Nobutaka Arai

Evaluation of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black mouse model for parkinsonism

We evaluated neurochemically, behaviorally, and neuropathologically the availability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 black (BL) mice as a model for Parkinsons disease. The dopamine and 3,4-dihydroxyphenyl acetic acid content in the striatum, measured by high-performance liquid chromatography with an electrochemical detector, decreased by 70% at 10 and 20 days after the withdrawal of MPTP (30 mg/kg, i.p. twice daily for 5 days). During these days, the mice showed a decrease in locomotor activity and exhibited akinesia in both pole and traction tests. Light microscopically, 44% of the MPTP-treated mice showed neuronal degeneration in the substantia nigra 1 month after the withdrawal (damaged group), and 56% showed no change (undamaged group). Morphometric analysis revealed that the number of neurons in the substantia nigra decreased by 33% on the average in both groups. Electron microscopically, an electron-dense degeneration of most neurons was seen in the substantia nigra of the damaged group, and even in the undamaged group, loss of rough endoplasmic reticulum and mitochondrial deformity were seen in 50-70% of the neurons. Electron-dense bodies were seen in the striatum of both groups. These results show the validity of the MPTP-treated C57 BL mice as a suitable model for parkinsonism, including Parkinsons disease.

Neurodegenerative Mechanisms in Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis is caused by persistent brain infection of mutated measles virus, showing inflammation, neuronal loss, and demyelination. We neuropathologically examined six autopsy cases of subacute sclerosing panencephalitis, using in situ nick end-labeling and immunohistochemistry. Both the neurons and glial cells in the cerebral cortex showed immunoreactive nuclei in the nick end-labeling in two cases with disease duration within 2 years, whereas they were confined to the glial cells in the demyelinated cerebral white matter in three cases with disease duration ranging from 2 to 10 years. The nuclei and cytoplasm were immunoreactive for 8-hydroxy-2-deoxyguanosine and 8-hydroxyguanosine, markers of oxidative damage to DNA and ribonucleic acid, respectively, in the cerebral cortex in three cases with disease duration within 9 years. In contrast, 4-hydroxy-2-nonenal-modified proteins, products of lipid peroxidation, were deposited in the demyelinated white matters in four cases with disease duration longer than 9 years. In three cases with long survival, the expression of glial glutamate transporters was reduced in the cerebral cortex. It is speculated in subacute sclerosing panencephalitis that apoptosis and oxidative stress to DNA can contribute to the early neuronal damage, whereas lipid peroxidation and disturbed glutamate transport may be related to the subsequent neurodegeneration. (J Child Neurol 2002;17:725—730).

Numerous glial fibrillary tangles in oligodendroglia in cases of subacute sclerosing panencephalitis with neurofibrillary tangles

Both neurons and oligodendroglia are preferentially infected in subacute sclerosing panencephalitis (SSPE). Massive argyrophilic and tau-positive glial fibrillary tangles (GFT) were found in oligodendroglia in two autopsy cases of SSPE with neurofibrillary tangles (NFT). GFT shared common phosphorylated tau-epitopes with NFT, but were negative for ubiquitin. Electron microscopically, GFT consisted of compact bundles of irregularly woven tubules. Thus, GFT in SSPE differed from NFT showing regular constriction of tubules and from GFT in some other cytoskeletal disorders in which GFT reportedly consisted of straight tubules.

Oxidative stress and disturbed glutamate transport in spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a hereditary motor neuron disease, and three clinical subtypes of autosomal recessive SMA, including Werdnig Hoffmann disease (type 1), have been shown to be induced by deletion within the same genes. In order to clarify the pathogenesis of motor neuron degeneration in SMA, we immunohistochemically examine the expressions of oxidative stress-related materials (oxidative products) and glutamate transporters, which can prevent glutamate neurotoxicity, in five autopsy cases of SMA type 1. Age-matched controls did not show any deposition of oxidative products in the brain. In contrast, the abnormal deposition of 4-hydroxy-2-nonenal-modified protein, a product of membrane lipid oxidation, was observed in the spinal motor neurons in three cases, although the motor neurons did not show an increase of nitrotyrosine, which was observed in adult-onset amyotrophic lateral sclerosis. In addition, the nuclei of neurons and glial cells in the precentral gyrus, thalamus or cerebellar cortex were immunoreactive for 8-hydroxy-2-deoxyguanosine in two cases, which was one of the most commonly used markers for oxidative DNA damage. Regarding glial glutamate transporters, three of five cases of SMA type 1 showed a reduction in immunoreactivity for excitatory amino acid transporter-1 (GLAST) in the ventrolateral nucleus of the thalamus, in which there was neither neuronal loss nor gliosis in routine histochemistry. One case, having mechanical ventilation, demonstrated a reduced expression of another glial glutamate transporter (GLT-1) throughout the central nervous system. These data suggest that oxidative stress and disturbed glutamate transport can partly be involved in the motor neuron devastation and/or latent thalamic degeneration in SMA type 1.

Lewy bodies in progressive supranuclear palsy.

Abstract. Lewy bodies (LBs), whose major component is α-synuclein, are a pathological hallmark of Parkinsons disease (PD) but have rarely been reported in progressive supranuclear palsy (PSP). Whether LBs in PSP represent the aging process or the coexistence of PD remains unclear. We found LBs in 5 of 16 patients with PSP. In 4 patients LBs were distributed widely throughout the brain stem and cerebrum in a pattern similar to that in PD. In the remaining patient one LB was found in the pontine reticular formation. Semiquantitative analysis showed that neuronal loss in the locus coeruleus and the dorsal vagal nucleus was more severe in patients with LBs than in patients without LBs. Double-labeling immunohistochemical studies showed co-localization of α-synuclein and tau in some neurons. Our study suggests that patients who have PSP with LBs constitute a subset of patients with PSP in whom Lewy body disease is also present.

A New Surgical Method for the Treatment of Hemispheric Dysplastic Lesions.

tients having convulsive status epilepticus (8.9 2 4.7 years) as compared with patients having CT/ MRI lesions (13.9 ? 8.8 years). We also studied pathoetiology and subtypes of TLE in a separate group of 105 patients who underwent long-term intracranial recording before resection. Seventy-four patients were classified with mesial temporal epilepsy (MTE). Of these 74,24 (32%) patients were classified with convulsive status epilepticus, and three (4%) had CT/MRI lesions. Thirtyone were classified with lateral temporal epilepsy (LTE). Of these 31, one (3%) with convulsive status epilepticus and 22 (70%) with CT/MRI lesion had LTE . Patients having convulsive status epilepticus in infancy or childhood were prone to develop MTE, and the majority had an initial epileptic seizure of TLE by age 15 years. Considering the excellent seizure outcome after surgery in this type of patient, if their epilepsy is confirmed to be intractable, earlier surgical intervention should be recommended. Most of the patients having CT/MRI lesions showed good seizure outcome after surgery; therefore surgery in an early stage should be recommended.

Immunohistochemical expression of microtubule-associated protein 5 (MAP5) in glial cells in multiple system atrophy

An immunohistochemical study focusing on glial cells was performed using monoclonal antibodies against microtubule-associated proteins (MAP1, MAP2 and MAP5), transferrin, leukocyte common antigen (LCA) and glial fibrillary acidic protein (GFAP) in 5 cases of multiple system atrophy (MSA) exhibiting olivopontocerebellar atrophy and striatonigral degeneration. An antibody to MAP5, a fetal antigen in developing brain, was strongly demonstrated in the glial cytoplasmic inclusions (GCIs) which have recently drawn a great deal of attention and were observed in all 5 cases of MSA. Moreover, MAP5-positive glial cells (MAP5-Gs) were present in significantly higher number than in the controls in various regions where GCIs were found, predominantly in putamen, substantia nigra, cerebellar white matter and internal capsule. LCA and transferrin, markers of microglia and oligodendroglia, respectively, were immunohistochemically detected in some MAP5-Gs. GFAP, on the other hand, was not expressed in MAP5-Gs at all. These findings suggest that MAP5-Gs consist of reactive microglia and oligodendroglia. Our study is the first to demonstrate immunohistochemical detection of MAP5 in glial pathological changes in MSA.

Study on surgical treatment of intractable childhood epilepsy

We studied the clinical details of 14 children with intractable epilepsies, all of whom underwent epilepsy surgery before age 18 years. All 14 suffered catastrophic seizures, which were resistant to the full range of available medical treatments. The ages at operation ranged from 4 years 7 months to 17 years 2 months, with a mean of 9 years 11 months. In nine patients, the age at onset of epilepsy was less than 2 years. The seizure disorders were classified as temporal lobe epilepsy in two patients, extratemporal lobe epilepsy in 10, and symptomatic generalized epilepsy in two. Eight patients had a hemicorporeal deficit (hemiparesis or hemiplegia) preoperatively. All 14 patients showed localized magnetic resonance imaging (MRI), single photon emission computer tomography (SPECT) and/or positron emission tomography (PET) abnormalities, providing crucial information regarding the epileptic focus. As to the surgical outcomes, four patients became seizure-free and the other 10 showed significant improvement during a mean follow-up period of 2 years 5 months. As to etiology, cortical dysplasia was identified in seven patients. Epilepsy surgery should be considered for intractable childhood epilepsy based on individual clinical characteristics, including seizure status, cognitive development, and evidence indicating location of the seizure focus, rather than age.

Nasu-Hakola's disease (membranous lipodystrophy)

SummaryAn autopsy case of Nasu-Hakolas disease (membranous lipodystrophy) is reported. A 43-year-old Japanese man, whose parents were not consanguineous, had been suffering from frequent long bone fractures since the age of 10. Neuropsychiatric symptoms, which were characterized by euphoria, disturbance of attention and dementia, appeared at his thirties and generalized and/or localized seizures and apallial syndrome at the later stage. The neuropathology revealed diffuse leukoencephalopathy of the cerebrum. The peculiar aspects in this case were membranocystic changes in the lungs [Yagishita et al. Virchows Arch [A] 408:211–217 (1985)], diffuse degeneration of the cerebral cortex, chiefly in frontal and temporal lobes, and many axonal spheroids throughout the cerebral cortex. The ultrastructure of spheroids in the cerebral cortex demonstrated aggregations of mitochondria, dense bodies and minute concentric bodies and a small amount of neurofilaments.

«Grumose degeneration» of the dentate nucleus: a light and electron microscopic study in progressive supranuclear palsy and dentatorubropallidoluysial atrophy

So-called grumose degeneration (GD) of the dentate nucleus (DN) which is a unique alteration in progressive supranuclear palsy and dentatorubropallidoluysial atrophy was studied by light and electron microscope. Light microscopically, the presence of a large amount of eosinophilic granular and/or amorphous material around the neurons is the most conspicuous feature of GD. In addition, the number of neurons is decreased and some of them are swollen as with central chromatolysis. Electron microscopically, the granular and/or amorphous material mainly consists of the altered axon terminals of the Purkinje cells (Pax), which are relatively electron-dense and characteristically contain varying numbers of deformed lamellar bodies, highly electron-dense mitochondria and many vacuoles which are adherent to the astrocytic processes. GD is a unique histological change of both the chromatolytic DN neurons and the grumose appearance of the altered Pax. Possible mechanisms are discussed.