Noriaki Yoshimura

Histochemical localization of copper in various organs of brindled mice

In order to disclose histochemically the localization of copper in various organs in Menkes disease, untreated brindled mouse hemizygotes (BM) and normal male littermates were examined by the modified sulfide silver method of Kozma, where the specificity for copper staining has been proved to be enhanced by trichloroacetic acid treatment. When compared with normal controls, renal tubules – most of which were of proximal convoluted segments – and intestinal mucosal epithelium of BM clearly showed increased staining with copper. Hepatocytes in the liver and neurons in the brain, however, displayed an obvious reduction in staining despite a marked increase in staining of capillaries in these two organs. Electron microscopy of the specimens stained with the Kozma method revealed numerous fine silver grains which represented Cu++ localization, distributing within the cytoplasm outside both mitochondria and the nucleus.

Juvenile Parkinson's disease with widespread Lewy bodies in the brain

SummaryA clinico-pathological case report on a case of juvenile Parkinsons disease (JPD) with widespread Lewy bodies (LBs) in the brain is presented with comparative morphological studies on two demented cases of “classical” Parkinsons disease (CPD) with disease onset at an older age. The clinical and histological pictures of this JPD case were typical of Parkinsons disease, excepting numerous Lewy bodies in the cerebrum. There were no neurofibrillary change nor senile plaques throughout the CNS. The distribution and histochemical and ultrastructural characters of the histological lesions (i.e., LBs) in the JPD and the two CPD cases were investigated and compared. The comparison showed no qualitative but only quantitative differences between the two types of Parkinsons disease. The present study also revealed that in CPD cases significant numbers of LBs could be present in the cerebral cortex, amygdaloid and claustrum. These lesions can be in part responsible for dementia in CPD.

Histochemical localization of copper in various organs of brindled mice after copper therapy

Copper (Cu) distribution in various organs of brindled mice (BM), an animal model of Menkes disease, was studied histochemically and by atomic‐absorption‐spectrophotometry 7 months after Cu injections. The results were compared with those of untreated BM. In the treated BM brain, a diffuse reduction in Cu‐related staining of neurons and astroglia was still evident, though it had improved to some extent. The reduction was noticeable in the thalamus, brain stem and cerebellum, although intensely stained capillaries were noted occasionally in the retrosplenial and mediobasal temporal areas, including the hippocampus. In the treated BM liver, near normalization of Cu distribution was observed. In the treated BM intestine, the main localization of Cu accumulation was in histiocytes/macrophages in the lamina propria, while in the untreated BM it was in the absorptive and secretory epithelial cells. In the treated BM kidney, there was no clear improvement in Cu distribution. These histochemical results were consistent with the data obtained by the spectrophotometric assay. Electron microscopic histochemistry of affected renal tubular epithelial cells revealed numerous silver grains, which represent Cu++ localization, distributed only within the cytoplasm outside organella and nucleus. This suggests impaired intracellular Cu transport from cytosol to organella, which in the kidney is refractory to the Cu therapy adopted.

DIFFUSE MALLORY BODIES IN THE LIVER, DIFFUSE LEWY BODIES IN THE BRAIN AND DIFFUSE FAT REPLACEMENT (LIPOMATOUS PSEUDOHYPERTROPHY) OF THE PANCREAS IN A PATIENT WITH JUVENILE PARKINSON'S DISEASE

A 38‐year‐old male patient with the juvenile variant of Parkinsons disease, in whom onset had occurred at the age of 24 yr, was autopsied. There were no clear symptoms of pancreatic or hepatic insufficiency during the entire clinical course. The only notable features were a slightly delayed decrease of the blood glucose level in an oral glucose tolerance test, slightly elevated levels of serum alkaline phosphatase and serum lactate dehydrogenase, and episodic loose stools. Autopsy revealed uniform enlargement of the pancreas due to massive fat replacement (lipomatous pseudohypertrophy): the exocrine glandular elements showed marked atrophy and loss, while the islets of Langerhans were preserved. The liver exhibited a histology closely mimicking alcoholic hepatitis associated with the diffuse presence of Mallory bodies (MBs), possibly indicative of a disturbance of protein metabolism. The nervous system showed the diffuse presence of Lewy bodies (LBs) in the cerebrum in addition to the ordinary lesions of Parkinsons disease. Although the etiopathogenesis of none of these three lesions has been well elucidated, common epitopes of MBs and LBs have recently been demonskated. Therefore, the present case study suggests that a specific underlying toxic agent may cause diffuse LBs in the brain on the one hand, and diffuse MBs in the liver and lipomatous pseudohypertrophy of the pancreas on the other. Acta Pathol Jpn 42: 826–831, 1992.

Olfactory bulb involvement in Pick's disease

SummaryThe olfactory bulbs and stalks were examined in a case of Picks disease that showed numerous and widespread Pick bodies in the brain. Typical argyrophilic inclusions (Pick bodies) were found not only in many cells of the anterior olfactory nucleus but also in some mitral cells and tufted cells. In addition, neuronal loss and astrocytosis were evident. No neurofibrillary change or senile plaque were detected anywhere in these structures. Electron microscopy disclosed that there was no ultrastructural difference between Pick bodies in the olfactory bulb and those in the cerebral cortex or hippocampus. These data indicate that in Picks disease mitral cells and tufted cells, as well as anterior olfactory nucleus cells, are affected by degeneration specific to Picks disease.

ChronologicaI Observations of HistologicaI Changes, Cytochrome Oxidase Activity and Copper Level in the Brain of the Postnatal Brindled Mouse

Neuropathological and enzyme‐histochemical studies were performed on brindled mouse hemizygotes (BMs) and normal littermates at the age of 2 days, 7 days, 11 days and 14 days, together with an investigation of their tissue cop per levels. A greatly increased copper concentration was confirmed in the kidney and intestine and a greatly reduced concentration in the liver and brain of BMs. The copper concentration in the brain increased gradually with age in the normal littermates, whereas this did not occur in BMs. There was no significant difference in the tissue copper concentration between the cerebrum and the cerebellum brainstem in BMs or in normal littermates. Light and electron microscopy of the BM brain revealed progressive neuronal degeneration in association with increased mito‐chondrial changes (ballooning and crista disintegration). Enzyme histochemical examinations demonstrated a progressive comparative decrease (i.e., an increased difference from normal) of cytochrome oxidase activity in the BM brain. These data suggest that progressive degeneration of the brain in Menkes’disease is attributable to mitochon‐drial degeneration caused by a comparative decrease of both copper concentration and cytochrome oxidase activity in the brain.

Down's Syndrome in Middle Age

A 45 year old patient with Downs syndrome was autopsied. The brain, weighing 800 g, was small in size, and serial sections revealed generalized gyral atrophy and ventricular dilatation. In the gray matter, there was diffuse neuronal degeneration characterized by numerous neurofibrillary tangles (NFTs), senile plaques and frequent amyloid angiopathy. Histochemical and electron microscopical analyses of these lesions showed no qualitative difference from those in Alzheimers disease. A topographical study of NFTs showed that they were numerous in the limbic system and cerebral neocortex. Various numbers of NFTs were seen in the olfactory bulb, thalamus, medial geniculate body, innominate substance, putamen, caudate, pallidum, central gray, reticular formation, certain midline nuclei of the brainstem, substantia nigra, red nucleus and dorsal vagal nucleus. This distribution pattern was not different qualitatively from that in Alzheimers disease, and such a similarity was especially evident in the olfactory bulb, where many tufted and mitral cells as well as anterior olfactory nucleus cells showed NFTs. These common features of brain pathology in Downs syndrome and Alzheimers disease may be due to a specific gene defect in both diseases. Acta Pathol Jpn 40: 735 743, 1990.

NEURONAL DEGENERATION IN THE BRAIN OF THE BRINDLED MOUSE

In order to investigate the levels of cytochrome oxidase activity in neuronal mitochondria in the brain of the brindled mouse hemlzygote (BM), the cerebella and brain stems from 12 pairs of brindled and normal littermates aged 13‐16 days were examined. The diaminobenzidine method for light‐ and electron‐microscopic histochemistry was adopted. Light microscopy revealed that mitochondria in the normal cerebellum showed an intensely positive reaction to diaminobenzidine, whereas those in the BM cerebellum showed a very weak reaction indicating an evident reduction of cytochrome oxidase activity. Electron microscopy disclosed a diaminobenzidine‐OsO4 product densely appearing on the inner membranes of most mitochondria in Purkinje cells in the normal cerebellum. However, it was very faint or absent in those in the BM cerebellum. The same was true in Golgi II cells, granule cells, glomeruli and brain stem nuclei, but the degree of reduction was not uniform among these structures. In conclusion, there is not only a generalized reduction of cytochrome oxidase activity but also a topographical predilection of areas showing a reduction of the enzyme in the BM cerebellum and brain stem. These facts may explain the pathogenesis of neuronal degeneration in the brain of the BM.

Cerebral Microthrombosis, Synthesis Imbalance of TXA2-PGI2, and Subarachnoid Focal Acidosis in the Pathogenesis of Symptomatic Cerebral Vasospasm

Numerous investigations of cerebral vasospasm (hearafter referred to as vasospasm) confirm the pathogenesis to be various and complicated. In accounting for the pathogenesis of vasospasm, it is our contention that subarachnoid focal acidosis resulting from anaerobic changes in subarachnoid clots may play a role in inducing multiple cerebral microthrombosis, which in turn induces cerebral ischemia or infarction by platelet aggregation caused by an imbalance in the synthesis of TXA2 and PGI2 (Fig. 1) [6–9]. In this paper, we tried to corroborate that contention in clinical studies focussed firstly on the pH of intracranial irrigation fluid for aneurysmal surgery during the vasospasm predilection period and, secondly, on the effectiveness of TXA2 synthetase inhibitors in the prevention of symptomatic vasospasm, and in histopathological studies of the brains of patients who died of subarachnoid hemorrhage.

Cervical cord ependymoma with numerous microrosettes.

Abstract“Microrosette ependymoma,” which is ependymoma with numerous microrosettes throughout the tumor, has rarely been reported. We describe an autopsy case of cervical cord ependymoma with two unusual features: the presence of numerous microrosettes and the formation of trabecular architecture. The tumor originated in the C2 segment of a man aged 23 years and gradually expanded over the following 15 years and 10 months until the entire cervical cord was involved. Beside the low grade of malignancy, the tumor cells exhibited a strong tendency to form microrosettes and trabecular architecture, which formed many perivascular pseudorosettes. The microrosettes mostly consisted of only two or a few more cells, in the absence of large rosettes. Thus the constituent cells were those forming perivascular pseudorosettes. Electron microscopy and immunohistochemistry characterized the ependymal properties of the microrosettes, whose lumina frequently contained fibril bundles similar to those of the Reissners fiber fibrils, in addition to cilia and microvilli. The pathogenesis of the occurrence of numerous microrosettes is unknown; however, a defect in the mechanism of regulation of rosette formation and enlargement is the most likely explanation.