Mieko Otsuka

A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer's disease

Several lines of evidence have suggested altered functions of the brain-derived neurotrophic factor (BDNF) in the pathogenesis of neurodegenerative diseases including Alzheimers disease (AD). In the search for polymorphisms in the 5′-flanking and 5′-noncoding regions of the BDNF gene, we found a novel nucleotide substitution (C270T) in the noncoding region. We performed an association study between this polymorphism and AD in a Japanese sample of 170 patients with sporadic AD (51 early-onset and 119 late-onset) and 498 controls. The frequency of individuals who carried the mutated type (T270) was significantly more common in patients with late-onset AD than in controls (P = 0.00004, odds ratio: 3.8, 95% CI 1.9–7.4). However, there was no significant difference in the genotype distribution between the patients with early-onset AD and the controls, although this might be due to the small sample size of the early-onset group. Our results suggest that the C270T polymorphism of the BDNF gene or other unknown polymorphisms, which are in linkage disequilibrium, give susceptibility to late-onset AD. We obtained no evidence for the possible interactions between the BDNF and apolipoprotein E (APOE) genes, suggesting that the possible effect of the BDNF gene on the development of late-onset AD might be independent of the APOE genotype.

Life style risks of Parkinson's disease: association between decreased water intake and constipation.

Abstract.Gastrointestinal dysfunction, especially constipation, is one of the major problems in the daily life of patients with Parkinson’s disease (PD). About 60 to 80% of PD patients suffer from constipation. Several studies have proven that constipation appears about 10 to 20 years prior to motor symptoms. More recently, Abbott et al. have found from a large scale prospective study that lower frequency bowel movements predict the future risk of PD. Furthermore, Braak et al. have found that Lewy neuritis and Lewy bodies, the hallmarks of PD pathology, appear in the dorsal nucleus of vagus in the earliest stage of the disease and then extend upward through the brain stem to reach the substantia nigra in the third stage. They also hypothesize that some yet undefined toxins break through the mucosal barrier of the intestine and are incorporated into the axon terminal of the vagus nerve and transported in a retrograde manner to the vagus nucleus. In this study, we assessed bowel movements and nutritional status in Japanese patients with PD. We found that intake of water was significantly decreased in PD patients from early life and associated with their constipation.Ninety four patients with PD (M 50, F 44) were enrolled. Nutritional status was assessed using the Self-administered Diet History Questionnaire (DHQ). Total water intake was calculated from the consumption of coffee, green tea, and tea. We also questioned the behavior of water drinking from the early stage of life. The questionnaire for bowel movements concerned the frequency of defecation, age of onset of constipation, and age of onset of motor dysfunction. Less than one bowel movement in 3 days was defined as constipation.The nutritional status of PD patients did not differ significantly from those of controls though several studies have shown excess intake of animal fats or reduced consumption of coffee are risks in PD. In contrast, water intake was significantly lower in PD patients than controls (604.0±377.2 ml/d vs 909.5±531.6 ml/d; P<0.0001). Interestingly, PD patients tended not to feel thirsty and thus they had no desire to drink water throughout their life. Seventy four patients out of 94 (78.7 %) complained of constipation. Mean bowel frequency was once per 3.3±1.1 days and 71.1% of patients were defined as having constipation. Women suffered from constipation more frequently than men (82.4% vs 61.9 %). In 33 patients out of 74 (44.6 %), onset of constipation preceded motor disturbance by an average time of 18.1±18.8 years. Furthermore, the amount of water intake correlated inversely with the severity of constipation and the depletion of water intake preceded constipation in most cases.The present results support previous findings that constipation precedes the onset of motor dysfunction in PD. To our knowledge, this is the first report to point out latent water depletion in PD patients. It is not certain at present whether coffee or caffeine themselves are the protective factor for PD or alternatively the amount of water in coffee drinking is more essential. Prospective studies on a large scale are necessary to elucidate the real meaning of water depletion in PD.

Association study of structural mutations of the tyrosine hydroxylase gene with schizophrenia and Parkinson's disease

Tyrosine hydroxylase (TH) gene is the rate-limiting enzyme in the synthesis of catecholamines. Functional polymorphisms of the TH gene may be involved in the pathogenesis of neuropsychiatric diseases such as schizophrenia, affective disorders, and Parkinsonism. This study examined a possible association of two polymorphisms, both of which result in an amino acid change of the TH protein, with schizophrenia and Parkinsons disease (PD). The Val81Met polymorphism is a common variation, although its effect on the enzyme expression is unclear. Leu205Pro polymorphism is a rare mutation that is reported to cause Parkinsonism in infancy for individuals who are homozygous for the mutated type. We genotyped a Japanese sample of 194 schizophrenics, 99 patients with PD, and 161 controls for the Val81Met polymorphism by using mis-match PCR and digestion by the restriction enzyme BalI. There was no significant allelic or genotypic association of the Val81Met polymorphism with schizophrenia or PD. The Leu205Pro polymorphism was examined by using PCR and digestion by AluI; however, there was no individual who carried the mutated type of Pro205 among 50 schizophrenics or 50 patients with PD. Thus we obtained no evidence for the involvement of the two structural mutations of the TH gene in the pathogenesis of schizophrenia or PD.

Fibroblast growth factor (FGF)-9 immunoreactivity in senile plaques.

We examined fibroblast growth factor (FGF)-9 immunoreactivity in human hippocampal sections of Alzheimers disease (AD). FGF-9 immunoreactivity was observed in dystrophic neurites of senile plaques in AD and control cases, in addition to the hippocampal and cortical neurons. The amyloid core and neurofibrillary tangles lacked immunoreactivity. FGF-9 immunoreactive astrocytes were conspicuous in AD brains. FGF-9 may be involved in the neuropathology of AD.

Abnormal copper metabolism in Niemann–Pick disease type C mimicking Wilson's disease

Niemann–Pick disease type C is a rare lysosomal storage disease in infants, adolescents and adults.

Dietary factors and the risk of Alzheimer’s disease: a low fish consumption and a relative deficiency of ω-3 polyunsaturated fatty acids

Multiple risk factors, both genetic and environmental, are involved in the development of late-onset Alzheimer’s disease (AD). Though diet is a potentially modifiable factor, few studies have reported on the association between AD and diet. Recently, Kalmijn and colleagues [1] have found in a large prospective study in Rotterdam that fish consumption is inversely related to the incidence of AD.

α1-Antichymotrypsin and Apolipoprotein E Polymorphism in Alzheimer’s Disease

The apolipoprotein E-e4 allele (apoE-e4) is a major risk factor for late onset, familial and sporadic Alzheimer’s disease (AD). The frequency of e4 in patients with AD is about three times higher than yhat in controls, and approximately 60% of AD patients have at least one copy of the e4 allele (Strittmatter et al., 1993; Poirier et al., 1993; Saunders et al, 1993a; Saunders et al., 1993b; Rebeck et al., 1993; Ueki et al., 1993; Dai et al., 1994). ApoE-e4 reduces the onset age of dementia in a gene dosage manner (Corder et al., 1993). However, e4 is not a sufficient factor for developing AD, and some individuals carrying e4 remain cognitively intact past age 90 (Lehtovirta et al., 1995; Asada et al., 1996). Furthermore, the prevalence of AD in various ethnic groups does not correlate simply with variations of e4 frequencies in general populations (Hendrie et al., 1995). These facts suggest additional genetic or environmental factors must be involved in the manifestation of the disease. Family history of dementia (Duara et al., 1996), VLDL-receptor gene polymorphism (Okuizumi et al., 1995; Mui et al., 1996), low density lipoprotein-like receptor (LRP) gene polymorphism (Mui et al., 1996), C/G polymorphism in the apoE intron 1 enhancer element (Lendon et al., 1997), al-antichymotrypsin (ACT) signal peptide gene polymorphism (Kamboh et al., 1995), and past history of head trauma (Mayeux et al., 1995) are the candidates factors.

Phenotypes and Genotypes of Apolipoprotein E in Japanese Patients with Late-Onset Sporadic Alzheimer’s Disease, Vascular Dementia, Down’s Syndrome or Parkinson’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Most patients are sporadic and develop the disease after 60 years of age. Senile plaques (SP), neurofibrillary tangles (NFT) and amyloid angiopathies are observed histopathologically and the deposition of β-amyloid protein is postulated to play a crucial role in the development of AD.1 Extensive genetic studies in this late-onset AD have failed to identify any consistent abnormalities in the gene encoding amyloid precursor protein (APP) so far, and the mechanism for deposition of β-amyloid is yet to be determined.