Preclinical trial for dysarthria treatment in Parkinson disease

项目总结 帕金森病(PD)对沟通具有破坏性，同时也会受到认知和认知障碍的影响 情感障碍。标志性的病理--多巴胺丢失--几十年来一直指导着治疗；然而， 以多巴胺为中心的治疗不会改善发声交流、认知或情感。事实上，在经典之前 多巴胺丢失，蓝斑是一个富含去甲肾上腺素的脑干区域，有显著的变性 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(运动、药物、社交)的方法，其基础是 调节去甲肾上腺素能脑系统将改善帕金森病相关的沟通障碍和认知 和影响。我们假设这些疗法的好处将是改善沟通、认知和 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 治疗时，可能会有不想要的副作用，如焦虑、运动错误增加或增强 由于药物的神经毒性而导致的神经进展(神经元的丧失)。用于卓越的实验控制和 以更高的科学严谨性研究潜在的神经机制，我们将使用公认的 大鼠模型。PINK1-/-大鼠是基于一种早期和进行性帕金森病(PARK6)的遗传形式，这种遗传形式几乎 等同于特发性帕金森病。我们已经显示出沟通、运动、认知和情感缺陷以及神经缺陷。 类似人类的异常，包括大脑重要区域早期去甲肾上腺素的丢失 为了交流。目标1将分析干预对沟通、认知、 和影响。PINK1-/-大鼠将接受以下治疗之一：(1)心血管运动，(2)有针对性的发声训练，(3) 哌醋甲酯，(4)心得安，(5)社会充实，或(6)10个月龄的对照条件，即 相当于诊断和治疗开始时的人类年龄。发声，注意力，准确度， 将测试记忆力、快感缺失和焦虑，并计算每种治疗的效果大小 确定治疗对所有结果的影响。目标2将用这些来量化大脑的变化 干预措施。来自AIM 1的大鼠将接受体内microPET扫描，以确定如何干预 调节去甲肾上腺素。在体外，脑组织将被分析神经递质含量，细胞数量， 以及与发声、认知和影响使用相关的区域中神经营养素/受体的变化 高压液相色谱和免疫组织化学检测。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)。这项工作具有创新性，因为它是第一个强有力地评估行为的对照研究 对以去甲肾上腺素为基础的干预的反应和同时测量体内调节 去甲肾上腺素和其他重要的大脑机制作为干预的结果。调查结果将会很容易 转化为直接的人体临床试验，以对抗这一毁灭性的人类健康问题。

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.