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: 10663385
• 负责人: Nicolaas Ida Bohnen
• 金额: $ 61.16万
• 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/10663385
• 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; human old age (65+); improved; information processing; motor symptom; multimodality; neural network; new therapeutic target; normal aging; novel; novel therapeutic intervention; portability; posture instability; 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.

摘要 多巴胺抵抗姿势不稳定和步态困难(PIGD)特征的处理，如跌倒， 可能代表帕金森氏病(PD)患者最重要的未得到满足的临床需求，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 认知功能减退和痴呆症的同时出现，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，如胆碱能系统的改变。前庭 损害，尤其是老年人较慢性的双侧前庭功能障碍(定义为 老前庭病(PVP)是导致美国老年人身体不平衡和跌倒的重要因素。不同于急性 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丧失。使用数据驱动的全脑选择囊泡型乙酰胆碱的方法 Transporter(Vacht)[18F]FEOBV PET脑区，我们还发现在PD中PVP的存在是 与胆碱能系统相关的改变最显著的是内侧膝状核(MGN)，由 内侧颞叶结构参与多通道感觉加工、空间定位和导航。 MGN胆碱能结合降低及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失衡相关的脑区。鉴于最近认识到重要的 前庭MGN的信息处理功能，我们的数据提示，这个小的后丘脑核团 可能是前庭中枢神经网络中的一个关键节点。这些对帕金森病患者的观察可能 也适用于患有PVP的非帕金森病老年人。胆碱能和多巴胺能损失不仅发生在帕金森病患者 但也是从青壮年开始的正常衰老的一部分。我们有初步数据显示 胆碱能神经末梢丢失的年龄相关性易感性在MGN和MGN中最为明显 近颞叶。这表明正常衰老的胆碱能易损性可能与 帕金森病患者PVP与胆碱能系统改变的关系相反，与年龄相关的脆弱性 这些结构可能解释了非帕金森病老年人PVP的高患病率和不断增加的患病率。我们建议 脑胆碱能[18F]FEOBV和多巴胺转运体[11C]PE2I PET显像与平衡 帕金森病患者和非帕金森病老年人的评估和前庭测试。这件事的首要目标是 这项研究旨在检验大脑区域特异性胆碱能系统变化与 帕金森病患者中存在PVP和Fall状态，与多巴胺能丢失无关。我们也 建议检验第二个假设，即MGN和MGN中与年龄相关的胆碱能脆弱性 非帕金森病老年人中的内侧颞叶与PVP和跌倒状态相关 与正常衰老的多巴胺能损失无关。

项目成果

Structural and molecular cholinergic imaging markers of cognitive decline in Parkinson's disease.

帕金森病认知能力下降的结构和分子胆碱能成像标志物。

• DOI: 10.1093/brain/awad226
• 发表时间: 2023
• 期刊: Brain : a journal of neurology
• 作者: Schumacher,Julia;Kanel,Prabesh;Dyrba,Martin;Storch,Alexander;Bohnen,NicolaasI;Teipel,Stefan;Grothe,MichelJ
• 通讯作者: Grothe,MichelJ

Atrophy of the Cholinergic Basal Forebrain can Detect Presynaptic Cholinergic Loss in Parkinson's Disease.

胆碱能基底前脑萎缩可以检测帕金森病的突触前胆碱能丧失。

• DOI: 10.1002/ana.26596
• 发表时间: 2023
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: Ray,NicolaJ;Kanel,Prabesh;Bohnen,NicolaasI
• 通讯作者: Bohnen,NicolaasI