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.

摘要