Fusahiro Ikuta

Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA)

Hereditary dentatorubral–pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

Familial juvenile parkinsonism : clinical and pathologic study in a family

We describe a family with juvenile-onset parkinsonism, which improved following sleep. Four of the five siblings in this family developed a similar onset of parkinsonism at an early age, and the parents were first cousins. In one of the siblings, a 67-year-old woman, pathologic changes at autopsy were confined to the substantia nigra pars compacta (SNPC) and locus ceruleus. The SNPC revealed obvious neuronal loss and gliosis in the medial and ventrolateral regions. In the remainder of the SNPC and the locus ceruleus, the population of neurons was reduced and there was low melanin content in most of the neurons but no detectable gliosis or extraneuronal free melanin pigment suggestive of a neurodegenerative process. There were no Lewy bodies. The entire pathologic picture was different from that of Lewy body Parkinsons disease.

Parkinson's disease: Distribution of Lewy bodies and monoamine neuron system

SummaryA systematic study of the central and peripheral nervous systems in 3 cases of Parkinsons disease has demonstrated that Lewy bodies are present in 27 nuclei. Of these 20 nuclei (12 pigmented and 8 unpigmented) are involved in 2 or all 3 cases.It is noticed that the distribution of Lewy bodies in Parkinsons disease described here corresponds surprisingly well to that of monoamine (dopamine, noradrenaline and serotonin) cell bodies demonstrated in rats by the histochemical fluorescence method. This correlation is similar to that of Alzheimers neurofibrillary changes in postencephalitic Parkinsonism as described by Ishii. Inasmuch as these viewpoints are also in agreement with previously reported biochemical data on Parkinsonism, it is suggested that Parkinsonism (idiopathic and postencephalitic) should represent a system degeneration of monoamine neuron systems.

Neuropathology with clinical correlations of sporadic amyotrophic lateral sclerosis: 102 autopsy cases examined between 1962 and 2000.

Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbar‐onset form (30 cases) than for the limb‐onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower‐motor‐predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido‐nigro‐luysian degeneration (2 cases). The age at onset was significantly higher for lower‐motor‐predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin‐immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin‐immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin‐immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar‐onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar‐onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS.

Corticobasal degeneration : etiopathological significance of the cytoskeletal alterations

We have studied brain tissues from three patients with corticobasal degeneration (CBD) histologically, ultrastructurally and immunohistochemically. Ballooned neurons in the cerebral cortex and severe degeneration of the substantia nigra were observed in them all and weakly basophilic neurofibrillary tangles (NFTs) were distributed widely in the basal ganglia and brain stem. Ultrastructural examination demonstrated that the NFTs comprised characteristic 15-nm-wide straight tubules, which showed positive immunohistochemical staining with an antibody against tau, but not ubiquitin. Tau-immunoreactive neuronal cell bodies without NFTs also were found in the cerebral cortex and subcortical nuclei, predominantly in the brain stem, and the greatest number of tau-positive glial inclusions occurred in the cerebral gray and white matter of the pre- and post-central gyri. These inclusions comprised tubular structures with diameters of about 15 nm and were localized in the oligodendroglial cellular cytoplasm and processes. These findings indicate that there is a close cytoskeletal pathological relationship between CBD and progressive supranuclear palsy.

Histologic evidence of absorption of sequestration-type herniated disc.

Study Design The reactions to sequestrated disc fragments, which were removed surgically from 35 patients, were examined histologically. Objectives To elucidate whether or not there is histologic evidence of absorption of sequestrated discs. Summary of Background Data Spontaneous disappearance of diminution of lumbar herniated discs in the spinal canal has been recognized, and this could be a possible explanation for relief of symptoms without surgery. The mechanism of this phenomenon is unclear. Methods Sequestrated discs removed surgically from 35 patients were examined histologically. Results In 30 cases, neovascularization was observed at the periphery of the sequestrated discs. Many foamy cells (macrophages) were present in the vascularized areas. In addition, immunohistochemistry revealed that many spindle-shaped, fibroblast-like cells were positive for CD68, a marker of macrophages. No fibrous scar formation was observed in any region. Conclusion These findings suggest that organization is not a main course for this type of herniated disc and that a kind of “absorption” process occurs predominantly in the healing stage.

Cervical Spondylotic Myelopathy: Clinicopathologic Study on the Progression Pattern and Thin Myelinated Fibers of the Lesions of Seven Patients Examined During Complete Autopsy

Study Design This study was designed to reveal the progression pattern and essential histological findings of the lesions in the spinal cord affected by cervical spondylotic myelopathy. Objectives The purpose of this study was to gain new information about symptom progression and recovery in cervical spondylotic myelopathy. Summary of Background Data The characteristics of the distribution and the progression pattern of the lesions and whether demyelination and remyelination processes actually occur in cervical spondylotic myelopathy remain unclear. Methods Tissues from seven patients with cervical spondylotic myelopathy were taken during autopsy and examined macroscopically and microscopically. An ultrastructural examination of spinal cord from two patients was also performed. Results The anterior horn and intermediate zone of the gray matter in the compressed segments showed atrophy in all the cases and in one, atrophy was limited to these areas. Atrophy and myelin pallor in the lateral and posterior funiculi were observed in six patients, and the lateral funiculi of two were severely affected. Many thin myelinated fibers and denuded axons were demonstrated ultrastructurally in the damaged white matter of two patients. Conclusion There appears to be a common pattern of lesion progression in cervical spondylotic myelopathy: atrophy and neuronal loss in the anterior horn and intermediate zone develop first, followed by degeneration of the lateral and posterior funiculi. Eventually, marked atrophy develops throughout the entire gray matter and severe degeneration occurs in the lateral funiculus. Furthermore, the existence of thin myelinated fibers in the white matter suggests focal demyelinating and remyelinating processes occur in cervical spondylotic myelopathy.

Cerebral glioblastoma with cerebrospinal fluid dissemination: a clinicopathological study of 14 cases examined by complete autopsy

During the last 17 years, complete autopsies were performed on 51 patients who died of cerebral glioblastoma, and 14 were found to have dissemination by cerebrospinal fluid (CSF). In these 14 cases of glioma, the extent of intraparenchymal invasion by the primary tumor and the degree of seeding were studied in connection with histological findings and immunohistochemical staining for glial fibrillary acidic protein (GFAP) as the most reliable marker of astrocytic differentiation. From the findings obtained, the cases were divided into two groups. In one group, consisting of 7 gliomas, autopsy revealed intense seeding, despite only slight invasion by the primary tumor. Among these 7 extensively disseminated gliomas, 4 expressed almost no GFAP, 2 contained only a few GFAP-positive cells, and only 1 displayed an immunohistochemically high degree of astrocytic differentiation. Clinically, 6 of the 7 affected patients developed symptoms attributable to CSF seeding. In the other group consisting of the remaining 7 gliomas, only slight dissemination was seen, despite extensive infiltration of the primary tumor. Each of these 7 gliomas contained many GFAP-positive cells. None of the affected patients developed symptomatic seeding. This study shows the existence of two clinicopathologically distinct groups of disseminated cerebral glioblastomas and suggests that, regardless of morphological features, glioblastomas showing immunohistochemically poor astrocytic differentiation tend to shed tumor cells more vigorously but are less invasive at the primary site than those with many GFAP-positive cells. It is also suggested that, as a consequence, the former glioma type produces symptomatic seeding more frequently than the latter type.

Subcortical hematoma caused by cerebral amyloid angiopathy: does the first evidence of hemorrhage occur in the subarachnoid space?

Six autopsy cases of subcortical hematoma caused by CAA were examined to elucidate the primary site of hemorrhage. Immunohistochemistry for amyloid β‐protein (Aβ) revealed extensive CAA in the intrasulcal meningeal vessels rather than in the cerebral cortical vessels. All of the examined cases had multiple hematomas in the subarachnoid space, mainly in the cerebral sulci, as well as intracerebral hematomas. Each intracerebral hematoma was connected to the subarachnoid hematomas at the depth of cerebral sulci or through the lateral side of the cortex. There was no debris of the cerebral cortical tissue in the subarachnoid hematomas. In case 2, another solitary subarachnoid hematoma, which was not connected to any intracerebral hematoma, was seen. In all of these subarachnoid hematomas, many ruptured Aβ‐immunopositive arteries were observed. These ruptured arteries did not accompany any debris of the brain tissue, some of them were large in diameter (250–300 µm), and several of them were far from the cerebral cortex. Therefore, it was considered that they were not cortical arteries but meningeal arteries. Within the cerebral cortex, there were only a few ruptured arteries associated with small hemorrhages. There were no ruptured vessels within the intracerebral hematomas. There was a strong suggestion that all of the subarachnoid hematomas, including the solitary one in case 2, originated from the rupture of the meningeal arteries. The present study indicates that in some cases of subcortical hematoma caused by CAA, the primary hemorrhage occurs in the subarachnoid space, in particular the cerebral sulci, because of rupture of multiple meningeal arteries. Infarction occurs subsequently in the cortex around the hematoma, the hematoma penetrates into the brain parenchyma, and finally, a subcortical hematoma is formed.

Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene

Several missense mutations within exons 1, 2, 4 and 5 of the gene for Cu/Zn-binding superoxide dismutase (SOD1) have been discovered to be involved in the development of chromosome 21q-linked familial amyotrophic lateral sclerosis (FALS). We describe here an autopsied patient with FALS, in whom we have recently identified a novel missense mutation in exon 1 of the SOD1 gene. The neuropathological findings were compatible with those described previously in patients with FALS with posterior column involvement. This suggests that mutations of the SOD1 gene may be responsible for this form of FALS.