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The autopsy findings of a multiple system atrophy (MSA) patient with remarkable frontal lobe atrophy are described. The patient was a 65-year-old woman with a 13-year history of untreatable parkinsonism, dysautonomia and progressive motor aphasia. The brain weight was 810 g, and there was remarkable atrophy of the cerebrum predominantly in the frontal lobe, striatum, pons and cerebellum. Microscopic examination revealed a preserved cortical structure with laminar gliosis in the sixth layer of the precentral and superior frontal gyri of the frontal lobe, and postcentral gyrus and inferior parietal lobule of the parietal lobe. The second layer of the cortices of these regions were also revealed to be in a spongy state, and mild cell loss was seen in the fifth and six layers. The frontal lobe white matter showed a mild loss of myelinated fibers and axons, and mild gliosis. Glial cytoplasmic inclusions (GCIs) were abundantly observed in the deep layer of the cortex in the regions mentioned above, and were more abundant in the white matter of the frontal and parietal lobes, callosal body, and internal, external and extreme capsules. There was severe degeneration in the olivopontocerebellar and striatonigral systems, and GCIs in widespread regions of the brain. No Pick bodies, Lewy bodies, ballooned neurons, senile plaques, or significant amounts of neurofibrillary tangles were detected. There were no vascular changes. Thus, this was a verified MSA patient with progressive aphasia and remarkable frontal lobe atrophy. We indicate a possible involvement of the cerebral lobes in MSA.

We report an autopsy case of a 67-year-old man clinicogenetically diagnosed as having spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease), showing slowly progressive muscle wasting and weakness of the extremities. His brother showed similar manifestations. Autopsy revealed neuronal loss and severe gliosis in the anterior horns of the spinal cord, a marked neurogenic change of skeletal muscles and mild degeneration of cardiomyocytes. Chromatolytic change was seen in the anterior horn, but not in the Clarke's and thalamic nuclei. The anterior spinal roots were atrophic, and there was loss of myelinated fibers with abundant glial bundles. In addition, degeneration was also observed in the posterior column and dentate nucleus. The pathological features were essentially similar to those of SMA I. Chronic change was prominent while acute change was mild in degree, corresponding to a very long clinical course.

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Glucocorticoid hormones cause marked muscular atrophy, the mechanism of which is unknown. We employed a potent glucocorticoid antagonist, RU38486 [11 beta-(4-dimethylaminophenyl)17 beta-hydroxy-17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one], to determine whether intracellular glucocorticoid receptors are involved. RU38486 was shown to be an effective blocker of glucocorticoid receptor binding in vivo and in vitro. Furthermore, this compound significantly blocked the loss of body and muscle weight caused by injection of dexamethasone. These data indicate that intracellular glucocorticoid receptors are important in the etiology of steroid myopathy. Studies with glucocorticoid antagonists may lead to the design of specific therapeutic modalities for the treatment of both endogenously and exogenously produced steroid myopathies.

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The regulation of glutamine synthetase expression by dexamethasone was studied in rat skeletal muscles. Daily administration of dexamethasone caused striking enhancement of glutamine synthetase activity in plantaris, soleus, and diaphragm muscles. Northern blot analysis revealed that the dexamethasone-mediated increase of glutamine synthetase activity was associated with dramatically increased levels of glutamine synthetase mRNA. Both glutamine synthetase activity and mRNA levels were significantly elevated in plantaris muscle at 0.5 mg.kg-1.day-1 of dexamethasone, a dose that approximates endogenous corticosteroid levels in animals under severe stress. Quantification of changes in glutamine synthetase mRNA on the basis of total mRNA (by oligo dT hybridization) also revealed a major increase in glutamine synthetase mRNA. Dexamethasone was without effect on beta-tubulin mRNA levels, indicating that glutamine synthetase induction is not part of a global response to glucocorticoids. Dexamethasone treatment resulted in only an approximately 15% increase in glutamine synthetase activity in heart; there was no change in glutamine synthetase mRNA level in this tissue. Thus glucocorticoids regulate glutamine synthetase gene expression in rat skeletal muscles.