Tada Mari, Kakita Akiyoshi, Toyoshima Yasuko, Onodera Osamu, Ozawa Tetsutaro, Morita Takashi, Nishizawa Masatoyo, Takahashi Hitoshi
Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
Brain. 2009 Jul;132(Pt 7):1810-9. doi: 10.1093/brain/awp110. Epub 2009 May 8.
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 mum sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 +/- 7.1 versus 75.2 +/- 7.6 cells, P < 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 +/- 5.1 versus 72.8 +/- 13.6 cells, P < 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 +/- 9.2 versus 60.8 +/- 17.0 cells, P < 0.01), nucleus raphe obscurus (19.3 +/- 4.4 versus 75.3 +/- 8.6 cells, P < 0.001), nucleus raphe pallidus (2.1 +/- 2.7 versus 9.0 +/- 3.4 cells, P < 0.03), and arcuate nucleus (0.4 +/- 0.8 versus 2.3 +/- 1.5 cells, P < 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 +/- 3.5 versus 21.8 +/- 6.5 cells, P < 0.02) and nucleus raphe obscurus (15.0 +/- 2.0 versus 22.5 +/- 2.1 cells, P < 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.
多系统萎缩（MSA）是一种神经退行性疾病，其特征为伴有共济失调和/或帕金森综合征的显著自主神经功能衰竭。MSA的主要死因是猝死。我们已经表明，自主神经功能衰竭的早期发展是猝死的一个独立危险因素。脊髓中间外侧细胞柱（IML）中交感神经节前神经元及其传入的延髓儿茶酚胺能和5-羟色胺能神经元的耗竭被认为是MSA中自主神经功能衰竭的部分原因。在本研究中，我们调查了这些自主神经元组中任何一组的神经元耗竭是否导致MSA中的猝死。在52例经尸检证实的MSA患者中，我们选择了12例在疾病发作后3.5年内死亡的个体，以确定切片的准确水平并识别MSA中自主神经核的早期神经病理学变化。4例患者死于猝死，8例患者死于既定原因。从胸段脊髓第8节段和延髓头端获取连续的10μm切片。延髓切片用酪氨酸羟化酶和色氨酸羟化酶进行免疫染色。计算五个切片中的总细胞数进行比较。与对照组相比，MSA组IML中的神经元显著减少（38.0±7.1对75.2±7.6个细胞，P<0.001），延髓腹外侧（VLM）中酪氨酸羟化酶免疫反应性神经元减少（17.4±5.1对72.8±13.6个细胞，P<0.01），VLM中色氨酸羟化酶免疫反应性神经元减少（15.6±9.2对60.8±17.0个细胞，P<－0.01），中缝隐核减少（19.3±4.4对75.3±8.6个细胞，P<0.001），中缝苍白核减少（2.1±2.7对9.0±3.4个细胞，P<0.03），以及弓状核减少（0.4±0.8对2.3±1.5个细胞，P<0.05）。此外，在死于猝死的患者中，与有既定死因的患者相比，我们发现VLM中色氨酸羟化酶免疫反应性神经元显著减少（7.3±3.5对21.8±6.5个细胞，P<0.02），中缝隐核减少（15.0±2.0对22.5±2.1个细胞P<0.01）。结果表明，脊髓IML以及延髓儿茶酚胺能和5-羟色胺能系统甚至在MSA的早期阶段就已受累，调节心血管和呼吸系统的延髓5-羟色胺能系统功能障碍可能是MSA患者猝死的原因。
