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

帕金森病和老年人中枢性胆碱能性老年前庭病网络的变化和失衡

• 批准号: 10273747
• 负责人: Nicolaas Ida Bohnen
• 金额: $ 61.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273747
• 关键词: Activities of Daily Living; Acute; Adult; Affect; Age; Aging; Agonist; Amygdaloid structure; Area; Attention; Basal Ganglia; Bilateral; Binding; Brain; Brain region; Cell Nucleus; Chronic; Clinical; Cognitive; Data; Dementia; Denervation; Development; Disease; Dopamine; Dopaminergic Agents; Elderly; Equilibrium; Fall prevention; Freezing; Functional disorder; Fusiform gyrus; Gait; Geniculate body structure; Goals; Impaired cognition; Impairment; Inferior; Insula of Reil; Lateral Geniculate Body; Lobe; Measures; Medial; Methods; Motor; Movement; Nerve; Neurodegenerative Disorders; Neurotransmitters; Parahippocampal Gyrus; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Pontine structure; Positron-Emission Tomography; Posture; Prevalence; Pulvinar structure; Quality of life; Refractory; Research; Resistance; Rest Tremor; Sensory; Societies; Space Perception; Structure; System; Temporal Lobe; Testing; Thalamic structure; acetylcholine transporter; age related; cholinergic; comorbidity; dopamine transporter; equilibration disorder; falls; functional loss; improved; information processing; motor symptom; multimodality; neural network; new therapeutic target; normal aging; novel; portability; posture instability; treatment strategy; way finding; young adult

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.

抽象的 治疗多巴胺抵抗性姿势不稳和步态困难 (PIGD) 特征，例如跌倒、 也许代表了帕金森病 (PD) 患者最重要的未满足的临床需求，并且是 生活质量下降的主要原因。与此相关的功能能力和生活质量的丧失 认知能力下降和痴呆的同时出现进一步损害了 PIGD 的出现。这 可能反映进行性非多巴胺能病理，例如胆碱能系统变化。前庭 损伤，特别是老年的更慢性的双侧前庭功能障碍（定义为 老年前庭病 (PVP) 是导致美国老年人失衡和跌倒的重要原因。与急性不同 前庭疾病是散发性的，PVP 在帕金森病等与年龄相关的疾病中也很常见。我们有 新的初步数据表明，PD 中 PVP 的存在与不平衡有关，独立于 黑质纹状体多巴胺能损失。使用数据驱动的囊泡乙酰胆碱全脑选择方法 转运蛋白 (VAChT) [18F]FEOBV PET 脑区域，我们还发现 PD 中存在 PVP 与胆碱能系统变化相关的变化在内侧膝状核（MGN）中最为显着，并且通过 内侧颞叶结构涉及多模式感觉处理、空间定向和导航。 MGN 中胆碱能结合的降低以及 PVP 相关特异性胆碱能结合的综合测量 与帕金森病患者存在不平衡相关的大脑区域。鉴于最近认识到重要 MGN 的前庭信息处理功能，我们的数据表明这个小后丘脑核 可能作为中枢前庭神经网络的关键节点。这些在帕金森病患者中的观察结果可能 也与患有 PVP 的非 PD 老年人相关。胆碱能和多巴胺能损失不仅发生在帕金森病中 但也是从青年时期开始的正常衰老的一部分。我们有初步数据表明 与年龄相关的胆碱能神经末梢损失的脆弱性在 MGN 和 近颞叶。这表明正常衰老的胆碱能脆弱性可能导致 PD 中 PVP 与胆碱能系统变化的关系。相反，与年龄相关的脆弱性 这些结构可以解释 PVP 在非 PD 老年人中的高患病率且不断增加。我们建议 进行脑胆碱能 [18F]FEOBV 和多巴胺转运蛋白 [11C]PE2I PET 成像和平衡 对帕金森病患者和非帕金森病老年人进行评估和前庭测试。本次活动的总体目标是 研究的目的是检验以下假设：大脑区域特异性胆碱能系统的变化与 PD 患者同时存在 PVP 和跌倒状态，与多巴胺能损失无关。我们也 建议检验次要假设，即 MGN 中与年龄相关的胆碱能脆弱性 颞叶内侧叶与非 PD 老年人的 PVP 和跌倒状态相关 与正常衰老的多巴胺能损失无关。