Masaya Hironishi

Changes in the incidence of amyotrophic lateral sclerosis in Wakayama, Japan

In the 1960s, the incidence of amyotrophic lateral sclerosis (ALS) in the Kozagawa and Koza areas in Wakayama prefecture was much higher than that in other areas of the world. However, between 1980 and 1993, a gradual decrease in the incidence of the disease in these areas was reported. To ascertain whether the decreased incidence has persisted, we conducted a retrospective epidemiological study, and determined the average annual incidence of ALS in Wakayama prefecture from 1998 to 2002. The number of ALS cases encountered during the period was 134 (male 79, female 55). The crude average annual incidence in Wakayama prefecture in total was 2.50 (male 3.08, female 1.99) per 100,000. In the Kozagawa and Koza areas in Wakayama prefecture, where the senility rate rapidly increased in recent years, the average annual incidence of ALS in the present research was 10.56 (male 14.14, female 7.66). When the crude rate was standardized for both age and sex to the Japanese population in 1990, the expected value was 5.24 (male 7.34, female 3.18), which was lower than that of our previous survey. The prevalence in Wakayama prefecture at 31 December 2002 was 11.31 (male 14.40, female 8.53). In Kozagawa and Koza areas, the crude prevalence was 52.81 (male 70.70, female 38.28). These results indicated that the incidence of ALS in Wakayama prefecture, especially for females, steadily decreased compared to that in previous reports. However, a high incidence of ALS persisted among males in Wakayama prefecture, especially in the Kozagawa and Koza areas. Some environmental factors and gender specificity may be related to the decreased incidence of ALS in focus areas.

Nuclear localization of glyceraldehyde‐3‐phosphate dehydrogenase is not involved in the initiation of apoptosis induced by 1‐Methyl‐4‐phenyl‐pyridium iodide (MPP+)

Nuclear localization of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is implicated in the process of apoptosis. To study the function of GAPDH, we expressed GAPDH C‐terminally fused with or without nuclear localization signal (NLS) in SH‐SY5Y and NB41A3 cells using a retrovirus expression system. GAPDH carrying NLS (GAPDH‐NLS) was expressed mainly in the nucleus. However, expression of GAPDH‐NLS did not cause any difference in cell survival rate as compared to that of the vector alone or GAPDH without NLS. Treatment with 1‐Methyl‐4‐phenyl‐pyridium iodide (MPP+) caused no difference in the cell survival rate or in the pattern or extent of apoptosis among the three transductants. In the cells expressing GAPDH without NLS, MPP+ did not cause visible translocation of GAPDH into nucleus before the onset of apoptosis. Since GAPDH is known to comprise a CRM1‐mediated nuclear export signal, we blocked the nuclear export of GAPDH by treatment with leptomycin B, an inhibitor of CRM1‐mediated nuclear export. The treatment did not cause any difference in apoptosis among the three transductants. An additional treatment with MPP+ induced no apoptotic difference in these cells. Thus, we have concluded that a simple nuclear localization of GAPDH does not induce apoptosis, and that MPP+‐induced apoptosis is not caused by nuclear translocation of GAPDH.

Transcranial sonography of the substantia nigra and MIBG myocardial scintigraphy: complementary role in the diagnosis of Parkinson's disease.

Both transcranial sonography (TCS) of the substantia nigra (SN) and metaiodobenzylguanidine (MIBG) myocardial scintigraphy have been determined to be useful for the diagnosis of Parkinsons disease (PD). In the present study, we performed both tests in 65 consecutive Japanese patients with idiopathic PD. In 30 PD patients (46.2%), the midbrain was adequately displayed by TCS allowing quantitative measurements of SN hyperechogenic areas. No significant correlation was found between the area of SN echogenicity and the reduction of myocardial uptake of MIBG. However, if the cut-off value was appropriately set, 29 patients (97%) were identified as abnormal by combined TCS and MIBG myocardial scintigraphy. Since TCS and MIBG myocardial scintigraphy can distinctively detect PD-related pathological phenomenon, it is expected that the combination of these tests could contribute to an accurate diagnosis of PD.

Neuronal degeneration in amyotrophic lateral sclerosis is mediated by a possible mechanism different from classical apoptosis

In order to determine the potential role of apoptosis in the degeneration in amyotrophic lateral sclerosis (ALS), we correlated the morphological characteristics of the remaining neurons in the spinal cord with the results of in situ DNA fragmentation detected by terminal transferase‐mediated deoxyuridinetriphosphate (dUTP)‐biotin nick‐end labeling (TUNEL) in 17 cases of ALS, five age‐matched control cases, six aged control cases, and three disease control cases with spinal cord lesions. The remaining neurons were classified into five categories: normal appearing, chromatolytic, degenerative, atrophic, and inclusion laden. We measured the areas of the per©karya, the nuclei, and the nucleoli of the neurons in these categories. The areas of perikarya, nuclei, and nucleoli in the postero‐posterolateral neurons of the ALS cases were significantly decreased compared with those of the age‐matched controls. The nucleolar and nuclear areas of even normal‐appearing neurons from the ALS cases were significantly decreased compared with those from the age‐matched controls, suggesting that nuclear and nucleolar shrinkage in normal‐appearing neurons in ALS is an early change in this disease. However, the frequency of TUNEL‐positive neurons in the normal‐appearing, degenerative, atrophic, or inclusion‐laden neurons in the spinal cord of the ALS cases was not significantly elevated compared with those in the age‐matched, aged, or disease controls. No apoptotic bodies were detected by electron microscopy in the ALS spinal cords examined. Our results suggest that neuronal degeneration in ALS involves a certain mechanism different from classical apoptosis. We hypothesize that classical apoptosis may be a terminal event of neuronal degeneration in ALS, even though classical apoptosis has a role in the disease processes of ALS.

FKBP12 immunoreactivity in the human spinal cord of motor neuron disease patients

We investigated the FKBP12 immunoreactivity in the spinal cord of neurological controls and motor neuron disease (MND) patients. In the neurological controls, the spinal neurons were markedly stained with antihuman FKBP12 (N‐19 and C‐19) antibodies. FKBP12 immunoreactivity was associated with lipofuscin in formalin‐fixed paraffin‐embedded samples. In an electron microscopic view, the 10‐nm colloidal gold particles labeled by the anti‐FKBP12 (N‐19) antibody were present on the lipofuscin of the spinal anterior horn neurons. In the MND cases, atrophic neurons with an abundance of lipofuscin granules in the anterior horns of the spinal cord were mildly stained with the anti‐FKBP12 (N‐19 and C‐19) antibodies. Normal‐appearing neurons, inclusion‐laden neurons and chromatolytic neurons of MND cases were weak or negatively stained with anti‐FKBP12 (N‐19) antibodies. These findings suggest that FKBP12 (N‐19) may decrease in the early stages of degeneration in MND. Complexes of FKBP12 and ligands were reported to have neuroprotective and/or neuroregenerative properties. It is speculated that the decrease in FKBP12 (N‐19) plays some causative role in the development of neurodegeneration in MND. Further investigation of FKBP12 and ligands may help elucidate the pathogenesis of MND.

Superficial siderosis associated with duplicated dura mater detected by CISS reverse MRI

Superficial siderosis (SS) of the central nervous system is a rare disease caused by chronic or repeated hemorrhages in the subarachnoid space. Closure of dural defects is an effective therapy for SS. Conventional magnetic resonance imaging (MRI), however, cannot sufficiently detect dural tears. To better detect these defects, we analyzed the clinical data of consecutive patients admitted to our department with SS and performed constructive interference in steady-state (CISS) reverse MRI of the brain and spinal cord. CISS reverse method emphasizes the contrast between the dura and cerebrospinal fluid, enabling detection of dural defects better than usual T2-weighted MRI. CISS reverse MRI detected fluid-filled collections in five of the seven SS patients we studied. These images showed that the fluid-filled collections were packed within duplicated dura mater. In three of the five, dural defects were confirmed intraoperatively. We postulate that fluid-filled collections are actually derived from dissection of the dura mater. In accordance with the Monro-Kellie hypothesis, we propose that CSF transferal into the fluid-filled collections via dural defects induces an increase in blood volume and promotes the exudation of blood from engorged vessels. In patients with SS, it is very important to repair dural defects to prevent further associated neurological impairment. CISS reverse MRI is useful for detecting such dural defects.