Cerebellar cholinergic connections as a biomarker of dementia and gait impairment in Parkinson disease

帕金森病(PD)是第二常见的进行性神经退行性疾病，其特征是 巨大的临床异质性。帕金森病合并痴呆被认为是与阿尔茨海默病有关的疾病之一 痴呆症。痴呆症，困扰着高达80%的帕金森氏症患者和步态障碍导致显著的发病率和 由于缺乏有效的治疗方法，导致死亡，并极大地放大了社会经济负担。这两者都是 这种损害对多巴胺类药物无效，提示涉及其他神经递质系统或大脑。 黑质纹状体通路以外的区域。大多数神经影像研究都集中在纹状体多巴胺能缺陷上。 也不能充分解释帕金森病患者的步态和认知障碍。中脑桥脑脚核 (PPN)将胆碱能输入发送到小脑鞭，后者有更多的胆碱能神经支配。 人类的大脑比小脑的半球要强。已知的帕金森病患者PPN变性可导致胆碱能 蚯蚓的失神经。蚯蚓调节步态和认知，但对其在帕金森病中的作用知之甚少。近期 小脑静息状态功能连接(FC)分析显示感觉运动改变的Vermal FC 和帕金森病患者的联想皮质，以及它们各自的步态和认知相关性。这项拟议的研究利用了 多模式方法将扩展先前的工作，并调查Vermal Fc的纵向变化是否反映了 帕金森病患者的步态和认知能力的下降，以及用水泡测量是否有蠕虫胆碱能神经的失神经 胆碱能转运蛋白活性(Vacht)PET成像是FC和行为缺陷的基础。从长远来看 目的是调查Vermal FC和胆碱能PET测量是否可以作为 痴呆症和帕金森病患者跌倒。拟议的研究有三个主要目标。第一个目标是调查 蠕虫胆碱能失神经与帕金森病的Vermal FC的两个重要方面：客观反映的能力 步态和认知损害的进展及其与潜在胆碱能病理的关系 Vacht PET，可靠成像生物标记物的两个关键属性。第二个目标是利用 高度有利和支持性的环境，获得横截面和纵向多式联运的财富 成像数据和全面、复杂的行为测量，以及一支出色的多样化导师团队 为应聘者提供a)正电子发射计算机断层扫描分析和b)进行纵向研究的培训 强调多变量、纵向统计，以确保及时向独立过渡。最终目标 因为候选人是继续撰写手稿，特别是涉及PET的手稿，并生成初步数据 走向R01应用程序。虽然有独立的研究目的，但这项研究有幸使用这些数据 收集作为大规模纵向研究的一部分，并获得既定资金。拟议的研究可能会 通过阐明痴呆和帕金森病跌倒的病理生理基础，确定潜在的临床影响 治疗目标和目标参与的可能指标，在这些残疾之前对高危患者进行分层 症状的发展不可逆转，可能导致未来个性化的治疗选择。

Parkinson disease (PD) is the second most common progressive neurodegenerative disorder characterized by tremendous clinical heterogeneity. PD with dementia is considered one of the Alzheimer disease related dementias. Dementia, afflicting up to 80% of PD patients and gait impairment cause significant morbidity and mortality, and tremendously amplify the socioeconomic burden as effective treatments are lacking. Both these impairments are refractory to dopaminergics suggesting involvement of other neurotransmitter systems or brain regions beyond nigrostriatal pathways. Most neuroimaging studies have focused on striatal dopaminergic deficits and fail to adequately explain gait and cognitive impairments in PD. The midbrain pedunculopontine nucleus (PPN) sends cholinergic input to the cerebellar vermis, which has much greater cholinergic innervation in humans than the cerebellar hemispheres. Degeneration of PPN, known to occur in PD could lead to cholinergic denervation of vermis. Vermis modulates gait and cognition, but little is known about its role in PD. Recent cerebellar resting-state functional connectivity (FC) analysis demonstrates altered vermal FC with sensorimotor and association cortices in PD and their respective gait and cognitive correlates. This proposed study utilizing a multimodal approach will extend the prior work and investigate whether longitudinal changes in vermal FC reflect decline in gait and cognition in PD and whether cholinergic denervation of the vermis, as measured by vesicular cholinergic transporter activity (VAChT) PET imaging, underlie these deficits in FC and behavior. The long term goal is to investigate whether vermal FC and cholinergic PET measures can serve as antecedent markers of dementia and falls in PD. The proposed study serves three major objectives. The first objective is to investigate cholinergic denervation of vermis and two important aspects of vermal FC in PD: its ability to objectively reflect progression of gait and cognitive impairment and its ties to underlying cholinergic pathology as measured by VAChT PET, the two key attributes of a reliable imaging biomarker. The second objective is to leverage the highly conducive and supportive environment, access to wealth of cross-sectional and longitudinal multimodal imaging data and comprehensive, sophisticated behavioral measures, and an excellent diverse team of mentors to provide the candidate with training in a) PET analysis and b) conducting longitudinal studies with special emphasis on multivariate, longitudinal statistics to ensure a timely transition to independence. The final objective for the candidate is to continue to author manuscripts especially involving PET and generate preliminary data towards a R01 application. Although with independent research aims, this study is privileged to use the data collected as a part of large scale longitudinal study with established funding. The proposed study could have substantial clinical impact by elucidating pathophysiologic bases of dementia and falls in PD, identifying potential therapeutic targets and possible metrics of target engagement, stratifying at risk patients before these disabling symptoms progress irreversibly, potentially leading to individually tailored therapeutic options in the future.