Paraneoplastic cerebellar ataxia with mild cerebello-olivary degeneration and an anti-neuronal antibody: a clinicopathological study.
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Aged↗
Biomedical subjects
T Uchihara
Publications and source records attributed to T Uchihara.
France and Japan in neuropathology.
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Education, Medical, Graduate↗
Postmortem study of ataxia with retinitis pigmentosa by mutation of the alpha-tocopherol transfer protein gene.
A new syndrome of ataxia and retinitis pigmentosa with vitamin E deficiency caused by the missense mutation of alpha-tocopherol transfer protein (alpha-TTP) gene was recently proposed. After studying the first postmortem case with this mutation pathologically and biochemically, whether the symptoms can be treated by supplementation of vitamin E or not is discussed. The major pathological findings were retinal atrophy; severe dying back-type degeneration of the posterior column; and massive accumulation of lipofuscin in neurons including dorsal root ganglion (DRG) cells, which were almost identical to those in vitamin E deficient animals and patients with fat malabsorption. Also, mild loss of Purkinje cells was noted. Because robust expression of alpha-TTP was detected in the cerebellum as well as in the liver and the tissue concentration of vitamin E in the cerebellum was still low even after oral supplementation, the mild Purkinje cell loss might be related to the mutant alpha-TTP in the cerebellum. By contrast, in the DRG, thought to be mainly responsible for ataxia, no expression of alpha-TTP was detected, and the tissue concentration of vitamin E increased to normal after supplementation. It is therefore considered that oral supplementation of vitamin E should effectively counteract the progression of ataxia.
Aged↗
Neuronal intranuclear inclusions in spinocerebellar ataxia type 2.
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Humans↗
Neuronal intranuclear inclusions in spinocerebellar ataxia type 2: triple-labeling immunofluorescent study.
Spinocerebellar ataxia type 2 (SCA2) is associated with an expansion of CAG/polyglutamine-repeat of a gene of unknown function. We performed an immunohistochemical study to identify the immunolocalization of the disease protein ataxin-2 in normal and SCA2 patients. Although normal and expanded ataxin-2 were ubiquitously localized to the cytoplasm of neurons, ubiquitinated intranuclear inclusions were observed selectively in 1-2% of neurons of affected brain regions except the cerebellum. Triple-labeling immunofluorescence revealed that ataxin-2, expanded polyglutamine and ubiquitin were colocalized to these neuronal intranuclear inclusions (NIs), indicating that SCA2 shares morphological characteristics common to other neurological disorders associated with an expansion of CAG/polyglutamine-repeat. Lack of NIs in the cerebellar lesion, however, suggests the discrepancy between formation of NIs and neuronal degeneration in SCA2.
Ataxins↗
Bunina bodies in amyotrophic lateral sclerosis on Guam: a histochemical, immunohistochemical and ultrastructural investigation.
An investigation of Bunina bodies is important when studying the pathoetiology and pathomechanisms involved in amyotrophic lateral sclerosis (ALS). It may serve as a clue essential for the study of the pathogenesis of Guamanian amyotrophic lateral sclerosis (ALS-G), and it may provide a means of answering the question of whether ALS-G is the same disease as classical ALS or a different entity. In ALS-G, however, no precise histochemical, immunohistochemical, or detailed ultrastructural examination has been published to date. To elucidate the pathological differences/similarities of Bunina bodies between classical ALS and ALS-G, we performed histochemical, immunohistochemical, topographic and ultrastructural examinations. Histochemically, hematoxylin and eosin, Masson's trichrome, methylgreen-pyronin, phosphotungstic acid-hematoxylin, Klüver-Barrera, Bodian and periodic acid-Schiff staining were utilized. Immunohistochemical examination was performed using antibodies for cystatin C, ubiquitin, Tau-2, Cu/Zn superoxide dismutase, phosphorylated neurofilament and glial fibrillary acidic protein. Histochemical findings were consistent with those previously described for classical ALS. The immunohistochemical study showed that in ALS-G Bunina bodies were intensely labeled by an anti-cystatin C antibody. Topographic examination demonstrated that Bunina bodies were distributed in the spinal anterior horns and Clarke's column in the spinal cord. Ultrastructurally, Bunina bodies were composed of electron-dense amorphous/ granular material accompanied by vesicular structures and neurofilaments. The results of the present study have revealed that the pathological features of Bunina bodies in ALS-G are identical to those seen in classical ALS. These findings strongly suggest that a similar degenerative process occurs in the spinal anterior horn cells in both ALS-G and classical ALS.
Adult↗
Glial expression of presenilin epitopes in human brain with cerebral infarction and in astrocytoma.
Presenilins, some gene mutations of which are associated with familial Alzheimer's disease (AD), are expressed mainly in neurons in normal brains and brains from patients clinicopathologically diagnosed as AD. They are thought to be related to cell death and survival. We studied the immunolocalization of presenilin to investigate its possible relation to cell death and glial proliferation, using two antibodies against different portions of the presenilin 1 protein, in human brains with cerebral infarction and in astrocytoma, where abundant cell death and glial proliferation are present. Expression of presenilin epitopes was more marked in glial cells than in neurons in and around the ischemic focus, and it was also robust in astrocytoma cells. These findings suggest that presenilins are functioning not only in neurons but also in glial cells in reactive and neoplastic proliferation.
Aged↗
Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations.
Historical review on hereditary spinocerebellar degenerations (SCD) revealed that some CAG repeat diseases were formerly diagnosed under several different names because of their clinical and pathological heterogeneity. A genetic abnormality in these hereditary SCDs (often with expanded CAG repeat) corresponds to a definite prototypic combination of the principal lesions in the cerebellar, extrapyramidal, and oculomotor systems, which allows neuropathological differentiation between these entities. Variability of both clinical and pathological features is mainly related to the patient's age at onset, which is often correlated with the number of CAG repeat size. Several characteristics are suggestive of these SCD: preferential degeneration of specific systems, size reduction at cellular or tissue level not accompanied by glial reaction (simple atrophy or hypoplastic change) and presence of recently identified ubiquitin positive inclusions in neurons are characteristics of these SCDs. These features provide further insight into the phenotypic development of a genetic abnormality.
Atrophy↗
Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase.
Humoral immune response to glutamic acid decarboxylase (GAD) has been implicated in the pathogenesis of stiff-man syndrome and cerebellar ataxia, but the underlying pathomechanism is unclear. Using a whole-cell patch-clamp technique with rat cerebellar slices, we found that immunoglobulins present in the cerebrospinal fluid of an ataxic patient acted presynaptically to cause a selective suppression of GABAergic transmission. This synaptic depression was most likely elicited by an autoantibody to GAD.
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Atypical neuronal inclusion bodies in meningioangiomatosis.
A case of meningioangiomatosis not associated with neurofibromatosis 2 in a 24-year-old man is reported. Abundant neurofibrillary tangles and threads, shown by immunohistochemistry and ultrastructural analysis to be similar to those seen in Alzheimer's disease, were found in the residual neuropil. Another lesion consisting of argyrophilic globular inclusion bodies with radial fibrils was found at the periphery. Single and double immunostaining with a panel of antibodies showed similarities between these inclusions and Pick bodies.
Adult↗
Discrepancy between tau immunoreactivity and argyrophilia by the Bodian method in neocortical neurons of corticobasal degeneration.
To clarify different features of cytoskeletal pathology in neocortical neurons between corticobasal degeneration (CBD) and Alzheimer's disease (AD), the relationship between neurofibrillary tangles (NFTs), which are defined as a fibrillary structure stained by the Bodian method, and tau-immunopositive neurons in layers II-III of the premotor cortex was assessed by sequential staining for tau immunohistochemistry followed by the Bodian method on the same section. In AD brains, tau-like immunoreactivity in neurons was uniformly colocalized with Bodian-positive NFTs. In CBD brains, however, tau-immunopositive neurons could be classified into three different types: (1) those not stained at all by the Bodian method (diffuse cytoplasmic type), which represented the majority of these immunopositive neurons, (2) some partly stained by the Bodian method (mixed type), and (3) a few for which argyrophilia demonstrated by the Bodian method was completely colocalized with immunoreactivity (NFT type). This discrepancy between tau-like immunoreactivity and Bodian method is characteristic of CBD and suggests that the tau molecule is less liable to form argyrophilic fibrils in neocortical neurons of CBD.
Aged↗
Increased CSF tau protein in corticobasal degeneration.
Using a sensitive sandwich enzyme-linked immunosorbent assay (ELISA) method, we measured the concentration of total tau protein in the cerebrospinal fluid (CSF) from nine patients with corticobasal degeneration (CBD) in comparison with 12 normal control subjects in order to assess its diagnostic value. The CSF concentration of tau in patients with CBD (0.69, 0.20 ng/ml; mean, SD) was higher than that in, the normal controls (0.48, 0.14 ng/ml, P = 0.0076 unpaired t test). This increase in CBD patients may reflect widespread tau pathology in CBD, but should be interpreted with reserve as an aid to diagnosis.
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Dissociation of Alzheimer type pathology in a disconnected piece of cortex.
A woman with Alzheimer's disease died at the age of 85 years. A left sphenoid meningioma had been removed 27 years earlier. The tumor and the operation had severely altered the white matter of the frontal lobe and of the anterior part of the temporal lobe on the left side and massively disconnected a small piece of frontal cortex. There were numerous senile plaques and neurofibrillary tangles in the limbic and isocortical samples. The white matter lesions, on the operated (left) side, were associated with a lower density of neuritic plaques and of neuropil threads and with a higher density of beta-amyloid (A beta) deposits. The density of tau-positive neuritic plaques, neurofibrillary tangles and neuropil threads was close to zero, whereas the diffuse deposits of A beta were abundant, in the small disconnected piece of cortex. In this area, the white matter was severely damaged, as in the adjoining cortex, but the continuity of the cortical ribbon was also disrupted. These data show that neuritic and A beta pathologies may be dissociated and suggest that the neuritic alterations mainly involved cortico-cortical fibers coursing tangentially in the cortical ribbon.
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Tumor necrosis factor-alpha, microglia and astrocytes in AIDS dementia complex.
The pathogenesis of HIV-associated cognitive changes is poorly understood. Cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been postulated to contribute to the mechanism of the neurological complications of HIV infection. One of the effects of TNF-alpha is to induce astrocyte proliferation in vitro. The purpose of this study was to look for a correlation between the expression of TNF-alpha, astrogliosis and the degree of cognitive impairment in 12 prospectively assessed AIDS cases without focal brain lesion, 8 of whom were demented. They were compared with 6 control patients without neurological disease. Neuropathological examination showed myelin pallor in 5 of the 8 demented patients. TNF-alpha expression was detected by immunohistochemistry in the midfrontal cortex, subcortical and deep white matter, and basal ganglia. Not only perivascular macrophages but also some microglial and endothelial cells were labeled. Most TNF-alpha-positive cells were in close contact with glial fibrillary acidic protein-positive astrocytes. They were more numerous than gp41-positive cells. Their density increased with increasing cognitive impairment and in parallel to the astrogliosis in the frontal cortex, basal ganglia and deep white matter. These findings further support the hypotheses that lesions of the deep white matter, driven by TNF-alpha, are associated with cognitive alteration, and that indirect effects of HIV infection in the brain participate in the development of HIV-associated dementia through a diffuse immune activation, mediated by cytokines.
AIDS Dementia Complex↗
Distribution of cerebral cortical lesions in corticobasal degeneration: a clinicopathological study of five autopsy cases in Japan.
We investigated five Japanese patients with autopsy-proven corticobasal degeneration (CBD) both clinically and pathologically, and examined the distribution of their cerebral cortical lesions in hemisphere specimens. The lesions were classified into three categories (slight, moderate and severe). Only two of our patients had clinical features considered to be typical of CBD. Severe lesions were present in the posterior portions of the frontal lobe, anterior to the precentral gyrus in two patients with the clinical diagnosis of CBD. By comparison, in two patients with clinically diagnosed frontal Pick's disease, and one with the clinical diagnosis of progressive supranuclear palsy (PSP), severe lesions were seen in the anterior portions of the frontal lobe. The primary motor area of all five had mostly slight to moderate lesions. We postulate that the clinical features of CBD have a much wider spectrum than previously believed. Our data also indicate that the lesion responsible for limb-kinetic apraxia in CBD is in the premotor cortex. We suggest that when the anterior portions of the frontal lobe are damaged, the clinical picture mimics those of Pick's disease and PSP. In addition, we consider that focal cerebral atrophy of CBD is multicentric.
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Activated microglial cells are colocalized with perivascular deposits of amyloid-beta protein in Alzheimer's disease brain.
BACKGROUND AND PURPOSE: Microglial cells are present in the center of senile plaques (SPs) in Alzheimer's disease (AD) brain. Such a localization of microglial cells suggests that they are involved in the deposition or the clearance of amyloid-beta protein (A beta) in the brain. We examined their association with another type of parenchymal A beta deposit, which is termed the perivascular deposits of A beta (PA beta). METHODS: Thick sections from AD brain were stained with a three-color immunofluorescence method that labeled A beta, activated microglial cells, and vascular endothelial cells simultaneously. RESULTS: Three-dimensional observation under a laser scanning microscope confirmed that perivascular aggregates of activated microglial cells were colocalized with PA beta. CONCLUSIONS: Microglia occur in association with both SPs and PA beta, suggesting that they play important roles in the metabolism of A beta in AD brain.
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Human immunodeficiency virus type 1 DNA and RNA load in brains of demented and nondemented patients with acquired immunodeficiency syndrome.
The relationship between dementia and human immunodeficiency virus type 1 (HIV-1) cerebral load is not clearly understood. We used immunohistochemistry and competitive polymerase chain reaction to evaluate the density ofgp 41 immunostained cells and the amount of HIV-1 DNA and RNA in the midfrontal gyrus of 21 HIV-1 infected patients, nine of whom were demented. The amounts of HIV-1 DNA and RNA, and the density of gp 41-positive cells were significantly linked. In this small series of cases, (1) although as a mean, there was a larger viral load in demented patients than in nondemented, this did not reach the significance level (2) discrepancies appeared in the population under study, some demented patients having low viral loads.
AIDS Dementia Complex↗