Influence of neuromuscular pathology on parkinsonian communication deficits

 描述(申请人提供)：帕金森病(PD)患者经历破坏性的沟通和吞咽缺陷，对生活质量产生负面影响。最近的研究表明，帕金森病的病理分布广泛，不仅包括中枢神经系统区域，还包括参与沟通和吞咽的神经和肌肉等周围结构。然而，尽管有这些最近的数据，人们对外周病理如何促进沟通和吞咽缺陷以及在疾病过程中何时出现这些缺陷知之甚少。此外，目前尚不清楚临床上使用的行为疗法，如基于运动的发声和吞咽疗法，是如何影响这些缺陷的表现的。为了开发更有效的治疗方法，必须清楚地了解外周病变的进展以及这些病变影响沟通和吞咽的方式。在拟议的研究中，这些未知因素将通过研究一种渐进的、新的帕金森病遗传大鼠模型来解决：PINK1的纯合子敲除(KO)，已知的导致帕金森病的基因突变，将这些大鼠与未受影响的对照组(野生型；WT)进行比较，并通过操纵运动条件。这种方法提供了与人类帕金森病的直接机制联系，洞察了当前临床使用的治疗方法的效果，并了解了与发声和吞咽障碍相关的帕金森病以前未被探索的外周病理学知识。采用类似于人类使用的任务和行为将最大限度地促进翻译。大鼠将在对应于早、中、晚期PD的年龄(6、10和14个月)进行研究。我们的中心假设是：(1)PINK1-KO大鼠将表现出行为缺陷，并伴有外周病理，并随着疾病阶段的加重而逐渐加重。(2)PINK1-KO大鼠接受运动后，将表现出预防或逆转功能障碍和外周神经肌肉病理的调节。为了解决这些假说，这项建议有三个具体的目标：(1)量化周围神经和肌肉的病理变化，这些变化调节PD各阶段的发声和吞咽；(2)确定神经肌肉病理与PD各阶段发声、舌力和功能性进食障碍的关系；以及(3)确定舌头和喉部的运动如何影响神经肌肉病理。这一建议是及时和创新的，因为我们对帕金森病的理解现在体现了包括肌肉和神经在内的广泛病理。这项拟议的研究将提供帕金森病中相对未被探索的神经肌肉病理学的深入知识，也将是第一次研究运动如何防止或逆转舌头和喉部的生物变化。我们在PINK1 KO大鼠上进行的系统和对照研究结合了行为、解剖学和生理学的技术和理论，并提供了一个机会来了解神经肌肉病理如何影响发声和吞咽中观察到的行为变化。这种转化性研究很有可能产生与重要的科学和临床问题相关的有意义的发现。

 DESCRIPTION (provided by applicant): Individuals with Parkinson disease (PD) experience devastating communication and swallowing deficits that negatively impact quality of life. Recent research has shown that PD pathology is widespread, including not only central nervous system regions, but also peripheral structures such as nerves and muscles involved in communication and swallowing. However, despite these recent data, very little is known about how peripheral pathologies contribute to communication and swallowing deficits and when in the disease process these deficits emerge. Furthermore, it is unknown how behavioral treatments used clinically, such as exercise-based voice and swallow therapies, affect the manifestation of these deficits. To develop more effective treatments, a clear understanding of the progression of peripheral pathologies and the manner in which these pathologies affect communication and swallowing must be obtained. These unknowns will be addressed in the proposed research by studying a progressive, novel genetic rat model of PD: homozygous knock-out (KO) of PINK1, a gene mutation known to cause PD, comparing these rats to non-affected controls (wild type; WT), and by manipulating exercise conditions. This approach provides a direct mechanistic link to PD in humans, insight into the effects of treatments in current clinical use, and knowledge of previously unexplored peripheral pathology in PD associated with vocalization and swallowing deficits. Employing tasks and behaviors analogous to those used in humans will maximize translation. Rats will be studied at ages that correspond to early, mid, and late stage PD (6, 10 and 14 months). Our central hypotheses are: (1) PINK1 KO rats will show behavioral deficits accompanied by peripheral pathologies that will progressively increase in severity by disease stage, (2) PINK1 KO rats that undergo exercise will show prevention or reversal of functional deficits and modulation of peripheral neuromuscular pathology. To address these hypotheses, this proposal has 3 specific aims: (1) To quantify pathological changes to peripheral nerves and muscles that mediate vocalization and swallowing across stages of PD; (2) To determine how neuromuscular pathology relates to deficits in vocalization, tongue strength and functional eating across stages of PD; and (3) To determine how exercise of the tongue and larynx affects neuromuscular pathology. This proposal is timely and innovative because our understanding of PD now embodies widespread pathology that includes muscles and nerves. The proposed research will provide in-depth knowledge of neuromuscular pathology that is relatively unexplored in PD and will also be the first to examine how exercise can prevent or reverse biological changes within the tongue and larynx. Our systematic and controlled studies in the PINK1 KO rat combine techniques and theory from behavioral, anatomical, and physiological sciences and provide an opportunity to learn how neuromuscular pathologies inform observed behavioral changes in vocalization and swallowing. This translational research has a high likelihood of yielding meaningful findings related to important scientific and clinical issues.