Masahito Yamada

Chronic manganese poisoning: A neuropathological study with determination of manganese distribution in the brain

SummaryAn autopsy case of a 52-year-old man suffering from chronic manganese poisoning (CMP) is reported with determination of the manganese distribution in the brain. The patient had been working in a manganese ore crushing plant since 1965. In 1967 he began to complain of difficulties in walking and diminished libido. Later, he developed various neuro-psychiatric symptoms including euphoria, emotional incontinence, masked face, monotonous speech, “cock-walk”, increased muscle tone, weakness of upper and lower extremities, tremor of the eye lids, and exaggeration of knee jerks. The major neuro-pathological change was degeneration of the basal ganglia, in which the pallidum was severely affected. The pallidum discolsed a loss and degeneration of nerve cells, which was especially marked in the medial segment, a prominent decrease of myelinated fibers, and moderate astrocytic proliferation. The substantia nigra was intact. Distribution of manganese in the brain of the present case of CMP was determined using flameless atomic absorption spectrometry and compared with control cases and also a case of Parkinsons disease (PD). There was no significant difference between the control cases and the case of PD in average concentration of manganese and its ditribution in the brain. The present case of CMP showed no elevation in average concentration of manganese in the brain. However, there were some changes in its distribution. Thus, the continuance of neurological disorders in CMP is not linked to an elevated manganese concentration itself in the brain. CMP appears to be different from PD in neuropathology and manganese behavior in brain.

Cerebral amyloid angiopathy: A significant cause of cerebellar as well as lobar cerebral hemorrhage in the elderly

We investigated consecutive 1000 autopsied cases (average age 82.9 years) clinicopathologically in order to reveal the significance of cerebral amyloid angiopathy (CAA) as a cause of senile intracranial hemorrhages. We found 101 cases with intracerebral hemorrhages, and CAA accounted for 10.9% of them (31.0% of lobar cerebral hemorrhages, and 14.3% of cerebellar ones). In contrast to hypertensive hemorrhages, CAA-related ones (1) ruptured into the subarachnoid space without exception, (2) often coexisted with dementia of Alzheimers type, and (3) frequently occurred in the night without elevated blood pressure at onset. The cerebrovascular amyloid was strongly immunoreactive with antibody to beta-protein in all of the cases with CAA-related hemorrhages, and less intensively with antibody to cystatin C in 91% of them. Our data indicate that CAA is an important etiological factor of cerebellar hemorrhages, as well as lobar cerebral hemorrhages, in normotensive, aged patients.

Cerebral amyloid angiopathy in the aged

SummaryCerebral amyloid angiopathy (CAA) was found in 57% of 123 autopsy brains removed from patients aged 59–101 years. The incidence of CAA increased with age. CAA was seen most frequently in the occipital cortex. Immunohistochemically, amyloid of CAA was positive for amyloid P component and negative for human AA protein and human prealbumin. The presence and severity of CAA were significantly correlated with the number of senile plaques and neurofibrillary tangles. The incidence of CAA in 17 patients with dementia of Alzheimer type (DAT) was estimated to be 88% and was significantly higher than that in 26 patients with dementia of non-Alzheimer type. CAA had a pathogenetic relationship with both brain ageing and DAT. Lobar cerebral haemorrhage was found in 3 patients with CAA of marked or moderate degree. Lobar cerebral haemorrhage in the aged and in patients with DAT suggest the presence of CAA.

Gastrointestinal amyloid deposition in AL (primary or myeloma-associated) and AA (secondary) amyloidosis: Diagnostic value of gastric biopsy

Gastrointestinal amyloid deposition was investigated in 21 autopsy cases of nonhereditary systemic amyloidosis, 18 of the AL (primary or myeloma-associated) type and three of the AA (secondary) type. Vascular deposition of amyloid, most apparent in the submucosa, was found in all cases. Parenchymal deposition was observed mainly in the muscularis mucosae and muscularis externa in the AL type, and in the lamina propria mucosae in the AA type. Comparison of amyloid deposition in the stomach and rectum revealed no differences for the AA type. In the AL type, however, deposition in the lamina propria mucosae and muscularis mucosae was more frequent and marked in the wall of the stomach than in the rectum. Thus, gastric biopsy would be more valuable than rectal biopsy in the diagnosis of AL amyloidosis.

Computer-assisted three-dimensional image analysis of cerebral amyloid angiopathy.

Background and Purpose Microaneurysms and fibrinoid necrosis of cerebral cortical arteries have been reported to be related to the pathogenesis of intracerebral hemorrhage associated with cerebral amyloid angiopathy. To elucidate the pathogenesis of such vascular lesions, we conducted the present study. Methods Five hundred serial sections from brain tissue of a patient with severe amyloid angiopathy and intracerebral hemorrhage were analyzed histologically and immunohistochemically. Three-dimensional reconstructions of the vascular lesions were performed using a computer-assisted image analysis system. Results The microaneurysms were found to develop in small cortical arteries with diameters of about 40 to 50 μm. They were spindle-shaped dilatations, with a maximum diameter of about 200 μm, and appeared within vascular segments bearing severe amyloid deposition. In the walls of the aneurysms, the intima was thickened, and the media and adventitia showed thinning and disruption. Fibrinoid necrosis was found in the vascular walls of the most dilated, middle portions of the aneurysm. The vascular walls undergoing fibrinoid necrosis did not show any βA4 or cystatin C but presented with fibrinogen-like immunoreactivities, indicating invasion of plasma components. Conclusions These results suggested the following sequential events for the pathogenesis of the cerebral amyloid angiopathy-associated vascular lesions leading to hemorrhage: (1) damage of the media and adventitia due to severe amyloid deposition results in dilatation of the cortical arteries, (2) the vascular dilatation progresses and is accompanied by thickening of the intima and disruption of the media and adventitia (microaneurysm formation), (3) plasma components invade to the vascular wall (fibrinoid necrosis), and (4) finally, hemorrhage develops. (Stroke. 1993;24:1857-1864.)

Abnormal cytoskeletal pathology peculiar to corticobasal degeneration is different from that of Alzheimer's disease or progressive supranuclear palsy.

An autopsy case of clinically diagnosed “corticobasal degeneration (CBD)” was investigated. In addition to status spongiosus and neuronal achormasia around the central sulcus, cortical pyramidal neurons and thread-like structures were densely stained by Gallyas stain and tau immunohistochemistry, but apparent fibrillary structures like Alzheimers disease neurofibrillary tangle were absent. Bodian, methenamine-Bodian, Congo red, thioflavin S, or Bielshowsky stains failed to visualize these structures. They were not stained by immunohistochemical stain with anti-ubiquitin antibody. The widespread cytoskeletal pathology, which is distinct from that in Alzheimers disease or progressive supranuclear palsy, is suggestive of CBD.

Distribution of demyelinating lesions in pontine and extrapontine myelinolysis — Three autopsy cases including one case devoid of central pontine myelinolysis

SummaryThree autopsy cases of pontine and extrapontine myelinolysis are reported; one, a malignant lymphoma in a man of 66 years, the other an alcoholic liver cirrhosis in a man of 54 years, and an esophageal cancer in a woman of 68 years who presented only with extrapontine myelinolysis, but lacked central pontine myelinolysis (CPM). The extrapontine lesions in these three cases revealed a characteristic and common localization; they occurred mostly (1) in the bundles of myelinated fibers in the gray matter, such as in the pons, basal ganglia, and thalamus; and (2) in the white matter surrounded by massive gray matter, such as the deeper layers of the cortex and subjacent white matter of the crowns and sides of the cerebral gyri, the white matter of the cerebellar folia and internal, external, and extreme capsules. Therefore, the third patient was classified as a subtype of pontine and extrapontine myelinolysis, which may be called the “extrapontine form” because of absence of CPM. Moreover, bilateral demyelination of the mamillary body was found in all cases, and laminar cortical astrocytosis and necrosis similar to Morels cortical laminar sclerosis in two of them. From the clinical and pathologic findings, the significance of the changed osmolarity of the blood as a cause and the importance of some specificity of the tissue architecture in the pathogenesis are discussed.

An immunohistochemical study of centenarian brains: a comparison

To evaluate the pathology of centenarian brains, which would reflect the ultimate stage of the aging process, 13 centenarians (M:F=1:12; mean+/-SD, 101.5+/-1.5 years) from the consecutive autopsy series were studied. None had severe dementia compatible with Alzheimers disease (AD). As younger controls, 20 nondemented (ND) individuals (79.8+/-3.2 years) and 20 AD patients (80.8+/-3.0 years) were selected. In addition to the routine examination including methenamine-Bodian staining, an immunohistochemical study was performed, using antibodies to amyloid beta protein, tau, ubiquitin, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-MIP (a marker of the microglial and perivascular cells). No centenarian subjects satisfied the neuropathological criteria for definite AD. The densities of senile plaques and neurofibrillary tangles (NFTs) were significantly lower in almost all examined subdivisions than the AD patients, and tended to be higher than the ND subjects. Cerebral amyloid angiopathy of the centenarian was less severe than the AD patients, as well as the proliterations of GFAP-positive astrocytes and Ki-MIP-positive microglial cells, and the loss of synaptic terminal density. The relative mildness of the age-related morphological changes in the centenarians compared with the AD patients supports the idea that AD would not be the ultimate condition of the aging process, but would develop through the switching to the pathological process.

Dementia of the Alzheimer type and related dementias in the aged: DAT subgroups and senile dementia of the neurofibrillary tangle type

The aims of this study are to elucidate variations in the neuropathology of dementia of the Alzheimers type (DAT) and related dementias in the elderly, and to delineate a senile dementia characterized by abundant neurofibrillary tangles (NFT) in the hippocampal region and by a scarcity of senile plaques (SP) throghout the brain (senile dementia of the NFT type; SD‐NFT) in comparison with usual DAT cases. One hundred and five autopsied patients who developed dementia at age 70–100 years were investigated. The autopsy series included 57 cases of DAT, five of diffuse Lewy body disease (DLBD) with Alzheimer‐tyupe neuropathological changes, and five of SD‐NFT. The 57 DAT patients were classified into three subgroups depending onthe severity of the neocotical neuronal degeneration (NFT and neuronal loss): the diffuse, severe type (DAT‐DS, extensive and severe involvement of the neocortex; n= 18); the diffuse, mild type (DAT‐DM, mild involvement of the neocortex; n= 29); and the localized type (DAT‐L, neuronal degeneration almost localized to the hippocampal region; DAT without neocortical NFT; n= 10). The frequencies of the DAT subgroups, DLBD, and SD‐NFT in each age group at the onset were DAT‐DS (41%) > DAT‐DM (38%) > DLBD (16%) > DAT‐L (6%) of patients in their 70s, DAT‐DM (52%) > DAT‐L (24%) > DAT‐DS (16%) > SD‐NFT (8%) of those in their 80s, and DAT‐DS (40%) > SD‐NFT (30%) > DAT‐L (20%) > DAT‐DS (10%) of those in their 90s and older. In a morphometric comparison with age‐mathced DAT cases, the SD‐NFT showed a significantly higher density of hippocampal NFT and a significant scarcity of SP and cerebral amyloid angiopathy in the brain. Analysis of genotypes of apolipoprotein E gene revealed that no patient with the SD‐NFT had ε4 allele which was shown to be frequently associated with DAT. Our results have indicated (i) that the later onset of DAT and related dementias is linked with the milder neuronal degeneration in the neocortex, and (ii) that the SD‐NFT is a common neuropathological condition that causes dementia in the very aged, in which the pathogenetic process may be different from that in DAT.

Involvement of the spinal posterior horn in Gerstmann–Sträussler–Scheinker disease (PrP P102L)

Objective: The authors studied the pathomechanisms of the characteristics associated with Gerstmann–Sträussler–Scheinker disease (GSS). Background: GSS, associated with a missense mutation at codon 102 of the prion protein (PrP) gene (GSS102), is a hereditary disorder that presents with progressive ataxia and dementia, and is characterized by the loss of deep tendon reflexes and painful dysesthesias of the legs in its early stage. Methods: The authors conducted immunohistochemical studies of the spinal cord and peripheral nervous system in one of two patients from a Japanese family with GSS102 in comparison with patients with GSS105. Results: The authors found intense PrP immunoreactivities mainly in the posterior horn of the spinal cord, but not in the dorsal root ganglia or peripheral nerves. In addition to PrP amyloid plaques, synaptic-type, fine granular PrP deposits were distributed in the spinal posterior horns. In contrast to the GSS102 patient, the spinal cords of the GSS105 patients showed no granular PrP deposits. Conclusions: 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.