Neuronal alterations in five cases of multiple system atrophy (MSA) were investigated histologically, immunocytochemically and ultrastructurally. Argentophilic neuronal cytoplasmic inclusions (NCIs) were observed in all cases. They were distributed, in order of decreasing frequency, in the pontine nucleus, striatum, subiculum, amygdala, hippocampus, dentate fascia, substantia nigra and inferior olivary nucleus. Anti-ubiquitin antibodies visualized many thickened neurites in the degenerating gray matter as well as NCIs. Some NCIs were also recognized by anti-phosphorylated neurofilament antibodies. Ultrastructurally, NCIs consisted of a meshwork of granule-associated filaments, the diameter ranging from 18 to 28 nm, that were mixed with neurofilaments. The granule-associated filaments were also present in the axoplasm of myelinated fibers. Our studies demonstrate widespread distribution of NCIs in the central nervous system of MSA. The same pathological process that forms the granule-associated filaments in axons may also be responsible for the formation of ubiquitin-positive thickened neurites. These axonal alterations, as well as neuronal perikaryal changes, may play an important role in the impaired neuronal function in MSA.

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The distribution of axonal spheroids was examined in the central nervous system of gracile axonal dystrophy (GAD) mutant mice. Only few spheroids are observed in the gracile nucleus of the medulla in normal mice throughout the period examined, while they are first noted in GAD mice as early as 40 days after birth. The incidence of spheroids shifts from the gracile nucleus to the gracile fasciculus of the spinal cord with the progress of disease, suggesting that the degenerating axonal terminals of the dorsal ganglion cells back from the distal presynaptic parts in the gracile nucleus, along the tract of the gracile fasciculus, toward the cell bodies in the dorsal root ganglion. This phenomenon indicates that the distribution of spheroids is age dependent and reflects a dying-back process in degenerating axons. In addition to the gracile nucleus and the gracile fasciculus, which is one of the main ascending tracts of primary sensory neurons, it was noted that the other primary sensory neurons joined with some of the second-order neurons at the dorsal horn and neurons at all levels of the dorsal nucleus (Clarke's column) are also severely affected in this mutant. The incidence of the dystrophic axons are further extended to the spinocerebellar tract and to particular parts of the white matter of the cerebellum, such as the inferior cerebellar peduncle and the lobules of I-III and VIII in the vermis. These results indicate that this mutant mouse is a potential animal model for human degenerative disease of the nervous system, such as neuroaxonal dystrophy and the spinocerebellar ataxia.

The PrP abnormalities in synaptic structures of the spinal posterior horn may cause synaptic dysfunction that leads to loss of deep tendon reflexes and painful dysesthesias in patients with GSS102.

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A case of a unique combination of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like syndrome (MELAS) with acanthocytosis is reported. Neuropathological examination revealed pellagra-like change in Betz cells, brain-stem neurons and anterior horn cells as well as findings compatible with mitochondrial encephalomyopathies. Abnormal function of nicotinic acid-related enzymes could be the cause of the complicated clinicopathologic findings in this case. This is the first report of MELAS with acanthocytosis.