Central cholinergic presbyvestibulopathy network changes and imbalance in Parkinson's disease and older persons

摘要 多巴胺抵抗性姿势不稳定和步态困难（PIGD）特征的管理，如福尔斯， 可能是帕金森病（PD）患者最重要的未满足的临床需求， 生活质量下降的主要原因。功能性能力和生活质量的丧失与 PIGD的出现进一步受到认知下降和痴呆的同时出现的影响。这 可能反映了进行性非多巴胺能病变，如胆碱能系统的变化。前庭 损伤，特别是老年人更慢性的双侧前庭功能障碍（定义为 老年性前庭神经病（presbyvestibulopathy，PVP）是美国老年人失衡和福尔斯的重要原因。与急性 除了散发性前庭疾病外，PVP在年龄相关疾病如PD中也很常见。我们有 新的初步数据显示，PD中PVP的存在与不平衡相关， 黑质纹状体多巴胺能损失。使用囊泡乙酰胆碱的数据驱动的全脑选择方法 通过对VACh转运蛋白（VAChT）[18 F]FEOBV PET脑区的研究，我们还发现PD中PVP的存在是 与胆碱能系统相关的变化在内侧膝状体核（MGN）中最为显著， 内侧颞叶结构参与多模态感觉处理、空间定向和导航。 MGN中较低的胆碱能结合和PVP相关特异性细胞中胆碱能结合的复合测量 与PD患者存在不平衡相关的大脑区域。鉴于最近认识到重要的 前庭信息处理功能的MGN，我们的数据表明，这个小的后丘脑核， 可以作为中枢前庭神经网络中的关键节点。PD患者的这些观察结果可能 也适用于患有PVP的非PD老年人。胆碱能和多巴胺能的损失不仅发生在PD 但也是从成年早期开始的正常衰老的一部分。我们有初步数据显示， 年龄相关的胆碱能神经末梢损失的脆弱性在MGN中最明显， 中颞叶这表明，正常衰老的胆碱能脆弱性可能有助于 PVP与PD胆碱能系统改变的关系相反，与年龄相关的脆弱性 这些结构可以解释非PD老年人PVP的高患病率和不断增加的患病率。我们提出 进行脑胆碱能[18F]FEOBV和多巴胺转运蛋白[11C]PE2I PET成像和平衡 评估和前庭测试的人与PD和非PD老年人。这个项目的首要目标是 这项研究的目的是检验脑区特异性胆碱能系统的变化与脑缺血相关的假设。 PD患者中PVP和跌倒状态的存在与多巴胺能损失无关。我们也 建议检验次要假设，即年龄相关的MGN胆碱能脆弱性， 中颞叶与非PD老年人PVP和跌倒状态的存在相关 独立于正常衰老的多巴胺能损失。

Abstract The management of dopamine resistant postural instability and gait difficulties (PIGD) features, such as falls, represents perhaps the most important unmet clinical need in persons with Parkinson's disease (PD) and is a major cause for reduced quality of life. The loss of functional abilities and quality of life associated with the emergence of PIGD is further compromised by coinciding emergence of cognitive decline and dementia. This may reflect progressive non-dopaminergic pathologies, such as cholinergic system changes. Vestibular impairment, in particular more chronic bilateral vestibular dysfunction of older age (defined as presbyvestibulopathy, PVP), is a significant contributor to imbalance and falls in older US adults. Unlike acute vestibular disorders that are sporadic, PVP is also common in an age-associated disorder like PD. We have novel preliminary data showing that the presence of PVP in PD is associated with imbalance independent from nigrostriatal dopaminergic losses. Using a data-driven whole brain selection method of vesicular acetylcholine transporter (VAChT) [18F]FEOBV PET brain regions, we also found that the presence of PVP in PD is associated with cholinergic system changes most prominently in the medial geniculate nucleus (MGN) and by medial temporal lobe structures involved in multimodal sensory processing, spatial orientation and navigation. Lower cholinergic binding in the MGN and a composite measure of cholinergic binding in PVP-related specific brain regions associated with presence of imbalance in people with PD. Given recent recognition of important vestibular information processing functions of the MGN, our data suggest that this small metathalamic nucleus may function as a key node in the central vestibular neural network. These observations in people with PD may also be relevant for non-PD older adults with PVP. Cholinergic and dopaminergic losses not only occur in PD but are also part of normal aging starting from young adulthood on. We have preliminary data showing that age-associated vulnerability of cholinergic nerve terminal losses is most conspicuous in the MGN and mesiotemporal lobe. This suggests that cholinergic vulnerability of normal aging may contribute to the relationship between PVP and cholinergic system changes in PD. Conversely, age-associated vulnerability in these structures may explain the high and increasing prevalence of PVP in non-PD older persons. We propose to perform brain cholinergic [18F]FEOBV and dopamine transporter [11C]PE2I PET imaging and balance assessment and vestibular testing in persons with PD and non-PD older adults. The overarching goal of this study is to test the hypothesis that brain region-specific cholinergic system changes associate with the presence of both PVP and fall status in persons with PD independent of dopaminergic losses. We also propose to test the secondary hypothesis that age-associated cholinergic vulnerability in the MGN and mediotemporal lobe associate with the presence of both PVP and fall status in non-PD older adults independent of dopaminergic losses of normal aging.