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

项目I：概要/摘要 姿势不稳定和步态困难（PIGD）运动特征在帕金森病（PD）中很常见， 也是难治性残疾的重要原因。越来越多的证据表明 系统功能障碍是步态和平衡障碍的重要因素。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[18 F]FEOBV， 评估高密度区域如纹状体的胆碱能末梢密度。我们最近的交叉- 断面研究结果表明，PwP参与者与孤立福尔斯和那些冻结步态（FoG） 在丘脑（外侧膝状体核[LGN]）和纹状体中， （尾状核）与更广泛的纹状体，边缘系统，和前额VAChT减少PwP与FoG。一致 项目II临床前数据表明纹状体胆碱能中间神经元（SCh I）在 注意力和运动功能的整合，这些数据表明，SCh I缺陷是常见的， 福尔斯和FoG病因学的分母。这些结果强调需要了解PIGD，福尔斯， 和FoG作为在注意-运动功能障碍的框架内胆碱能投射功能障碍的产物 整合（AMI）合并额外的多感觉和认知整合失败。 发作性活动障碍（福尔斯，FoG）通常在不知不觉中发展为非活动性障碍之前。 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， 这些结果暗示了非发作性PIGD的感觉运动整合受损的重要作用 PwP中的电机特性。这个项目的首要目标是研究胆碱能神经的进化， 多感觉、认知和运动整合脑区域内的缺陷以及 PwP中的PIGD功能。我们假设，这是从MGN和ERC，然后LGN和 尾状核，然后是更弥漫的纹状体，边缘系统和皮质（前额叶，然后是前扣带 和胆碱能缺陷。为了评估我们的假设，我们建议进行前瞻性队列研究 一项在有转换为PD风险的PD受试者中进行的基线和2年随访时[18 F]FEOBV脑PET研究 非发作性和发作性（福尔斯和FoG）PIGD运动功能。胆碱能变化的新见解 PIGD的潜在事件发展可能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和催化剂高度集成 研究项目，补充项目三，并将与所有核心广泛互动。我们的工作是 基于在前一个资助周期中开发的独特的深度表型PD参与者队列 使我们能够招募可能转换为跌倒和FoG状态的患者的丰富样本， 纵向受试者内评估。

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.