Pathology and treatment of vocal deficits in Parkinson disease

帕金森病发声缺陷的病理学和治疗

• 批准号: 9118957
• 负责人: Cynthia A Kelm-Nelson
• 金额: $ 5.7万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9118957
• 关键词: Accounting; Acoustics; Address; Affect; Age; Age-Months; Amygdaloid structure; Animal Model; Animals; Area; Behavior; Behavior Therapy; Behavioral; Brain; Brain Pathology; Brain Stem; Brain region; Brain-Derived Neurotrophic Factor; Clinical; Communication; Corpus striatum structure; Data; Disease; Dopamine; Exercise; Exhibits; Female; Foundations; Frequencies; Functional disorder; Gene Mutation; Genes; Genotype; Goals; Grooming; Health; Human; Individual; Intervention; Knock-out; Knowledge; Laboratories; Larynx; Lead; Link; Measures; Mediating; Medical; Methodology; Methods; Midbrain structure; Modeling; Motivation; Motor Cortex; Nucleus Accumbens; Operative Surgical Procedures; PINK1 gene; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Play; Prevention; Process; Property; Provider; Quality of life; Rattus; Recovery of Function; Research; Resistance; Science; Shapes; Social Interaction; Speech; Staging; Stimulus; Substantia nigra structure; Techniques; Testing; Therapeutic; Training; Transgenic Model; Transgenic Organisms; Translational Research; Voice; alpha synuclein; base; cohort; density; effective therapy; experience; functional restoration; improved; innovation; insight; interest; midbrain central gray substance; neuropathology; novel; nucleus ambiguus; prevent; relating to nervous system; research study; social; targeted treatment; theories; translational approach; treatment planning; vocalization; voice therapy

DESCRIPTION (provided by applicant): Individuals with Parkinson disease (PD) experience devastating vocal communication deficits that negatively impact quality of life. These deficits manifest early and are largely resistant to pharmacological and surgical interventions. Recent research has shown that PD pathology is widespread, including not only central dopamine loss in the midbrain, but additional neuropathology including α-synuclein aggregation and decreases in neuroproteins (including brain derived neurotrophic factor (BDNF)) within brainstem and cortical regions. Despite these recent data, very little is known about how PD-associated pathologies contribute to vocal communication deficits. Furthermore, it is unknown how behavioral treatments, such as exercise-based voice therapies, affect the pathology. To develop effective treatments for these deficits, relationships between pathology and the consequences on vocal communication function must be defined. These unknowns are addressed in the proposed research by studying a novel transgenic rat model of PD: homozygous knock-out (KO) of PINK1, a gene mutation known to cause autosomal familial PD, by comparing these rats to nonaffected controls (wild type; WT) and by manipulating vocal exercise conditions. This unique approach provides knowledge of previously unexplored pathology and insight into the effects of vocal exercise treatments in a model that represents a direct mechanistic link to PD. PINK1 KO rats will be studied at an age that corresponds to early stage PD (8 months) and compared to WT controls. Our central hypotheses are: (1) PINK1 KO rats will show functional vocal deficits accompanied by brainstem and cortical pathologies, (2) PINK1 KO rats that undergo exercise will show prevention or reversal of functional deficits, modulation of pathology and improvement in vocal communication quality. To address these hypotheses, this proposal has 2 specific aims: (1) To quantify pathological changes to brainstem and cortical regions that mediate vocalization in a model of PD; and (2) To determine impact of vocal exercise on acoustics and brain pathology in a model of PD. Specifically, we will test the hypotheses that there will be an increase in α-synuclein aggregation and a decrease in BDNF in the periaqueductal gray, nucleus ambiguus, substantia nigra, striatum, nucleus accumbens, amygdala and M1 laryngeal motor cortex in PINK1 KO rats. Additionally, we hypothesize that the pathology will correlate with vocal deficits, and that vocal exercise will improve deficits and modulate pathology by decreasing aggregated α-synuclein and increasing BDNF in these regions. Further, using playback methodology, we hypothesize that conspecifics will show increased interest in vocalizations from rats that have undergone vocal exercise. Thus, we can explore interactions among pathology, exercise, and the ability of exercise to reduce deficits. The proposed translational research combines techniques and theory from behavioral and physiological sciences and will provide in-depth knowledge of brain pathology related to vocalization deficits and how exercise can prevent or reverse changes in an innovative model of PD.

描述(由申请者提供)：帕金森病(PD)患者经历毁灭性的语音交流缺陷，对生活质量产生负面影响。这些缺陷表现得很早，很大程度上对药物和手术干预具有抵抗力。最近的研究表明，帕金森病的病理广泛存在，不仅包括中脑的中枢多巴胺丢失，还包括脑干和皮质区域的α-突触核蛋白聚集和神经蛋白减少。尽管最近有这些数据，但人们对帕金森病相关的病理如何导致发声沟通障碍知之甚少。此外，尚不清楚行为疗法，如基于运动的声音疗法，是如何影响病理的。为了开发有效的治疗这些缺陷的方法，必须明确病理和对声音交流功能的影响之间的关系。在拟议的研究中，通过研究一种新的帕金森病转基因大鼠模型：PINK1的纯合子敲除(KO)，通过将这些大鼠与未受影响的对照组(野生型；WT)进行比较，并通过操纵发声训练条件，解决了这些未知因素。这种独特的方法提供了以前未曾探索过的病理学知识，并在一个代表与帕金森病直接机制联系的模型中洞察了发声训练治疗的效果。PINK1KO大鼠的年龄将与早期PD(8个月)相对应，并与WT对照组进行比较。我们的中心假设是：(1)PINK1-KO大鼠将出现功能性发声障碍，并伴有脑干和皮质病理改变；(2)PINK1-KO大鼠经过训练后，功能障碍将被预防或逆转，病理改变和发声交流质量将得到改善。为了解决这些假说，这项建议有两个具体的目标：(1)量化PD模型中调节发声的脑干和皮质区域的病理变化；(2)确定发声训练对PD模型中声学和脑病理的影响。具体地说，我们将测试PINK1KO大鼠中脑导水管周围灰质、疑核、黑质、纹状体、伏隔核、杏仁核和M1喉运动皮质中α-突触核蛋白聚集增加和脑源性神经营养因子减少的假设。此外，我们假设病理与发声障碍相关，发声训练将通过减少这些区域聚集的α-突触核蛋白和增加脑源性神经营养因子来改善发声障碍并调节病理。此外，使用回放方法，我们假设相同的特异性将显示出对经过发声训练的大鼠发声的更大兴趣。因此，我们可以探索病理、运动和运动减少赤字的能力之间的相互作用。这项拟议的翻译研究结合了行为和生理科学的技术和理论，将提供与发声缺陷相关的大脑病理以及运动如何防止或逆转PD创新模型的变化的深入知识。

项目成果

Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease.

• DOI: 10.1016/j.neulet.2016.04.003
• 发表时间: 2016-05-16
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Kelm-Nelson CA;Stevenson SA;Ciucci MR
• 通讯作者: Ciucci MR

Characterization of oromotor and limb motor dysfunction in the DJ1 -/- model of Parkinson disease.

• DOI: 10.1016/j.bbr.2017.10.036
• 发表时间: 2018-02-26
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Yang KM;Blue KV;Mulholland HM;Kurup MP;Kelm-Nelson CA;Ciucci MR
• 通讯作者: Ciucci MR

Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease.

• DOI: 10.1016/j.brainres.2017.12.002
• 发表时间: 2018-02-01
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Kelm-Nelson CA;Brauer AFL;Barth KJ;Lake JM;Sinnen MLK;Stehula FJ;Muslu C;Marongiu R;Kaplitt MG;Ciucci MR
• 通讯作者: Ciucci MR

Quantitative Analysis of Catecholamines in the Pink1 -/- Rat Model of Early-onset Parkinson's Disease.

• DOI: 10.1016/j.neuroscience.2018.02.027
• 发表时间: 2018-05-21
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Kelm-Nelson CA;Trevino MA;Ciucci MR
• 通讯作者: Ciucci MR

Pink1 -/- Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology.

• DOI: 10.1007/s00455-018-9896-5
• 发表时间: 2018-12
• 期刊: Dysphagia
• 影响因子: 2.6
• 作者: Cullen KP;Grant LM;Kelm-Nelson CA;Brauer AFL;Bickelhaupt LB;Russell JA;Ciucci MR
• 通讯作者: Ciucci MR