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

摘要 帕金森病、路易体痴呆和相关的突触核蛋白病具有长的前驱期， 持续数年至数十年，在此期间，神经变性在神经系统中不知不觉地进行。 结构和功能连接的补偿性神经可塑性变化被认为发生在脑缺血期间。 前驱期掩盖了运动和非运动体征的表达，这可能会显着延迟 在关键的治疗窗口期间进行诊断。或者，神经可塑性的结构和功能变化 可能导致运动和非运动体征的出现和/或恶化。目前，人们所知甚少 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 这些因素如何有助于前驱期运动和认知体征的掩蔽和/或出现 疾病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REM期间肌肉活动升高为特征的睡眠障碍 睡眠，与梦的实施相结合。IRBD被认为是突触核蛋白病的前驱期 因为超过70%的患有这种疾病的人最终会发展为帕金森病，路易痴呆， 身体或多系统萎缩。这个项目的目标是描述 iRBD患者大脑结构和功能的神经可塑性变化，并确定影响因素 有助于运动和认知体征的掩蔽和/或出现。Aim 1将使用超高场MRI 在7 T获得的结构（扩散张量）和功能（休息状态）的连接性的措施，前额叶和 感觉运动通路，它们在两年中的进展，以及它们与运动和 认知功能Aim 2将使用配对的联合刺激（外周神经刺激与 经颅磁刺激）检查长时程增强（LTP）样的状态和进展 运动皮层通路的可塑性及其与运动功能测量的关系。同样，Aim 3将使用 配对联想刺激检测前额叶皮层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将研究 快速眼动睡眠肌肉活动水平，结构和功能连接的状态，以及皮质 神经可塑性以及运动和认知体征的进展。该项目将提供独特的见解， 高风险人群前驱疾病期间大脑神经可塑性变化的时间演变 发生帕金森综合征、路易体痴呆或相关的突触核蛋白病。

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.