Pathophysiology of Dystonia and Parkinsonism

肌张力障碍和帕金森病的病理生理学

• 批准号: 7579051
• 负责人: JONATHAN W. MINK
• 金额: $ 30.27万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-10 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7579051
• 关键词: Affect; Animals; Basal Ganglia; Behavioral; Bradykinesia; Chronic; Chronic Phase; Corpus striatum structure; Development; Disease; Dopamine; Dystonia; Functional disorder; Globus Pallidus; Individual; Injection of therapeutic agent; Intracarotid; Joints; Lead; Measures; Mediating; Methods; Minority; Monkeys; Motor Manifestations; Movement; Movement Disorders; Muscimol; Muscle; Muscle Contraction; Muscle Rigidity; Neurons; North America; Parkinson Disease; Parkinsonian Disorders; Pars Externa; Pars Interna; Pattern; Phase; Physiology; Positron-Emission Tomography; Posture; Rest; Rodent Model; Severities; Smooth Muscle; Specificity; Techniques; Testing; Time; Training; Tremor; Work; behavior measurement; computerized data processing; dopaminergic neuron; human subject; improved; insight; limb movement; neuronal patterning; neurotransmission; putamen; research study; response

DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects nearly one million people and dystonia affects up to 500,000 people in North America. It is generally accepted that the motor manifestations of PD are due to degeneration of nigrostriatal dopamine neurons with resulting striatal dopamine depletion. The causes of dystonia are more numerous. Recent evidence has indicated that dystonia (involuntary muscle contractions that produce twisting postures) can also be associated with deficiencies in striatal dopamine neurotransmission. In monkeys, it has been shown that unilateral striatal dopamine depletion induced by intracarotid injection of MPTP causes a biphasic disorder with transient dystonia followed by stable parkinsonism. The association of both dystonia and parkinsonism with equivalent degrees of striatal dopamine deficiency raises questions about the fundamental pathophysiology of these conditions. The purpose of this project is to investigate the pathophysiology of parkinsonism and dystonia by recording the activity of globus pallidus neurons before and after the administration of MPTP in monkeys trained to perform a reaching task. Quantitative behavioral methods and PET imaging will be used to measure the severity of dystonia, parkinsonism, and dopamine depletion. The activity of single neurons in globus pallidus internal segment (GPi) and external segment (GPe) will be recording in monkeys before MPTP and in the transient dystonic phase and chronic parkinsonian phase after MPTP. The specific aims are: 1) to determine to determine the relationship of resting pallidal discharge rates, patterns, and synchronization to dystonia and parkinsonism; 2) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism; 3) to determine whether there is loss of somatotopic selectivity in the sensorimotor region of putamen and whether the loss of somatotopic selectivity in globus pallidus is due to abnormal signal processing in the putamen. These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will advance our understanding of the pathophysiology of parkinsonism and dystonia in ways not possible from studies in rodent models or in human subjects. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.

描述（由申请人提供）：帕金森氏病（PD）影响了近100万人，而北美最多可影响50万人。普遍认为，PD的运动表现是由于骨纹状体多巴胺神经元的变性而导致的，导致纹状体多巴胺的耗竭。肌张力障碍的原因更多。最近的证据表明，肌张力障碍（产生扭曲姿势的非自愿肌肉收缩）也可能与纹状体多巴胺神经传递的缺陷有关。在猴子中，已经表明，通过注射MPTP的核内注射引起的单侧纹状体多巴胺耗竭会导致瞬时肌张力障碍的双相疾病，随后是稳定的帕金森氏症。肌张力障碍和帕金森氏症与纹状体多巴胺缺乏程度的关联引发了有关这些疾病基本病理生理学的问题。该项目的目的是通过记录在受过训练以执行达到达到任务的猴子的猴子之前和之后，通过记录MPTP之前和之后的Globus Pallidus神经元的活动来研究帕金森氏症和肌张力障碍的病理生理。定量行为方法和PET成像将用于测量肌张力障碍，帕金森氏症和多巴胺耗竭的严重程度。 Globus Pallidus内部片段（GPI）和外部片段（GPE）中单神经元的活性将在MPTP之前记录在猴子中，并在MPTP之后的瞬时肌张纸阶段和慢性帕金森氏阶段记录。具体目的是：1）确定确定静止苍白的放电速率，模式和同步与肌张力障碍和帕金森氏症的关系； 2）确定肌张力障碍和帕金森氏症伴随运动相关的神经元活动的特定变化； 3）确定壳虫的感觉运动区域中的体位选择性是否丧失，以及pallidus球体选择性的丧失是否是由于壳质中异常的信号处理所致。这些目标将检验与肌张力障碍和帕金森氏症有关的基底神经节功能障碍的特定假设。这项研究的结果将通过在啮齿动物模型或人类受试者中无法进行研究的方式来提高我们对帕金森氏症和肌张力障碍的病理生理学的理解。更好地了解病理生理学可能会导致新疗法或改善当前可用疗法的应用。