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

项目一：摘要/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， 以及治疗的一个重要原因--难治性残疾。越来越多的证据表明胆碱能 系统功能障碍是造成步态和平衡障碍的重要因素。在最初的资助过程中 期间，我们建立了囊泡乙酰胆碱转运体(Vacht)配体[18F]FEOBV，它是唯一的 评估纹状体等高密度区域的胆碱能终末密度。我们最近的交叉- 横断面研究结果表明，单纯性跌倒和步态冻结(雾)的PWP参与者 丘脑(外侧膝状体[LGN])和纹状体有共同的胆碱能缺陷 (尾状)伴有雾的PWP中纹状体、边缘和前额叶Vacht减少更广泛。一致 项目II的临床前数据表明纹状体胆碱能中间神经元(Schi)在 注意和运动功能的整合，这些数据表明，Schi缺陷是一种常见的 在跌倒和雾的病因学中的分母。这些结果强调了理解PIGD、FLOWS、 注意运动障碍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。 间歇性的流动性扰动(跌倒、雾)通常在之前潜伏地发展成非 插曲的PIGD特写。我们有新的初步数据显示内侧膝状体胆碱能缺陷 核团(MGN)和内嗅皮层(ERC)与非发作性PIGD缺陷密切相关， 这些结果暗示了感觉-运动整合受损在非发作性PIGD中的重要作用 PWP中的马达特征。这个项目的首要目标是研究胆碱能 多感觉、认知和运动统合脑区的缺陷与脑发育 PWP中的PIGD功能。我们假设这是从MGN和ERC开始的，然后是LGN和 尾状核，然后是更多弥漫的纹状体、边缘和皮质(前额叶后是前扣带 和脑岛)胆碱能缺陷。为了评估我们的假设，我们建议进行一项前瞻性队列研究 帕金森病患者基础状态下的[18F]FEOBV脑部PET研究及2年随访 非间歇性和间歇性(跌倒和雾气)PIGD马达功能。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 使人虚弱的运动并发症。项目一与项目二和催化剂在主题上高度集成 研究项目是对项目III的补充，并将与所有核心广泛互动。我们的工作是 基于上一个供资周期中形成的一组独特的、表型深刻的PD参与者 使我们能够招募更多可能转为跌倒和雾化状态的患者样本，从而 纵向受试者内部评估。

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.