Preclinical trial for dysarthria treatment in Parkinson disease

帕金森病构音障碍治疗的临床前试验

• 批准号: 10290887
• 负责人: Michelle Renee Ciucci
• 金额: $ 65.35万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10290887
• 关键词: Affect; Affective; Age; Age-Months; Anhedonia; Anxiety; Attention; Behavior; Behavioral; Biological Assay; Brain; Brain Stem; Brain region; Cardiovascular system; Cell Count; Cell Death; Clinical Trials; Cognition; Cognitive; Communication; Controlled Study; Data Set; Diagnosis; Disease; Disease Progression; Dopamine; Dysarthria; Emotional; Ethics; Exercise; Gait; Genetic; Health; High Pressure Liquid Chromatography; Human; Idiopathic Parkinson Disease; Immunohistochemistry; Impairment; Intervention; Intervention Studies; Levodopa; Measures; Mediating; Memory; Mental Depression; Modeling; Motor; Nerve Degeneration; Nerve Growth Factor Receptors; Neurons; Neurotransmitters; Norepinephrine; Outcome; Outcomes Research; PINK1 gene; Parkinson Disease; Pathology; Patients; Performance; Persons; Pharmaceutical Preparations; Procedures; Propranolol; Quality of life; Rattus; Refractory; Ritalin; Role; Scanning; Side; Socialization; Substantia nigra structure; System; Testing; Therapeutic; Therapeutic Intervention; Time; Translating; Treatment Side Effects; Withholding Treatment; Work; base; behavioral response; brain behavior; brain tissue; combat; dopamine system; dopaminergic neuron; executive function; experience; improved; in vivo; innovation; intervention effect; locus ceruleus structure; microPET; negative affect; neuromechanism; neuron loss; neuroprotection; neurotoxicity; neurotrophic factor; noradrenergic; norepinephrine system; preclinical trial; primary outcome; randomized controlled design; relating to nervous system; side effect; social; treatment center; vocalization

PROJECT SUMMARY Parkinson disease (PD) is devastating to communication, which is also impacted by concurrent cognitive and affective impairments. The hallmark pathology, loss of dopamine, has guided therapy for decades; however, dopamine-centered treatments do not improve vocal communication, cognition, or affect. In fact, prior to classic dopamine loss, there is significant degeneration in the locus coeruleus, a norepinephrine-rich brainstem region that is vital to communicative and cognitive behaviors. Here, we propose to study three different therapeutic approaches that modulate norepinephrine (exercise, drugs, socialization) based on the rationale that modulating noradrenergic brain systems will improve PD-related communication deficits, as well as cognition and affect. We hypothesize that the benefit of these therapies will be improved communication, cognition, and affect as well as neuroprotection (i.e. sparing of neurons, increased neurotrophins). However, as with any treatment, there may be unwanted side effects such as anxiety, increased motor errors, or enhanced neuroprogression (loss of neurons) due to neurotoxicity of drugs. For superior experimental control and to study underlying neural mechanisms with increased scientific rigor, we will use a well-established translational rat model. The Pink1-/- rat is based on a genetic form of early and progressive PD (PARK6) that is nearly identical to idiopathic PD. We have shown communication, motor, cognitive, and affective deficits and neural abnormalities that are analogous to humans, including early loss of norepinephrine in brain regions important to communication. Aim 1 will analyze the benefits and side effects of intervention on communication, cognition, and affect. Pink1-/- rats will be treated with either: (1) cardiovascular exercise, (2) targeted vocal exercise, (3) methylphenidate, (4) propranolol, (5) social enrichment, or (6) control conditions at 10 months of age, which is equivalent to human age at time of diagnosed and treatment initiation. Vocalization, attention, accuracy, memory, anhedonia, and anxiety will be assayed, and effect sizes of each treatment will be calculated to determine the impact of treatment on all outcomes. Aim 2 will quantify changes to the brain with these interventions. Rats from Aim 1 will undergo in vivo microPET scanning to determine how interventions modulate norepinephrine. Ex vivo, brain tissues will be analyzed for neurotransmitter content, cell numbers, and changes to neurotrophins/receptors in regions associated with vocalization, cognition, and affect using high pressure liquid chromatography and immunohistochemistry. We hypothesize that interventions will result in either neuroprotection (e.g., increases in neurotrophic factors) or neurodegeneration (e.g., cell death/loss of neurotransmitter). This work is innovative because it is the first controlled study to robustly assess behavioral responses to noradrenergically-based interventions and concurrently measures in vivo modulation of norepinephrine and other important brain mechanisms as a result of intervention. Findings will be readily translated to directed human clinical trials to combat this devastating human health problem.

项目摘要 帕金森病（PD）对沟通是毁灭性的，沟通也受到并发认知和 情感障碍标志性的病理学，多巴胺的损失，已经指导了几十年的治疗;然而， 以多巴胺为中心的治疗不能改善声音交流、认知或情感。事实上，在经典 当多巴胺丢失时，蓝斑（一个富含去甲肾上腺素的脑干区域）出现明显的变性 这对交际和认知行为至关重要。在这里，我们建议研究三种不同的治疗方法， 调节去甲肾上腺素的方法（运动，药物，社会化）基于以下基本原理， 调节去甲肾上腺素能脑系统将改善PD相关的沟通缺陷，以及认知 和影响。我们假设这些疗法的好处将是改善沟通，认知， 影响以及神经保护（即保留神经元，增加神经营养因子）。然而，与任何 治疗，可能会有不必要的副作用，如焦虑，增加运动错误，或增强 由于药物的神经毒性而导致神经进展（神经元损失）。为了获得上级实验控制， 研究潜在的神经机制，增加科学严谨性，我们将使用一个完善的翻译 大鼠模型Pink 1-/-大鼠是基于一种早期和进行性PD（PARK 6）的遗传形式， 和特发性帕金森病一样我们已经证明了沟通，运动，认知和情感缺陷和神经 与人类类似的异常，包括大脑重要区域中去甲肾上腺素的早期丢失， 到沟通。目标1将分析干预对沟通，认知， 和影响。Pink 1-/-大鼠将接受以下治疗：（1）心血管运动，（2）有针对性的发声运动，（3） 哌甲酯，（4）普萘洛尔，（5）社会丰富，或（6）控制条件下，在10个月大，这是 相当于诊断和治疗开始时的人类年龄。发声，注意力，准确性， 将测定记忆力、快感缺失和焦虑，并计算每种治疗的效应量， 确定治疗对所有结果的影响。Aim 2将量化大脑的变化， 干预措施。来自Aim 1的大鼠将接受体内microPET扫描，以确定干预如何 调节去甲肾上腺素离体分析脑组织的神经递质含量、细胞数量， 以及与发声、认知和情感相关区域中神经营养因子/受体的变化 高压液相色谱和免疫组织化学。我们假设干预会导致 在神经保护（例如，神经营养因子的增加）或神经变性（例如，细胞死亡/丧失 神经递质）。这项工作是创新的，因为它是第一个对照研究，以有力地评估行为 反应去甲肾上腺素为基础的干预措施，并同时测量体内调节 去甲肾上腺素和其他重要的大脑机制作为干预的结果。调查结果将很容易 转化为直接的人类临床试验，以应对这一毁灭性的人类健康问题。