Neuroplasticity and the emergence of motor and cognitive deficits in prodromal synucleinopathy

前驱期突触核蛋白病的神经可塑性以及运动和认知缺陷的出现

• 批准号: 10419719
• 负责人: COLUM D MACKINNON
• 金额: $ 233.62万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419719
• 关键词: Anisotropy; Attenuated; Basal Nucleus of Meynert; Bradykinesia; Brain; Cognition; Cognitive; Cognitive deficits; Data; Dementia with Lewy Bodies; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dreams; Electroencephalography; Evoked Potentials; Evolution; Functional Magnetic Resonance Imaging; Gait; Goals; Impaired cognition; Impairment; Individual; Lateral; Long-Term Potentiation; Magnetic Resonance Imaging; Masks; Measures; Motor; Motor Cortex; Multiple System Atrophy; Muscle; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Nervous system structure; Neuronal Plasticity; Neuropsychology; Parasomnias; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathway interactions; Peripheral Nerve Stimulation; Persons; Prefrontal Cortex; REM Sleep; REM Sleep Behavior Disorder; Research Priority; Rest; Shapes; Sleep disturbances; Speed; Structure; Structure of subthalamic nucleus; Testing; Therapeutic; Time; Transcranial magnetic stimulation; Work; alpha synuclein; arm; basal forebrain; cognitive function; cohort; design; executive function; functional adaptation; high risk; insight; motor deficit; motor impairment; preservation; prospective; relating to nervous system; synucleinopathy; white matter

Abstract Parkinson’s disease, dementia with Lewy bodies, and related synucleinopathies have a long prodromal stage, lasting years to decades, during which neurodegeneration progresses insidiously across the nervous system. Compensatory neuroplastic changes in structural and functional connectivity are thought to occur during the prodromal stage that mask the expression of motor and non-motor signs, which could markedly delay diagnosis during a critical therapeutic window. Alternatively, neuroplastic changes in structure and function may contribute to the emergence and/or exacerbation of motor and non-motor signs. Currently, little is known about the temporal evolution of structural and functional adaptations, the state of cortical neuroplasticity, and how these factors contribute to the masking and/or emergence of motor and cognitive signs during prodromal disease. This project will study the progression of disease in people with isolated rapid eye movement (REM) behavior sleep disorder (iRBD), a sleep disturbance characterized by elevated muscle activity during REM sleep, in conjunction with dream enactment. IRBD is recognized as a prodromal stage of synucleinopathy since more than 70% of people with this disorder eventually develop Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. The goal of this project is to characterize the temporal evolution of neuroplastic changes in the structure and function of the brain in people with iRBD and to identify factors contributing to the masking and/or emergence of motor and cognitive signs. Aim 1 will use ultra-high field MRI at 7T to obtain measures of structural (diffusion tensor) and functional (rest-state) connectivity of prefrontal and sensorimotor pathways, their progression over two years, and their relationships to measures of motor and cognitive function. Aim 2 will use paired associative stimulation (peripheral nerve stimulation paired with transcranial magnetic stimulation) to examine the state and progression of long-term potentiation (LTP)-like plasticity in motor cortical pathways and its relationship to measures of motor function. Similarly, Aim 3 will use paired associative stimulation to examine the state and progression of LTP-like plasticity in prefrontal cortex and its relationship to measures of cognitive function and gait. Aim 4 will look at the relationships between the level of REM sleep muscle activity, the state of structural and functional connectivity, and cortical neuroplasticity and the progression of motor and cognitive signs. This project will provide unique insight into the temporal evolution of neuroplastic changes in the brain during prodromal disease in people at high risk of developing parkinsonism, dementia with Lewy bodies, or related synucleinopathies.

抽象的 帕金森氏病、路易体痴呆和相关的突触核蛋白病有很长的前驱期， 持续数年至数十年，在此期间神经退行性病变在整个神经系统中悄然进展。 结构和功能连接的代偿性神经可塑性变化被认为发生在 前驱阶段掩盖运动和非运动体征的表达，这可能会显着延迟 或者，在关键治疗窗口期间进行诊断，进行结构和功能的神经塑性变化。 可能导致运动和非运动体征的出现和/或恶化，目前知之甚少。 关于结构和功能适应的时间演变、皮质神经可塑性的状态，以及 这些因素如何导致前驱期运动和认知体征的掩盖和/或出现 该项目将研究孤立性快速眼动 (REM) 患者的疾病进展。 行为睡眠障碍 (iRBD)，一种以快速眼动 (REM) 期间肌肉活动升高为特征的睡眠障碍 睡眠与梦的发生一起被认为是突触核蛋白病的前驱阶段。 因为超过 70% 的患有这种疾病的人最终会患上帕金森病、路易痴呆症 该项目的目标是表征物体的时间演化。 iRBD 患者大脑结构和功能的神经塑性变化并确定因素 目标 1 将使用超高场 MRI 7T 以获得前额叶和功能性（静止状态）结构（扩散张量）和功能（静止状态）连接的测量值 感觉运动通路、两年内的进展以及它们与运动和运动测量的关系 目标 2 将使用配对联想刺激（周围神经刺激与 经颅磁刺激）检查长时程增强（LTP）样的状态和进展 类似地，目标 3 将使用运动皮质通路的可塑性及其与运动功能测量的关系。 配对联想刺激检查前额皮质 LTP 样可塑性的状态和进展 及其与认知功能和步态测量的关系 目标 4 将着眼于两者之间的关系。 快速眼动睡眠肌肉活动水平、结构和功能连接状态以及皮质 该项目将为神经可塑性以及运动和认知迹象的进展提供独特的见解。 高危人群前驱疾病期间大脑神经塑性变化的时间演变 发展为帕金森病、路易体痴呆或相关的突触核蛋白病。