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，其特征在于 巨大的临床异质性。PD伴痴呆被认为是阿尔茨海默病相关疾病之一 痴呆症高达80%的PD患者患有痴呆症，步态障碍导致显著的发病率， 由于缺乏有效的治疗，死亡率高，社会经济负担大大加重。这两个 损害对多巴胺能药物是难治的，表明涉及其他神经递质系统或脑 黑质纹状体通路以外的区域。大多数神经影像学研究都集中在纹状体多巴胺能缺陷 并且不能充分解释PD中的步态和认知障碍。中脑脚桥核 (PPN)将胆碱能输入发送到小脑蚓部，小脑蚓部具有更大的胆碱能神经支配， 比小脑半球更大。已知PD中发生的PPN变性可能导致胆碱能 去蚓部神经支配蚓部调节步态和认知，但很少有人知道它在PD中的作用。最近 小脑静息态功能连接（FC）分析表明，改变了Vermal FC与感觉运动 以及PD中的联合皮层及其各自的步态和认知相关性。这项研究利用了 多模态方法将扩展先前的工作，并调查是否纵向变化，在vermal FC反映 PD患者的步态和认知能力下降，以及是否存在小脑蚓部胆碱能去神经支配，通过泡状神经测量 胆碱能转运体活性（VAChT）PET成像，是FC和行为这些缺陷的基础。长期 目的是研究是否可以作为早期标志物的蠕虫FC和胆碱能PET措施， 痴呆和福尔斯。拟议的研究有三个主要目的。第一个目标是调查 帕金森病患者小脑蚓部胆碱能神经的失支配和小脑蚓部FC的两个重要方面：客观反映帕金森病的能力， 步态和认知障碍的进展及其与潜在胆碱能病理学的关系（通过以下指标测量） VAChT PET是可靠的成像生物标志物的两个关键属性。第二个目标是利用 高度有利和支持性环境，可利用丰富的横向和纵向多式联运 成像数据和全面，复杂的行为测量，以及优秀的多元化导师团队 为候选人提供a）PET分析和B）使用特殊 强调多元、纵向统计，以确保及时过渡到独立。最终目标 候选人的工作是继续撰写手稿，特别是涉及PET的手稿，并生成初步数据 R01应用程序。尽管本研究具有独立的研究目的，但本研究有幸使用数据 收集作为大规模纵向研究的一部分，有固定的资金。拟议的研究本可以 通过阐明PD中痴呆和福尔斯的病理生理学基础，确定潜在的 治疗目标和目标参与的可能指标，在这些禁用之前对风险患者进行分层 症状不可逆转地发展，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.