Influence of neuromuscular pathology on parkinsonian communication deficits

神经肌肉病理学对帕金森沟通缺陷的影响

• 批准号: 9318494
• 负责人: NADINE P CONNOR
• 金额: $ 54.59万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318494
• 关键词: Address; Affect; Age; Age-Months; Anatomy; Animal Model; Behavior; Behavior Therapy; Behavioral; Biochemistry; Biological; Brain Stem; Cephalic; Clinical; Communication; Communication impairment; Complex; Controlled Study; Data; Deglutition; Deglutition Disorders; Denervation; Development; Disease; Disease Progression; Eating; Exercise; Gene Mutation; Genetic; Human; Individual; Intervention; Knock-out; Knowledge; Laboratories; Laryngeal muscle structure; Larynx; Lead; Learning; Light; Link; Mediating; Medical; Methods; Modeling; Muscle; Nerve; Neuraxis; PINK1 gene; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathology; Patients; Peripheral; Peripheral Nerves; Physiological; Population; Prevention; Process; Property; Quality of life; Rattus; Research; Science; Severity of illness; Structure; Techniques; Testing; Time; Tongue; Translational Research; Translations; Ultrasonics; Voice; Work; alpha synuclein; base; eating pathology; effective therapy; exercise intervention; experience; experimental study; innovation; insight; neuromuscular; neuromuscular system; novel; pre-clinical; prevent; public health relevance; research study; theories; translational approach; treatment effect; vocalization

 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.

 描述（由应用程序提供）：患有帕金森氏病（PD）的人经历了毁灭性沟通和吞咽的经历，这定义了对生活质量的负面影响。最近的研究表明，PD病理学是广泛的，不仅包括中枢神经系统区域，还包括外周结构，例如涉及交流和吞咽的神经和肌肉。但是，要求这些最近的数据，对周围病理如何促进交流和吞咽不足以及疾病过程中这些缺陷的出现时，知之甚少。此外，尚不清楚行为治疗在临床上使用的行为治疗如何影响这些缺陷的表现。为了开发更有效的治疗方法，必须清楚了解周围病理的进展以及这些病理影响沟通和吞咽的方式。这些未知数将在拟议的研究中通过研究PINK1的进行性，新型的PD：纯合子敲除（KO）的进行性研究，该模型是一种已知会导致PD的基因突变，将这些大鼠与未受影响的对照（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PD的直接机械链接，对治疗在当前临床使用中的影响的洞察力以及对与发声和吞咽不足有关的PD中以前出乎意料的外围病理的了解。采用类似于人类使用的任务和行为将最大化翻译。大鼠的年龄将与早期，中期和晚期PD（6、10和14个月）相对应。我们的中心假设是：（1）PINK1 KO大鼠将显示出通过疾病阶段逐渐增加严重程度的外周病理学来定义的行为，（2）进行运动的PINK1 KO大鼠将显示出预防或反向外周神经肌肉病理学的调节。为了解决这些假设，该提案具有3个具体目的：（1）量化外围神经和肌肉的病理变化，中位发声和跨PD阶段吞咽的肌肉； （2）确定神经肌肉病理如何与PD阶段的发声，舌头强度和功能饮食定义； （3）确定舌头和喉运动如何影响神经肌肉病理。该建议是及时且创新的，因为我们对PD的理解现在体现了包括肌肉和神经在内的宽度病理学。拟议的研究将提供对PD中相对出乎意料的神经肌肉病理的深入了解，也将是第一个研究运动如何预防或逆转舌和喉内生物学变化的人。我们在PINK1 KO大鼠中进行的系统和对照研究结合了行为，解剖学和物理科学的技术和理论，并提供了一个机会，以了解神经肌肉病理如何为观察到的发声和吞咽的行为变化提供信息。这项转化研究很有可能产生与重要的科学和临床问题有关的有意义的发现。