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.