Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death
Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death
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DOI：
10.1093/brain/awp110
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发表时间：
2009-07-01
期刊：
影响因子：
14.5
通讯作者：
Takahashi, Hitoshi
中科院分区：
文献类型：
--
作者：
Tada, Mari;Kakita, Akiyoshi;Takahashi, Hitoshi
多系统萎缩（MSA）是一种神经退行性疾病，其特征是显著的自主神经功能衰竭伴共济失调和/或帕金森综合征。MSA的主要死亡原因是猝死。我们已经证明，自主神经功能衰竭的早期发展是猝死的独立危险因素。脊髓中间外侧细胞柱（intermediolateral cell column，IML）交感节前神经元及其传入的延髓儿茶酚胺能和多巴胺能神经元的耗竭被认为是MSA自主神经功能衰竭的部分原因。在这项研究中，我们调查了这些自主神经元组中的任何一个神经元的耗竭是否有助于MSA中的猝死。在52名尸检证实的MSA患者中，我们选择了12名在发病后3.5年内死亡的患者，以定义切片的准确水平并识别MSA自主神经核的早期神经病理变化。4名患者死于猝死，8名患者死于确定的原因。取第8段胸髓和延髓头端连续10 μ m切片。对延髓切片进行甲状腺素羟化酶和色氨酸羟化酶免疫染色。计算五个切片中的总细胞数以进行比较。与对照组相比，MSA组IML神经元明显减少（38.0 +/- 7.1 vs 75.2 +/- 7.6个细胞，P < 0.001），延髓腹外侧（VLM）中的甲状腺素羟化酶免疫反应神经元（17.4 +/- 5.1对72.8 +/- 13.6细胞，P < 0.01）和色氨酸羟化酶免疫反应阳性神经元在VLM（15.6 +/- 9.2 vs. 60.8 +/- 17.0个细胞，P < 0.01），中缝隐核（19.3 +/- 4.4 vs 75.3 +/- 8.6个细胞，P < 0.001），中缝苍白核（2.1 +/- 2.7对9.0 +/- 3.4个细胞，P < 0.03）和弓状核（0.4 +/- 0.8对2.3 +/- 1.5个细胞，P < 0.05）。此外，在猝死患者中，与已确定死因的患者相比，我们发现VLM中色氨酸羟化酶免疫反应神经元明显减少（7.3 +/- 3.5对21.8 +/- 6.5个细胞，P < 0.02）和中缝隐核（15.0 +/- 2.0对22.5 +/- 2.1个细胞，P < 0.01）。结果表明，脊髓IML和延髓的儿茶酚胺能和肾上腺素能系统的参与，即使在MSA的早期阶段，和延髓肾上腺素能系统的功能障碍，调节心血管和呼吸系统可能是负责MSA患者的猝死。
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 mu m 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.