Neurochemical substrates of rigidity and chorea in Huntington's disease.
Neurochemical substrates of rigidity and chorea in Huntington's disease.
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亨廷顿病中强直和舞蹈症的神经化学底物。
DOI：
10.1093/brain/116.5.1201
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Beal,MF
中科院分区：
文献类型：
--
作者：
Storey,E;Beal,MF
概述亨廷顿氏病是一种进行性退行性神经系统疾病，其产生称为舞蹈病的特征性运动障碍。虽然舞蹈病与基底神经节的功能障碍有关，但运动障碍如舞蹈病产生的潜在机制仍知之甚少。最近在灵长类动物中的研究已经导致了舞蹈病的实验模型，并假定涉及特定的神经通路。在本研究中，我们试图确定实验模型的有效性，通过测量γ氨基丁酸（GABA），谷氨酸，P物质和甲硫氨酸脑啡肽在亨廷顿病患者的基底节中的浓度，这些患者在死亡后6个月内表现为舞蹈症或僵硬/运动迟缓。我们还根据病理分级描述了亨廷顿病患者的变化，因为这可能是一个混杂因素。我们分析了12名对照组、11名3级和12名4级亨廷顿病患者的死后脑组织。3级和4级病例包括8例成人发作的舞蹈病，9例成人发作的僵硬和6例青少年发作的僵硬患者。我们还分析了11例2级成人舞蹈病亨廷顿病患者的壳核和苍白球。基于灵长类动物实验研究的舞蹈病模型提出，纹状体GABA能抑制性投射到苍白球外的损失导致投射到丘脑底核的抑制性苍白球外GABA能神经元的活性增加。据信，外苍白球的GABA能输入的损失先于内苍白球的GABA能输入的损失，内苍白球的GABA能输入的损失发生在疾病的后期，并且与僵硬和运动迟缓的发展相关。在我们研究的舞蹈病亨廷顿氏病患者中，苍白球外侧的GABA损失比苍白球内侧的GABA损失更大，并且苍白球内侧：苍白球外侧GABA的比率与僵硬患者相比显著增加。在舞蹈病患者的丘脑底核中也有GABA的增加，尽管这并没有达到显著性。甲硫氨酸脑啡肽的差异损失苍白球外相比，P物质的损失苍白球内没有观察到的舞蹈病患者的晚期疾病或II级患者。有一个显着增加GABA浓度在丘脑腹前核的舞蹈病患者相比，刚性/运动迟缓的患者。这些结果与实验动物中提出的运动障碍模型的主要原则雅阁;然而，丘脑中GABA增加的发现需要修改当前的理论。
SUMMARYHuntington's disease is a progressive degenerative neurological disorder which produces a characteristic movement disorder termed chorea. Although chorea is associated with dysfunction of the basal ganglia, the underlying mechanisms by which dyskinesias such as chorea are produced, are poorly understood. Recent studies in primates have led to experimental models of chorea with postulated involvement of specific neural pathways. In the present study we attempted to determine the validity of the experimental models by measuring concentrations of γaminobutyric acid (GABA), glutamate, substance P and met-enkephalin in the basal ganglia of Huntington's disease patients who manifested either chorea or rigidity/bradykinesia within 6 months of death. We also characterized changes in the Huntington's disease patients according to pathological grade, since this may be a confounding factor. We analysed post-mortern brain tissue from 12 controls, and 11 grade 3 and 12 grade 4 Huntington's disease patients. The grade 3 and 4 cases consisted of eight adult-onset choreic, nine adult-onset rigid and six juvenile-onset rigid patients. We also analysed the putamen and globus pallidus from 11 grade 2 adult onset choreic Huntington's disease patients. A model of chorea based on experimental studies in primates proposes that a loss of striatal GABAergic inhibitory projections to the globus pallidus externa leads to increased activity of the inhibitory globus pallidus externa GABAergic neurons which project to the subthalamic nucleus. It is believed that the loss of GABAergic inputs to the globus pallidus externa precedes a loss of GABAergic input to the globus pallidus interna, which occurs later in the disease and is associated with the development of rigidity and bradykinesia. In the choreic Huntington's disease patients whom we studied, there was a greater loss of GABA in the globus pallidus externa than in the globus pallidus interna, and the globus pallidus interna: globus pallidus externa GABA ratio was significantly increased compared with rigid patients. There were also increases in GABA in the subthalamic nucleus in the choreic patients, although this did not reach significance. A differential loss of met-enkephalin in the globus pallidus externa compared with substance P loss in the globus pallidus interna was not observed in either the choreic patients with advanced disease or the grade II patients. There was a significant increase in GABA concentrations in the ventroanterior nucleus of the thalamus in the choreic patients compared with rigid/bradykinetic patients. These results are in accord with major tenets of proposed models of dyskinesia in experimental animals; however, the finding of increased GABA in the thalamus requires modification of current theories.