Tameko Kihira

Immunohistochemical expression of IGF-I and GSK in the spinal cord of Kii and Guamanian ALS patients

Insulin‐like growth factor‐I (IGF‐I) is a potent survival factor for motor neurons in animals, and glycogen synthase kinase‐3β (GSK‐3β) is suspected to play roles in apoptosis and tau phosphorylation. Here we report the immunological expression of IGF‐I, GSK‐3β, phosphorylated‐GSK‐3α/β (p‐GSK‐3α/β) and phosphorylated‐tau in the spinal cord and hippocampus of Kii and Guam amyotrophic lateral sclerosis (ALS) patients. Sixteen ALS patients (10 Japanese sporadic, 3 Kii and 3 Guam ALS) and 14 neurological controls (10 Japanese and 4 Guamanian) were examined. The immunoreactivity for each antibody was rated by the percentages of positive neurons to total anterior horn neurons in each patient and was analyzed statistically. Many normal‐looking neurons from Japanese sporadic ALS, Kii ALS and Guam ALS patients, as well as from Japanese and Guam controls, were positive for anti‐IGF‐I antibody. A positive correlation between IR scores for anti‐IGF‐I antibody and clinical durations of Japanese sporadic ALS patients was found in this study (P < 0.0001). This suggested that IGF‐I might have a protective effect against ALS degeneration. In Japanese sporadic ALS patients, abnormal as well as normal‐looking neurons showed significant high IR scores for anti‐GSK‐3β antibody than those of controls. Anterior horn neurons from Guam and Kii ALS patients characteristically showed weak staining for anti‐GSK‐3β antibody but were markedly positive for anti‐pGSK‐3α/β antibody compared to those from both Japanese controls and Japanese sporadic ALS patients, and showed the co‐localization of IGF‐I and p‐GSK‐3α/β. This suggested that the IGF‐I signaling pathway in Guam and Kii ALS patients might function to phosphorylate GSK‐3β to protect neurons from ALS degeneration. Neurofibrillary tangles (NFTs) in the hippocampus and spinal cord from Kii and Guam ALS patients showed the co‐localization of PHF‐tau and p‐GSK‐3α/β by a confocal laser scanning technique. The predominant expression of p‐GSK‐3α/β compared to GSK‐3β in spinal motor neurons and the co‐localization of p‐GSK‐3α/β and PHF‐tau in NFT‐laden neurons in the hippocampus and spinal cord were characteristic findings of Kii and Guam ALS patients.

An increase in ALS incidence on the Kii Peninsula, 1960 - 2009: A possible link to change in drinking water source

Abstract We investigated changes in the incidence of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto area (K. area) in the Kii Peninsula, Japan in 1960−2009. Probable and definite ALS cases diagnosed using El Escorial criteria were collected during a five-decade period: period I−V, 1960−2009. Forty-three ALS patients matched the selection criteria in the overall K. area, including three patients on Oshima, a small island opposite the mainland K. area. The age- and gender-adjusted incidence of ALS in the overall K. area (standardized for the 2005 Japanese population) decreased from 5.47/100,000 (95% CI 1.86–9.08) in period I to 0.61/100,000 (95% CI−0.28−1.50) in period III, and then increased to 4.39/100,000 (95% CI 1.70–7.07) in period V. On Oshima, the age- and gender-adjusted incidence of ALS was 9.45/100,000 (95% CI−7.39−26.29) in period V. The present research indicates an increase of ALS incidence in the K. area, especially on Oshima. A limitation of this study was the small population.

Mutational analysis of familial and sporadic amyotrophic lateral sclerosis with OPTN mutations in Japanese population

Our objective was to elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) and sporadic ALS (SALS) with OPTN mutations in the Japanese population. Mutational analysis of OPTN was conducted in 18 FALS pedigrees in whom mutations in other causative genes have been excluded and in 218 SALS patients by direct nucleotide sequence analysis. Novel non-synonymous variants identified in ALS patients were further screened in 271 controls. Results showed that although no mutations were identified in the FALS pedigrees, a novel heterozygous non-synonymous variant c.481G > A (p.V161M) was identified in one SALS patient, who originated from the southernmost part of the Kii Peninsula. The mutation was not present in 271 controls. As the clinical feature, the patient carrying V161M showed predominantly upper motor neuron signs with slow progression. This study suggests that mutations in OPTN are not the main cause of ALS in the Japanese population.

Lifestyle Changes and Oxidative Stress in a High-incidence Area of Amyotrophic Lateral Sclerosis in the Southwestern Kii Peninsula, Japan

Objective Lifestyle changes may play an important role in the incidence reduction and delay of onset age of amyotrophic lateral sclerosis (ALS) in the Koza/Kozagawa/Kushimoto (K) area. The aim of this study was to evaluate recent lifestyle changes in the K area and to investigate the relationships between lifestyle and oxidative stress among the residents. Methods We conducted a medical checkup for elderly residents in the K area and the control area and evaluated the urinary 8-OHdG levels, cognitive function test scores and metal contents in serum and scalp hair, coupled with a lifestyle questionnaire survey between 2010 and 2015. Results Recent lifestyle changes among the K residents, including a decrease in the Japanese pickle consumption, increase in fresh vegetable consumption and decrease in farm work, were evaluated in this study. Low consumption of Japanese pickles, high consumption of fresh vegetables, rare farm work and low levels of 8-OHdG/creatinine were all associated with high scores in the cognitive function tests. Frequent farm work and consumption of Japanese pickles was associated with high contents of transition metals, such as Mn, Al and V, in the scalp hair. Conclusion These lifestyle changes among residents in the K area may be associated with their oxidative stress.