PATHOPHYSIOLOGY OF DYSTONIA AND PARKINSONISM

在北美，帕金森病（PD）影响近100万人，肌张力障碍影响多达50万人。人们普遍认为帕金森病的运动表现是由于黑纹状体多巴胺神经元变性导致纹状体多巴胺耗竭。最近的证据表明，肌张力障碍（产生扭曲姿势的不随意肌收缩）也可能与纹状体多巴胺神经传递不足有关。在猴子中，研究表明颈动脉内注射MPTP诱导的单侧纹状体多巴胺耗竭会导致短暂性肌张力障碍的双相障碍，随后出现稳定的帕金森病。纹状体多巴胺缺乏与肌张力障碍和帕金森氏症的关系提出了有关这些疾病的基本病理生理学的问题。本项目的目的是通过记录猴子在接受MPTP训练后的白球神经元活动，来研究帕金森病和肌张力障碍的病理生理学。定量行为方法和[18F]FDOPA PET成像将用于测量帕金森病的严重程度和多巴胺消耗。在MPTP前和MPTP后的短暂性肌张力障碍期和慢性帕金森期，记录猴子苍白球内段和外段单个神经元的活动。具体目的是1)确定静息白质放电率和模式与肌张力障碍和帕金森病的关系，2)确定纹状体多巴胺缺乏是否导致体感觉接受野的扩张，这在肌张力障碍和帕金森病中都是常见的，3)确定运动相关神经元活动的特定变化伴随肌张力障碍和帕金森病。这些目的将测试与肌张力障碍和帕金森病相关的基底神经节功能障碍的特定假设。本研究的结果将补充本项目其他项目的结果，并将进一步了解帕金森病和肌张力障碍的病理生理学。对病理生理学的更好理解可能会导致新的治疗方法或改进现有治疗方法的应用。

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 nigrastriatal dopamine neurons with resulting striatal dopamine depletion. 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 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 [18F]FDOPA PET imaging will be used to measure the severity of 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 l) to determine the relationship of resting pallidal discharge rates and patterns to dystonia and parkinsonism, 2) to determine if there is expansion of somatosensory receptive fields due to striatal dopamine deficiency that is common to both dystonia and parkinsonism, and 3) to determine specific changes in movement-related neuronal activity that accompany dystonia and parkinsonism. These aims will test specific hypotheses of basal ganglia dysfunction related to dystonia and parkinsonism. The results from this study will complement those from the other projects in this program and will further understanding of the pathophysiology of parkinsonism and dystonia. Better understanding of the pathophysiology may lead to new therapies or improved application of currently available therapies.