Jellinger K A
Ludwig Boltzmann Institute of Clinical Neurobiology, Vienna, Austria.
J Neural Transm Suppl. 1999;56:1-29. doi: 10.1007/978-3-7091-6360-3_1.
Parkinson's disease (PD) is characterized by progressive neuronal loss associated with Lewy bodies in many subcortical nuclei leading to multiple biochemical and pathophysiological changes of clinical relevance. Loss of nigral neurons causing striatal dopamine deficiency is related to both the duration and clinical stages (severity) of the disease. The clinical subtypes of PD have different morphological lesion patterns: a) The akinetic-rigid type shows more severe cell loss in the ventrolateral part of substantia nigra zona compacta (SNZC) that projects to the dorsal putamen than the medial part projecting to caudate nucleus and anterior putamen, with negative correlation between SNZC cell counts, severity of akinesia-rigidity, and dopamine loss in the posterior putamen. Reduced dopaminergic input causes overactivity of the GABA ergic inhibitory striatal neurons projecting via the "indirect loop" to SN zona reticulata (SNZR) and medial pallidum (GPI) leading to inhibition of the glutamatergic thalamo-cortical motor loop and reduced cortical activation. b) The tremor-dominant type shows more severe neuron loss in medial than in lateral SNZC and damage to the retrorubral field A8 containing only few tyrosine hydroxylase and dopamine transporter immunoreactive (IR) neurons but mainly calretinin-IR cells. A8 that is rather preserved in rigid-akinetic PD (protective role of calcium-binding protein?) projects to the matrix of dorsolateral striatum and ventromedial thalamus. Together with area A10 it influences the strial efflux via SNZR to thalamus and from there to prefrontal cortex. Rest tremor in PD is associated with increased metabolism in the thalamus, subthalamus, pons, and premotor-cortical network suggesting an increased functional activity of thalamo-motor projections. In essential tremor, no significant pathomorphological changes but overactivity of cerebello-thalamic loop have been observed. c) In the akinetic-rigid forms of multisystem atrophy, degeneration is more severe in the lateral SNZC with severe loss of calbindin-IR cells reflecting initial degeneration of the striatal matrix in the caudal putamen with transsynaptic degeneration of striatonigral efferences that remain intact in PD. This fact and loss of striatal D2 receptors--as in advanced stages of PD--are reasons for negative response to L-dopa substitution. These data suggest different pathophysiological mechanisms of the clinical subtypes of PD that have important therapeutic implications. d) Involvement of extranigral structures in PD includes the mesocortical dopaminergic system, the noradrenergic locus coeruleus, dorsal vagal nucleus and medullary nuclei, serotonergic dorsal raphe, nucleus basalis of Meynert and other cholinergic brainstem nuclei, e.g. Westphal-Edinger nucleus (controlling pupillomotor function), posterolateral hypothalamus and the limbic system, e.g. amygdaloid nucleus, part of hippocampal formation, limbic thalamic nuclei with prefrontal projections, etc. Damage to multiple neuronal systems by the progressing degenerative process causing complex biochemical changes may explain the variable clinical picture of PD including vegetative, behavioural and cognitive dysfunctions, depression, pharmacotoxic psychoses, etc. Future comparative clinico-morphological and pathobiochemical studies will further elucidate the pathophysiological basis of specific clinical symptoms of PD and related disorders providing a broader basis for effective treatment strategies. Parkinson's disease (PD) is characterized by progressive degeneration of the nigrostriatal dopaminergic system and other subcortical neuronal systems leading to striatal dopamine deficiency and other biochemical deficits related to the variable clinical signs and symptoms of the disorder. (ABSTRACT TRUNCATED)
帕金森病（PD）的特征是许多皮质下核团中与路易小体相关的神经元进行性丧失，导致多种具有临床相关性的生化和病理生理变化。黑质神经元丧失导致纹状体多巴胺缺乏与疾病的持续时间和临床分期（严重程度）均有关。PD的临床亚型具有不同的形态学病变模式：a）运动不能-强直型在投射至背侧壳核的黑质致密部腹外侧部分比投射至尾状核和前壳核的内侧部分显示出更严重的细胞丧失，黑质致密部细胞计数、运动不能-强直的严重程度与后壳核中的多巴胺丧失之间呈负相关。多巴胺能输入减少导致通过“间接环路”投射至黑质网状部（SNZR）和内侧苍白球（GPI）的GABA能抑制性纹状体神经元活动过度，从而导致谷氨酸能丘脑-皮质运动环路受到抑制，皮质激活减少。b）震颤为主型在内侧黑质致密部比外侧显示出更严重的神经元丧失，并且红核后区A8受损，该区仅含有少量酪氨酸羟化酶和多巴胺转运体免疫反应性（IR）神经元，但主要是钙视网膜蛋白-IR细胞。A8在运动不能-强直型PD中相对保留（钙结合蛋白的保护作用？），投射至背外侧纹状体和腹内侧丘脑的基质。它与A10区一起通过SNZR影响纹状体向丘脑的流出，并从那里流向前额叶皮质。PD中的静止性震颤与丘脑、底丘脑、脑桥和运动前皮质网络的代谢增加有关，提示丘脑-运动投射的功能活动增加。在特发性震颤中，未观察到明显的病理形态学变化，但观察到小脑-丘脑环路活动过度。c）在多系统萎缩的运动不能-强直形式中，外侧黑质致密部的变性更严重，钙结合蛋白-IR细胞严重丧失，这反映了尾侧壳核中纹状体基质的初始变性以及纹状体黑质传出纤维的跨突触变性，而在PD中这些传出纤维保持完整。这一事实以及纹状体D2受体的丧失——如在PD晚期——是对左旋多巴替代治疗无反应的原因。这些数据提示PD临床亚型的不同病理生理机制具有重要的治疗意义。d）PD中黑质外结构的受累包括中皮质多巴胺能系统、去甲肾上腺素能蓝斑、迷走神经背核和延髓核、5-羟色胺能中缝背核、Meynert基底核和其他胆碱能脑干核，如动眼神经核（控制瞳孔运动功能）、下丘脑后外侧和边缘系统，如杏仁核、海马结构的一部分、具有前额叶投射的边缘丘脑核等。进行性变性过程对多个神经元系统的损害导致复杂的生化变化，这可能解释了PD包括自主神经、行为和认知功能障碍、抑郁、药物毒性精神病等在内的多变临床表现。未来的比较临床形态学和病理生物化学研究将进一步阐明PD及相关疾病特定临床症状的病理生理基础，为有效的治疗策略提供更广泛的基础。帕金森病（PD）的特征是黑质纹状体多巴胺能系统和其他皮质下神经元系统的进行性变性，导致纹状体多巴胺缺乏以及与该疾病多变的临床体征和症状相关的其他生化缺陷。（摘要截断）
