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ABSTRACT: An early-onset and rapidly progressive familial tauopathy with R406W mutation is described. The patient was a 47-year-old man who first presented with psychiatric symptoms followed by overt dementia at age 52 and died 1 year later. Postmortem study revealed tangle-associated neuronal degeneration, accentuated in the medial temporal lobe. R406W mutation was determined by sequence analysis and immunocytochemically with anti-mutant tau antibody.
Neurology 04/2002; 58(5):811-3. · 8.31 Impact Factor
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ABSTRACT: We report the muscle pathology in a 43-year-old woman who died of chronic graft versus host disease (GVHD) complicated by myositis and systemic transfusional hemosiderosis, after an allogeneic bone marrow transplantation and a donor leukocyte transfusion for acute myelogenous leukemia. Despite cyclosporin A treatment, fatal ventilatory failure progressed while she was still ambulant. Autopsy revealed the presence of chronic GVHD mildly involving the liver, skin, pericardium, pancreas, and salivary glands, in addition to skeletal muscles. Myopathic changes with mild inflammation and prominent iron deposition were found in the tibialis anterior muscle and, to a lesser degree, in the diaphragm and the intercostal muscle. There were iron deposits in both macrophages and sarcoplasm in the tibialis anterior. The iliopsoas and pectoralis major muscles showed prominent type 2 fiber atrophy; inflammation and iron deposition were minimal in the iliopsoas, but none in the pectoralis. Although we ascribed respiratory failure largely to GVHD myositis, weakness of the lower leg appeared to be aggravated by iron deposition superimposing the underlying GVHD myositis.
Rinsho shinkeigaku = Clinical neurology 10/2001; 41(9):612-6.
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ABSTRACT: Tau-related pathology was investigated in the spinal cord of 11 patients with AD. Ten ALS and 10 age-matched neurologically intact patients served as controls. Tau immunoreactivity was detected in neurons of the anterior horn in all AD cases and to a lesser extent in the intermediate zone and in the posterior horn. Tau immunoreactivity was rare in controls. Neurofibrillary tangles were identified in seven AD cases, but none was observed in the controls.
Neurology 01/2001; 55(11):1727-9. · 8.31 Impact Factor
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ABSTRACT: Hallervorden-Spatz syndrome (HSS) is a rare autosomal recessive disorder clinically characterized by extrapyramidal signs and progressive dementia. In a typical case, the clinical symptoms become apparent during late childhood, and usually the course is protracted over a decade or more. We recently had an opportunity to study the brains of two cases of HSS with a clinical course of over 30 years. Case 1 was a 44-year-old female and case 2 was a 37-year-old male. Grossly, the brains showed severe fronto-temporal lobar atrophy with abundant spheroids and mild iron deposits in the globus pallidus, associated with features of motor neuron disease. In addition, there was diffuse sponginess in the atrophic cortex as well as widespread Alzheimer's neurofibrillary tangles (NFTs) and Lewy bodies (LBs) in the cortical and subcortical regions, including the spinal cord. Ultrastructurally, NFTs were composed of paired helical filaments, and LBs of central dense cores with radiating fibrils. Discrete immunostaining was demonstrated in NFTs and neuropil threads with various antibodies against phosphorylated tau, and in LBs with antibody against alpha-synuclein. In addition, diffuse, overlapping immunoreactivity of alpha-synuclein and phosphorylated tau was seen within the cytoplasm of many neurons. However, when LBs and NFTs coexisted within the same neurons, they were clearly segregated. The findings of our present cases as well as those reported in the literature may indicate that simultaneous and extensive occurrence of abnormal phosphorylation of tau and accumulation of alpha-synuclein may constitute cardinal pathological features of HSS with protracted clinical course.
Journal of the Neurological Sciences 09/2000; 177(1):48-59. · 2.35 Impact Factor
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ABSTRACT: We report a 38-year-old man who had three episodes of pain and swelling in the right calf from the age of 27 years. On each episode, pain worsened gradually, lasted for a few months and subsided spontaneously. Venography performed at the first episode was reported to be unremarkable. At the third episode, physical examinations showed tender and hard muscles in the right calf without findings of knee arthritis. The right calf pain became stronger when standing than when lying and on the ankle dorsiflexion. Laboratory examinations showed leukocytosis, a slightly elevated level of CRP, and normal CK levels. MRI showed diffuse high intensities in the right soleus and the lateral head of right gastrocnemius on T2-weighted images, where CT showed slightly low densities. To rule out focal myositis, the right soleus was biopsied. The muscle specimen showed perimysial and endomysial edema, dilatation of venules and capillaries, and focal mononuclear cell infiltration in the venule wall. Intermyofibrillar networks were well preserved. There were no necrotic or regenerating fibers, nor sarcolemmal expression of HLA-ABC. On electron microscopy, the processes of fibroblasts in the endomysium were swollen. This case illustrated muscle edema caused by local venous congestion possibly due to venulitis of unknown cause.
Rinsho shinkeigaku = Clinical neurology 08/2000; 40(7):717-21.
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ABSTRACT: A 46-year-old woman presented progressive proximal weakness and dysphagia. Her serum creatine kinase and myoglobin levels were markedly elevated. Chest X-rays revealed bilateral swelling of the hilar lymph nodes. Needle electromyography demonstrated active denervation and early recruitment. MRI of her skeletal muscle showed focal high intensities on T1-weighted images that were associated with diffusely increased signal intensities on T2-weighted images. Muscle biopsy revealed infiltration of inflammatory cells associated with non-caseating granulomas, and there was widespread segmental fiber necrosis, where necrotic fibers appeared regardless of these granulomas. Immunohistochemical analysis of the surface markers of the infiltrating cells showed CD68- and CD4-positive cells infiltrating into the central area of the granuloma, while CD8-positive cells infiltrating into the endomysium and the periphery of the granulomas. The characteristic histology of the granuloma confirmed the diagnosis of sarcoidosis. The diffuse muscle pathology was consistent with the patient's severe clinical course.
Journal of the Neurological Sciences 05/2000; 175(2):140-4. · 2.35 Impact Factor
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ABSTRACT: A 51-year-old man inhaled sarin during a terrorist attack on the Tokyo subway system and died 15 months later. Neuropathologic examination revealed marked nerve fiber decrease in the sural nerve, moderate nerve fiber loss in the sciatic nerve, and unremarkable dorsal root ganglia, dorsal roots, and posterior column of the spinal cord. This pathology is consistent with dying-back degeneration of the peripheral nervous system and could represent a late sequela of sarin intoxication.
Neurology 11/1998; 51(4):1195-7. · 8.31 Impact Factor
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ABSTRACT: We describe a patient with progressive aphemia with agrammatism that was later overlaid with buccofacial apraxia and pseudobulbar palsy. Pathological findings were consistent with those of classic Pick's disease with argyrophilic inclusions and neuronal achromasia, except for restricted cortical atrophy in the frontal operculum posterior to the pars opercularis (Brodmann Area 44). In addition, major neuronal loss was confined to the premotor cortex and the anterior half of the precentral gyrus (Area 6), which apparently explained the aphemia. The present case demonstrated that classic Pick's disease can show quite limited cortical atrophy in a patient who clinically presents with progressive aphemia. Also, our patient differed from the progressive non-fluent aphasia patients reported as having Pick's disease, who were all Pick variants, revealing that classic Pick's disease can be included in the spectrum of progressive aphasia syndrome.
Journal of the Neurological Sciences 09/1998; 159(2):156-61. · 2.35 Impact Factor
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ABSTRACT: To evaluate the role of the sub-cortical white matter and cortical areas of the supramarginal gyrus in short-term memory impairment (shortened digit or letter span) and repetition difficulty, four patients with conduction aphasia and impaired short-term memory and two patients with only short-term memory impairment were given digit span, letter span, speech audiometry and dichotic listening tests. The results showed that in most of the patients letter span was inferior to digit span and that bilateral ear suppression in the dichotic listening test was observed in two patients with a lesion in the inferior part of the supramarginal gyrus, suggesting that what was affected was phonological information and that the supramarginal gyrus was the storage site. The overlapped lesion of conduction aphasia patients with short-term memory impairment was the periventricular white matter at the upper to middle part of the trigone, while patients with only short-term memory impairment had a lesion in the inferior supramarginal gyrus in common. Thus, damage to the periventricular white matter at the trigone may yield the phonemic paraphasia characteristic of conduction aphasia, while damage to the inferior part of the supramarginal gyrus may result in the impairment of short-term memory. We believe that as a part of the mechanisms of short-term memory and repetition, phonological information is processed in the primary auditory cortex and goes through the periventricular white matter to the inferior part of the supramarginal gyrus and is temporarily stored there.
Journal of the Neurological Sciences 03/1998; 154(2):182-93. · 2.35 Impact Factor
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S Murayama
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ABSTRACT: Clinical pathological approach is defined as combination of neurological, neurophysiological and neuroradiological findings for the interpretation of the morphology of the sural nerve. For this purpose, first, the usefulness of simultaneous biopsy of sural nerve and ipsilateral short peroneal muscle was presented. This method has helped establish the diagnosis of angitis or amyloidosis in some cases. Furthermore, motor-dominant clinical picture was ascertained by relative preservation of sural nerve in contrast with severe changes in intramuscular nerve fascicles. Second, histochemistry using UEA-1 lectin to detect somatic sensory C fibers was discussed. UEA-1 specifically binds to unmyelinated axons and small neurons in dorsal root ganglia as well as substantia gelatinosa of the spinal cord. Serial semithin and ultrathin sections were obtained. The semithin section was removed of epon and stained histochemically with UEA-1. Positive fibers in the semithin section was compared with the counterpart in the ultrathin sections. UEA-1 positive fibers were found to comprise 20% of all unmyelinated fibers and be randomly distributed among the entire nerve fascicles. The application of this technique to pathological specimens is now undergoing. Third, an autopsy case with sarin intoxication was reported as an example of systemic study of the peripheral nervous system. The patient was a 51-year-old man who inhaled sarin in the attack of Tokyo Subway. He fell into vegetative state and was passively maintained for 13 months. Peripheral sensory nerve showed typical pattern of dying back-type distal peripheral axonopathy. It might be indicated that peripheral nerve be carefully checked among the sarin victims. In conclusion, the aim of our approach is to combine all clinical information, introduce recent advance in neuroscience, and try to find possible cure to intractable neurological disorders.
Rinsho shinkeigaku = Clinical neurology 01/1998; 37(12):1103-4.
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ABSTRACT: Dentatorubral-pallidoluysian atrophy is an autosomal dominant neurodegenerative disorder characterized by dementia and spinocerebellar degeneration. Recently, part of the gene responsible for this disorder was cloned containing a CAG repeat, and predominant neuronal expression of the gene was proved only through Northern blot analysis in rats. In this study, we investigated the regional and cellular expression of the dentatorubral-pallidoluysian atrophy gene in the central nervous system of normal and affected humans, as well as in rat brains. In normal control human subjects, the gene messenger RNA was present in all brain regions examined, with the highest levels seen in the cerebellum, hippocampus, substantia nigra, and pontine nuclei. Its expression in the striatum, globus pallidus, and cerebral cortex was intermediate. The gene was expressed predominantly in neurons; a low but significant level of expression was also seen in glial cells. Neurons susceptible to degeneration in dentatorubral-pallidoluysian atrophy did not selectively express high or low levels of its gene messenger RNA. In brains affected by the disorder, the distribution and levels of gene messenger RNA were comparable to those of the normal controls in all the areas. In the rat brains, gene messenger RNA expression was very similar to that in human brain. It was also expressed predominantly in neurons, while low-level expression was observed in glial cells. It is apparent from these results that the presence of expanded trinucleotide repeats in dentatorubral-pallidoluysian atrophy does not result in the absence of its gene messenger RNA expression or in altered patterns or levels of expression.
Annals of Neurology 06/1997; 41(5):599-605. · 11.09 Impact Factor
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ABSTRACT: The demonstration of a genetic linkage between the copper-zinc superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis has aroused interest in the role of SOD1 in motoneuronal death. We investigated the expression of the human SOD1 gene at a cellular level in the motoneurons of patients with sporadic amyotrophic lateral sclerosis, patients with familial amyotrophic lateral sclerosis, and normal control subjects, using a quantitative in situ hybridization technique. There were no significant differences between the amounts of SOD1 messenger RNA observed in patients with sporadic disease, patients with familial disease, and normal control subjects. However, many of the atrophic motoneurons from patients with sporadic or familial disease had significantly lower levels of SOD1 messenger RNA, compared to morphologically intact motoneurons. Moreover, motoneurons in the normal spinal ventral horn and precentral motor cortex exhibited significantly higher levels of SOD1 messenger RNA than did other neurons. Our study indicated that vulnerable neurons in amyotrophic lateral sclerosis exhibit high levels of SOD1 messenger RNA, suggesting a close relationship between the SOD1 gene and the pathogenesis of amyotrophic lateral sclerosis.
Annals of Neurology 05/1997; 41(4):551-6. · 11.09 Impact Factor
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ABSTRACT: We report on a Japanese family affected by Emery-Dreifuss muscular dystrophy carrying a novel mutation of the emerin (STA) gene. The cardinal clinical feature of the family was cardiac conduction block and mild myopathy. A deletion of 11 bp with a frameshift was identified in exon 6, causing truncation of the predicted protein. The relationship between mutation and phenotype is discussed.
Annals of Neurology 04/1997; 41(3):399-402. · 11.09 Impact Factor
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ABSTRACT: We present a long-surviving patient with Wiskott-Aldrich syndrome complicated by atypical progressive multifocal leukoencephalopathy (PML). MRI showed multiple tiny spots of Gd-DTPA-enhanced lesions on the T1-weighted image. Pathologic findings for brain biopsy were patchy demyelinated vascularized lesions infiltrated by a surprising number of eosinophils. The presence of polyomavirus JC was confirmed by in situ hybridization and polymerase chain reaction. PML should be included in the differential diagnosis when Gd-DTPA-enhanced spotty lesions are present in the white matter, especially in patients who have a mild immunologic defect.
Neurology 02/1997; 48(1):279-82. · 8.31 Impact Factor
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ABSTRACT: Iron accumulation in the basal ganglia and spheroid formation are pathological hallmarks of Hallervorden-Spatz disease (HS). Since an overaccumulation of iron (iron thesaurosis) that exceeds the binding capacity of ferritin could cause oxidative damage, we studied the possible role of oxidative stress in the pathogenesis of HS. The basal ganglia and spinal cord from patients with HS were investigated at autopsy, using histochemistry for iron and immunohistochemistry for Cu/Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and ferritin. SOD1-like immunoreactivity (IR), SOD2-IR and ferritin-IR occurred frequently in spheroids observed in the basal ganglia, and associated iron accumulation indicated the possible existence of increased oxidative stress in HS patients. Spheroids in the spinal cord showed intense SOD1-IR and SOD2-IR in HS, in sharp contrast with the occasional weak SOD1-IR and SOD2-IR observed in spheroids from patients with amyotrophic lateral sclerosis (ALS). Neither increased ferritin-IR nor iron accumulation were observed in spinal spheroids from HS and ALS patients. These data may suggest that, at least in the spinal cord, SOD1-IR and SOD2-IR in spheroids in HS patients do not result from oxidative stress directly related to iron accumulation.
Acta Neuropathologica 02/1997; 93(1):19-23. · 9.32 Impact Factor
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ABSTRACT: Machado-Joseph disease (MJD) is an autosomal dominant disorder characterized pathologically by spinocerebellar degeneration. Recently, an expansion of CAG repeat in a gene located at the chromosome 14q32.1 was found to be responsible for the disease. Here, we investigated in situ the expression of the MJD gene (MJD1) in the central nervous systems of normal and affected individuals and in rat brains. This gene was expressed in all regions of rat and human normal brains with certain regional variations. MJD1 was transcribed preferentially in neurons, although low levels of MJD1 mRNA were also observed in glial cells. Neurons susceptible to degeneration in MJD expressed MJD1 but not selectively. In the affected brains, the MJD1 mRNA distribution and amount in all the areas examined were similar in patients and controls. In addition, the cellular MJD1 mRNA level correlated neither with clinical severity nor expanded length. Our study showed that the expression levels of trinucleotide repeats in MJD patients and normal controls did not differ, indicating that the pathogenesis of MJD may involve direct toxicity to vulnerable subsets and/or region-specific cofactors of MJD proteins.
Annals of Neurology 12/1996; 40(5):776-81. · 11.09 Impact Factor
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ABSTRACT: Presenilin 1 (PSNL1) is a novel causative gene for early-onset familial Alzheimer's disease (EOFAD). We have examined the regional and cellular distribution of PSLN1 gene expression in normal human and rat tissues. In situ hybridization and Northern blot analysis showed that PSNL1 mRNA was ubiquitously expressed in many different organs. We also demonstrated that PSNL1 mRNA was expressed predominantly in the neuronal cells of the central nervous system, but only at low-level in glial cells. Furthermore, the distribution of PSNL1 mRNA in human and rodent brains was similar.
Biochemical and Biophysical Research Communications 03/1996; 219(3):708-13. · 2.48 Impact Factor
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ABSTRACT: We report a patient with primary progressive aphasia who first presented with amnesic aphasia that developed over the course of 3 years into nonfluent aphasia with buccofacial apraxia, followed in the next year by cognitive impairment and parkinsonism. Pathological findings were typical for corticobasal degeneration except for the distribution of cortical atrophy. This case suggests that corticobasal degeneration should be included in the differential diagnosis of primary progressive aphasia, especially in association with parkinsonism.
European Neurology 02/1996; 36(3):134-7. · 1.81 Impact Factor
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ABSTRACT: Demonstration of a genetic linkage between the Cu/Zn superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis (ALS) has aroused interest in the role of SOD1 in spinal motoneuronal death. We used chronically beta,beta'-iminodipropionitrile (IDPN)-intoxicated rats as a model of ALS and investigated SOD1 changes in the spinal cord by immunocytochemical and in situ hybridization techniques. Compared with control rats, SOD1-like immunoreactivity (SOD1-IR) increased in swollen axons of the proximal spinal roots, but not in motoneuronal and dorsal root ganglion neuronal cell bodies where SOD1 gene transcription did not increase. The present data indicate that treatment with IDPN induces accumulation of SOD1 in the swollen axons by blocking slow axonal flow, suggesting the possibility that increased SOD1-IR in ALS is induced by axonal flow blockade.
Neuroscience Letters 08/1995; 194(3):205-8. · 2.11 Impact Factor
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ABSTRACT: Copper-zinc superoxide dismutase (SOD1)-like immunoreactivity has been demonstrated in Lewy body-like inclusions (LIs) in brain tissues from patients with familial and sporadic amyotrophic lateral sclerosis. Using immunocytochemistry, we studied Lewy bodies (LBs), the original inclusions from which the term LI was derived, in five patients with Parkinson disease (PD). Surprisingly, many LBs were immunostained by an antibody against SOD1. There were two types of staining pattern: a diffuse pattern, and a peripheral pattern with an unstained core. An immunoelectron microscopic study demonstrated that the immunoreactive products were restricted to the fibrillary profiles, sparing the unstructured core. Our results showed that SOD1-like immunoreactivity occurred frequently in LBs and LIs, suggesting that a common cytopathological process is responsible for the formation of LB-type neuronal intracytoplasmic inclusions. Our results also suggest that SOD1 plays a role in the neurodegeneration associated with PD.
Acta Neuropathologica 02/1995; 89(6):471-4. · 9.32 Impact Factor
