治疗干预措施提供治疗 使运动并发症使人衰弱。项目一世与项目II和催化剂高度集成 研究项目，对III项目的补充，并将与所有核心进行广泛的互动。我们的工作是 基于在先前的资金周期中开发的独特的，深厚的表型PD参与者的队列 允许我们招募可能转化为跌倒和雾状态的丰富患者样本，从而 纵向内部评估。