Alzheimer Disease: Urakami K

Urakami K. · No affiliation provided · Nippon Ronen Igakkai Zasshi. · Pubmed #16937931 No free full text.

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Urakami K, Wakutani Y, Wada K, Nakajima K. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #16190326 No free full text.

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Wakutani Y, Kowa H, Kusumi M, Yamagata K, Wada-Isoe K, Adachi Y, Takeshima T, Urakami K, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago 683-8504, Japan. · Ann N Y Acad Sci. · Pubmed #12480755 No free full text.

Abstract: Genetic risk factors for Alzheimer's disease (AD) have been extensively examined. Several risk factors for AD are shared with vascular dementia (VaD). We performed genetic case-control studies on polymorphisms of the apolipoprotein E (ApoE) gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin-converting enzyme (ACE) gene. The most acceptable genetic risk factor for the development of AD is the ApoE epsilon-4 (ApoE epsilon4) allele. ApoE promoter polymorphisms have also been reported to be associated with AD. As expected, the ApoE epsilon4 allele had strong association with AD in our samples. The ApoE epsilon4 allele was also estimated as a risk factor for VaD. An ApoE promoter polymorphism (-291T/G) did not show positive association with AD or any other diseases. Common MTHFR phenotypes are thought to genetically regulate blood homocysteine level, which has been associated with AD. We failed to show independent associations between AD and the common MTHFR polymorphisms (C677T and A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been associated with AD. In our study, we found a significant ethnic difference of the genotype distribution, but failed to replicate the positive association between the I allele and AD.

Urakami K, Wakutani Y, Wada-Isoe K, Yamagata K, Adachi Y, Nakashima K. · Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University. · Nippon Ronen Igakkai Zasshi. · Pubmed #11774719 No free full text.

Abstract: Recently, some Alzheimer-associated genes have been found: amyloid beta protein precursor (APP), apolipoprotein E (apoE), presenilin 1 (PS-1), and presenilin 2 (PS-2). First, we failed to discover other susceptibility genes of familial Alzheimer's disease (FAD). However, we disClosed a novel mutation. Asp678Asn (D678N), in the APP gene in a pedigree of early-onset Japanese FAD. The alteration in the aggregation properties of mutant A beta may be involved in the pathogenesis of FAD with D678N APP mutation. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheimer's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphism of the ER alpha gene may be a genetic risk factor for SAD.

Urakami K, Wakutani Y, Wada-Isoe K, Yamagata K, Adachi Y, Nakashima K. · Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori Universiey. · Nippon Ronen Igakkai Zasshi. · Pubmed #11305015 No free full text.

Abstract: Recently, some Alzheimer-associated genes have been found: amyloid precursor protein (APP), apolipoprotein E (apoE), presenilin 1 (PS-1) and presenilin 2 (PS-2). First, we examined mutations of APP, PS-1, and PS-2 genes in familiar Alzheimer's disease (FAD) (7 cases) found in San-in district by single-strand conformation polymorphism and sequence analysis. These seven cases with FAD did not show any mutations of APP, PS-1, and PS-2 genes. Other susceptibility genes of FAD still remain to be not identified. Many reports have established that apoE genotype distribution for the epsilon 4 allele is a susceptibility factor for the earlier onset and more rapid progression of Alzheier's disease (AD). However, the cause of sporadic AD (SAD) has not been elucidated fully. Other genetic factors may be associated with development of SAD. Second, we investigated the association between polymorphisms of the estrogen receptor (ER) alpha gene and SAD. The frequencies of P and X alleles in SAD were significantly higher than those in the control group (p < 0.05). Polymorphisms of the ER alpha gene may be a genetic risk factor for SAD. The apoE genotype is a genetic factor closely related SAD, but it is not full by appreciated how apoE has an effect on developing AD. There are few reports on the quantitative change of apoE, namely the expression of apoE mRNA. Third, ApoE mRNA level in the brains of patients with Alzheimer's disease (27 cases) and Down's syndrome (11 cases) was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ApoE mRNA level in the DS as well as AD was significantly higher than that in control group (p < 0.05, p < 0.05, respectively). High levels of apoE mRNA in AD and DS may play an important role in the development of Alzheimer pathology.

Shoji M, Kuwano R, Asada T, Imagawa M, Higuchi S, Urakami K, Arai H, Ihara Y, Anonymous00237, Anonymous00238. · Department of Neurology, Neuroscience, Biophysiological Science, Okayama University Graduate School of Medicine and Dentistry. · Rinsho Shinkeigaku. · Pubmed #15782613 No free full text.

Abstract: To clarify the risk and associated genes of Alzheimer's disease by genome-wide screening, a Japanese study group was organized in 2000 under Yasuo Ihara, Tokyo University, supported by a Grant-in-Aid for Science Research on Priority Areas (C) -Advanced Brain Science Project from Ministry of Education, Culture, Sports, Science and Technology, Japan. This is the first Japanese consortium study under permission of the ethical committees of the enrolled institutes based on the ethics guidelines for human genome/gene analysis research, Ministry of Education, Culture, Sports, Science and Technology Ministry of Health, Labor and Welfare Ministry of Economy, Trade and Industry. In this project, 2,000 genome samples from patients with Alzheimer's disease, 2,000 control subjects, and 200 siblings affected with Alzheimer's disease are collected and analyzed. For this purpose, it is necessary to analyze samples from accurately diagnosed Alzheimer patients and controls using standard criteria for diagnosis and neuropsychological evaluation, which have been confirmed by an evidence-based studying a Japanese population. Here, we propose criteria for the diagnosis and clinical assessment of Alzheimer's disease. This proposal consists of a definition of Alzheimer's disease based on recent advances in research, diagnostic criteria based on DSM-IV, NINCDS-ADRDA and ICD-10, exclusion criteria for other dementia disorders, routine and detailed tests for neuropsychological and laboratory evaluations, criteria for neuroimaging and biomarkers, definitive diagnostic criteria and classification of clinical subtypes.

Matsubara E, Sekijima Y, Tokuda T, Urakami K, Amari M, Shizuka-Ikeda M, Tomidokoro Y, Ikeda M, Kawarabayashi T, Harigaya Y, Ikeda S, Murakami T, Abe K, Otomo E, Hirai S, Frangione B, Ghiso J, Shoji M. · Department of Neurology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Schikata-cho, Okayama, Okayama 700-8558, Japan. · Neurobiol Aging. · Pubmed #15212837 No free full text.

Abstract: In order to assess whether lipoproteins are physiologically able to balance and modulate the sAbeta homeostasis in vivo, soluble Abeta levels in lipoprotein-depleted plasma were measured as a function of age in normal controls, Alzheimer's disease (AD) patients, and Down's syndrome (DS) cases. The reshaping of sAbeta homeostasis, in particular the sAbeta42-lipoprotein interaction, takes place over normal-60's, whereas mild AD patients appear to have impaired this anti-amyloidogenic mechanism resulting in a significant increase of lipoprotein-free sAbeta42. Similar loss of function takes place in Down's syndrome patients. Lipoprotein-free sAbeta remains significantly elevated from the pre-symptomatic through the symptomatic stages of the disease, and declines with the progression of the AD-like pathology. The dissociation of sAbeta from lipoprotein-particles also occurs in brain parenchyma and the presence of soluble dimeric lipoprotein-free Abeta prior to its parenchymal deposition in AD brains would support the hypothesis that functionally declined lipoproteins may be major determinants in the production of metabolic conditions leading to higher levels of sAbeta species and cerebral amyloidosis.

Higuchi S, Matsushita S, Nakane J, Arai H, Matsui T, Urakami K, Yuzuriha T, Takeda A. · Division of Clinical Research, National Institute on Alcoholism, Kurihama National Hospital, Yokosuka Kanagawa, Japan. · Neuroreport. · Pubmed #10817585 No free full text.

Abstract: Two genetic markers of the plasma protein alpha2-macroglobulin, a 5 bp deletion/insertion at the 5' splice site of exon 18 (A2MI) and the GTC/ATC (VaIIO00IIe) in exon 24 (A2M2), may have roles in the development of Alzheimer's disease (AD). Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients, 85 autopsy-confirmed Caucasian AD cases, and, as controls, 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson's disease patients showed racial diversity in the frequencies and relationship of the two markers. Comparison of genotype and allele frequencies, stratification of the samples by the presence of the apolipoprotein E epsilon4 allele, and logistic regression analysis revealed no association of these markers with AD in either racial group.

Ji Y, Urakami K, Adachi Y, Nakashima K. · Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan. · Dement Geriatr Cogn Disord. · Pubmed #10559562 No free full text.

Abstract: Human apolipoprotein A-IV (apoA-IV) is genetically polymorphic, the apoA-IV polymorphism being controlled by two alleles, apoA-IV1 and apoA-IV2. The association between the apoA-IV2 allele and late-onset Alzheimer's disease (LOAD) has been reported in Caucasian populations. We investigated the codon 360 mutation of the apoA-IV gene allele frequency in 173 LOAD and in 158 age-matched control subjects of the Japanese population, and we found that the allele frequency of apoA-IV2 in the Japanese population was very rare and was extremely lower than in Caucasian populations. We conclude that there was no association between apoA-IV genotype and LOAD in the Japanese population. Copyrightz1999S.KargerAG,Basel

Isoe-Wada K, Maeda M, Yong J, Adachi Y, Harada H, Urakami K, Nakashima K. · Division of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishimachi 36-1, Yonago, Tottori, Japan. · Eur J Neurol. · Pubmed #10362895 No free full text.

Abstract: Parkinson's disease (PD) is a common cause of dementia in the elderly. Dementia in Alzheimer's disease (AD) and PD share common biologic and clinical features. The estrogen receptor (ER) gene is one of the susceptibility genes for AD. In order to test the hypothesis that the overlap between AD and PD may have a genetic basis, we determined ER gene polymorphisms in 13 PD patients with dementia (PDD) (age +/- SD; 71.9 +/- 5.5 years), 71 PD patients without dementia (PDND) (68.4 +/- 7.5 years), 86 AD patients (76.8 +/- 8.0 years) and 51 control subjects (CTL) (74.9 +/- 6.9 years). ER genotypes were classified as a P or p allele on the basis of a Pvu II-RFLP, and X and x on the basis of a Xba I-RFLP. The frequency of the P allele in the PDD group as well as the AD group was higher than that in CTL. There was no significant difference in the distribution of the P allele between CTL and PDND. There were no significant differences in the distribution of the X allele among the PDD, PDND and CTL groups, whereas a higher incidence was found in AD. We conclude that the ER gene may be a common susceptibility gene for dementia in PD as well as AD.

Takei N, Miyashita A, Tsukie T, Arai H, Asada T, Imagawa M, Shoji M, Higuchi S, Urakami K, Kimura H, Kakita A, Takahashi H, Tsuji S, Kanazawa I, Ihara Y, Odani S, Kuwano R, Anonymous00084. · Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata 951-8585, Japan. · Genomics. · Pubmed #19442637 No free full text.

Abstract: The epsilon4 allele of APOE is a well-characterized genetic risk factor for late-onset Alzheimer disease (LOAD). Nevertheless, using high-density single nucleotide polymorphisms (SNPs), there have only been a few studies involving genetic association and linkage disequilibrium (LD) analyses of in and around the APOE. Here, we report fine mapping of a genomic region (about 200 kb) including the APOE in Japanese using 260 SNPs (mean intermaker distance, 0.77 kb). A case-control study demonstrated that 36 of these SNPs exhibited significance after adjustment for multiple testing. These SNPs are located in a genomic region including four genes, PVRL2, TOMM40, APOE and APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean |D'|=0.914). These data suggest that the three genes other than APOE, i.e. PVRL2, TOMM40 and APOC1, could also yield a predisposition to LOAD.

Inoue M, Jinbo D, Nakamura Y, Taniguchi M, Urakami K. · Information Media Center, Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University, Yonago, Japan. · Am J Alzheimers Dis Other Demen. · Pubmed #19150968 No free full text.

Abstract: AIM: To evaluate the capability of a computerized test battery for Alzheimer's disease screening which has been newly developed to provide a standardized and efficient method for widespread use in routine clinical and community-based settings. METHODS: Participants were 72 individuals diagnosed with Alzheimer's disease and 102 healthy elderly individuals. Both groups were tested by the battery. Receiver operating characteristic analysis was used to examine the ability of the battery to differentiate between those with Alzheimer's disease and cognitively healthy elderly individuals. RESULTS: On a group level, the Alzheimer's disease group performed worse than the control group on each of the 4 computerized test tasks. Receiver operating characteristic analysis yielded maximum sensitivity and specificity values of 96% and 86% for total scores, respectively. CONCLUSION: We believe the battery is very useful for routine clinical and community-based settings.

Taniguchi M, Okayama Y, Hashimoto Y, Kitaura M, Jimbo D, Wakutani Y, Wada-Isoe K, Nakashima K, Akatsu H, Furukawa K, Arai H, Urakami K. · Department of Biological Regulation, School of Health Sciences, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan. · Dement Geriatr Cogn Disord. · Pubmed #18654083 No free full text.

Abstract: BACKGROUND/AIMS: Alzheimer's disease (AD) is a well-known type of dementia. However, it remains difficult to identify AD in the early stage and to distinguish it from other dementing disorders. We examined glycoproteins in cerebrospinal fluid (CSF) as potential biological markers of AD. METHODS: CSF samples were collected from AD, other dementia and nondemented patients. Glycoproteins in CSF were detected by lectin blotting using wheat germ agglutinin (WGA), and sugar chain analysis was performed by isoelectric focusing. RESULTS: In Alzheimer's CSF, several glycoproteins had lower WGA-binding activities, one of which was sufficiently sensitive and specific to distinguish AD from nondemented controls and other dementias. Further analysis identified this glycosylated protein as transferrin, and altered sugar chain composition of transferrin isoforms was observed despite normal protein levels in CSF. CONCLUSION: The decreased WGA-binding activity of transferrin in AD is probably due to altered glycosylation of transferrin molecules. Transferrin glycosylation is thus a potential biological marker for AD diagnosis, and changes in this glycosylation may play an important role in the pathophysiology of AD.

Miyashita A, Arai H, Asada T, Imagawa M, Matsubara E, Shoji M, Higuchi S, Urakami K, Kakita A, Takahashi H, Toyabe S, Akazawa K, Kanazawa I, Ihara Y, Kuwano R, Anonymous00354. · Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan. · Hum Mol Genet. · Pubmed #17761686 links to  free full text

Abstract: Alzheimer's disease (AD), the most common form of dementia in the elderly, was found to exhibit a trend toward a higher risk in females than in males through epidemiological studies. Therefore, we hypothesized that gender-related genetic risks could exist. To reveal the ones for late-onset AD (LOAD), we extended our previous genetic work on chromosome 10q (genomic region, 60-107 Mb), and single nucleotide polymorphism (SNP)-based genetic association analyses were performed on the same chromosomal region, where the existence of genetic risk factors for plasma Abeta42 elevation in LOAD was implied on a linkage analysis. Two-step screening of 1140 SNPs was carried out using a total of 1408 subjects with the APOE-epsilon3*3 genotype: we first genotyped an exploratory sample set (LOAD, 363; control, 337), and then genotyped some associated SNPs in a validation sample set (LOAD, 336; control, 372). Seven SNPs, spanning about 38 kb, in intron 9 of CTNNA3 were found to show multiple-hit association with LOAD in females, and exhibited more significant association on Mantel-Haenszel test (allelic P-values(MH-F) = 0.000005945-0.0007658). Multiple logistic regression analysis of a total of 2762 subjects (LOAD, 1313; controls, 1449) demonstrated that one of the seven SNPs directly interacted with the female gender, but not with the male gender. Furthermore, we found that this SNP exhibited no interaction with the APOE-epsilon4 allele. Our data suggest that CTNNA3 may affect LOAD through a female-specific mechanism independent of the APOE-epsilon4 allele.

Urakami K, Taniguchi M. · No affiliation provided · Nippon Ronen Igakkai Zasshi. · Pubmed #17575430 links to  free full text

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Hori Y, Hashimoto T, Wakutani Y, Urakami K, Nakashima K, Condron MM, Tsubuki S, Saido TC, Teplow DB, Iwatsubo T. · Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. · J Biol Chem. · Pubmed #17170111 links to  free full text

Abstract: A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid beta-protein precursor or presenilins. Whereas some amyloid beta-protein precursor mutations alter its metabolism through effects on Abeta production, the pathogenic effects of those that alter amino acid residues within the Abeta sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Abeta mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Abeta production, synthetic Abeta(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Abeta(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Abeta were markedly inhibited despite enhanced fibril formation. These N-terminal Abeta mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Abeta peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.

Kuwano R, Miyashita A, Arai H, Asada T, Imagawa M, Shoji M, Higuchi S, Urakami K, Kakita A, Takahashi H, Tsukie T, Toyabe S, Akazawa K, Kanazawa I, Ihara Y, Anonymous00173. · Genome Science Branch, Center for Bioresource-Based Researches, Brain Research Institute, Niigata University, Niigata, Japan. · Hum Mol Genet. · Pubmed #16740596 links to  free full text

Abstract: The apolipoprotein E (APOE) gene has been consistently shown to be a major genetic risk factor; however, all cases of Alzheimer's disease (AD) cannot be attributed to the epsilon4 variant of APOE, because about half of AD patients have the APOE-epsilon3*3 genotype. To identify an additional genetic risk factor(s), we performed large-scale single nucleotide polymorphism (SNP)-based association analysis of 1526 late-onset AD patients and 1666 control subjects in a Japanese population. We prepared two independent sets consisting of exploratory and validation samples, respectively, with only the APOE-epsilon3*3 genotype, and first carried out genotyping for the exploratory set with 1206 SNPs in the region between 60 and 107 Mb on chromosome 10q that is implicated by linkage studies as containing an AD susceptibility locus. Thirty-five SNPs that showed significant values (P<0.01) were followed-up to detect any association with the validation samples. Finally, six SNPs exhibited replicated significant associations (P=0.000035-0.00048) on meta-analysis of both sets. These SNPs were clustered in a locus spanning 220 kb at genomic position 101 Mb, and three of the six SNPs were located in the dynamin-binding protein (DNMBP) gene. Quantitative real-time RT-PCR analysis demonstrated that neuropathologically confirmed AD brains exhibit a significant reduction of DNMBP mRNA compared with age-matched ones (P<0.0169). Thus, we confirmed the association of DNMBP with AD individuals with the APOE-epsilon3*3 genotype or lacking the epsilon4 allele, and DNMBP may be one of the susceptibility genes for AD.

Urakami K, Saito K, Seishima M, Nakashima K. · Department of Biological Regulation, School of Health Science, Faculty of Medicine, Tottori University. · Nippon Rinsho. · Pubmed #15628369 No free full text.

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Matsushita S, Arai H, Matsui T, Yuzuriha T, Urakami K, Masaki T, Higuchi S. · Division of Clinical Research, National Hospital Organization, Kurihama Alcoholism Center, Yokosuka, Kanagawa, Japan. · J Neural Transm. · Pubmed #15375678 No free full text.

Abstract: Several lines of evidence have made brain-derived neurotrophic factor (BDNF) an important candidate gene conferring risk for Alzheimer's disease (AD). Recently, three studies reported an association between two single-nucleotide polymorphisms (SNP)--i.e., C270T and G196A--in the BDNF gene and AD. This attempt to confirm these associations in a larger AD sample included examination of the linkage disequilibrium of these two SNPs. Comparison of 487 Japanese AD subjects with 471 cognitively normal elderly controls showed higher frequencies of the G allele (60.5 vs. 55.5%, p = 0.028) and of both the GG and GA genotypes (85.8 vs. 79.8%, p = 0.025) of the G196A polymorphism in AD subjects than in controls and higher frequency of the T allele of the C270T polymorphism in AD subjects who were negative for apolipotrotein E4 (2.0 vs. 4.4%, p = 0.035) or positive for AD family history (2.8 vs. 7.1%, p = 0.046). These findings suggest that BDNF gene polymorphisms play some role in the development of AD.

Hattori S, Sakuma K, Wakutani Y, Wada K, Shimoda M, Urakami K, Kowa H, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago-shi 689-8504, Japan. · Neurosci Lett. · Pubmed #15364419 No free full text.

Abstract: Early onset familial Alzheimer's disease with spastic paraparesis (FAD-SP) has been associated with mutations of the presenilin 1 gene (PSEN1). We report a pedigree of FAD-SP due to a novel missense mutation of PSEN1 (Y154N). The symptoms of the proband were characterized by presenile dementia in her 40s, preceded by spastic paraparesis in her 30s, whereas the mother of the proband presented with spastic paraparesis in her 40s, followed by symptoms of dementia in her mid 60s. The mutation was found only in the proband, and not in a normal family member, normal Japanese control subjects, patients with sporadic Alzheimer's disease or patients with familial spastic paraparesis without dementia. Thus, Y154N is a novel PSEN1 mutation responsible for FAD-SP of Japanese origin.

Urakami K. · Section of Environment and Health Science, Dept. of Biological Regulation, Faculty of Medicine, Tottori University. · Gan To Kagaku Ryoho. · Pubmed #15311761 No free full text.

Abstract: Dementia treatment is one of the most important in home medical care. Donepezil hydrochloride, a dementia treatment drug available in Japan, is a symptomatic therapy but alleviates memory, willingness and feeling disorders and significantly improves QOL. Family doctors will be required to diagnose Alzheimer disease (AD) but it is very difficult for general physician to diagnose AD. This is the reason that the authors devised the simple criteria for diagnosing AD. Meanwhile, recent data from a multi-center study of donepezil hydrochloride for mild cognitive impairment (MCI) conducted in the US suggest that donepezil hydrochloride is also as useful for MCI as for AD. This is considered to suggest the significance to start treatment for AD at the early stage. Care for demented patients is not only the improvement of the apparent dementia. Recent scientific study data may be directly connected to treatment. These days, not a few elderly patients with dementia attend "Day care Service" and the data indicate that rehabilitations they have under "Day-care Service" are important and useful. It is considered that non pharmacological treatment may also play an important role and necessary to accumulate evidences in the future.

Wada-Isoe K, Wakutani Y, Urakami K, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan. · Acta Neurol Scand. · Pubmed #15242421 No free full text.

Abstract: OBJECTIVES: To investigate a possible implication of inflammatory processes in the development of dementia in cerebrovascular disease. PATIENTS AND METHODS: We examined the levels of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) (n = 26), ischemic cerebrovascular disease without dementia (CVD) (n = 11), vascular dementia (VD) (n = 11), and other neurological disorders (n = 21) using sensitive enzyme-linked immunosorbent assay. RESULTS: The CSF concentrations of IL-6 were significantly elevated in patients with VD compared with those of patients with AD or CVD. CONCLUSION: The CSF IL-6 levels are increased in patients with VD, suggesting that inflammatory mechanisms may be involved in the development of cognitive decline in some patients with cerebrovascular disease. CSF IL-6 may be a biological marker for dementia in cerebrovascular disease.

Wakutani Y, Watanabe K, Adachi Y, Wada-Isoe K, Urakami K, Ninomiya H, Saido TC, Hashimoto T, Iwatsubo T, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, Japan. · J Neurol Neurosurg Psychiatry. · Pubmed #15201367 links to  free full text

Abstract: OBJECTIVE: To describe a novel missense mutation, Asp678Asn (D678N), in the amyloid precursor protein (APP) gene in a Japanese pedigree of probable familial Alzheimer's disease (FAD). SUBJECT: The proband was a women of 72. Symptoms of dementia that fulfilled the criteria for probable Alzheimer's disease appeared at about 60 years of age, and slowly worsened over more than 10 years without evident cerebrovascular complications, either clinically or neuroradiologically. METHODS: Polymerase chain reaction single strand conformational polymorphism (PCR-SSCP) analysis followed by sequence analysis was used to examine genomic DNA of the proband for mutations in the APP gene exons 16 and 17. RESULTS: Analysis of the APP exon 16 in the proband showed a GAC to AAC nucleotide substitution in codon 678 of the APP gene, causing an amino acid substitution of Asp to Asn (D678N). Heterozygosity of the APP D678N mutation was found in the proband and in the demented elder sister. CONCLUSIONS: The production and accumulation of mutated Abeta (Asn7-Abeta) or the misfunction of D678N mutant APP may have pathogenic properties for the development of Alzheimer's disease in this pedigree.

Wakutani Y, Kowa H, Kusumi M, Nakaso K, Yasui K, Isoe-Wada K, Yano H, Urakami K, Takeshima T, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago 683-8504, Japan. · Neurobiol Aging. · Pubmed #15123333 No free full text.

Abstract: Epidemiological studies have shown that elevated plasma homocysteine (Hcy) levels play an important role in the pathogenesis of Alzheimer's disease (AD). In spite of the evidence that a C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene elevates plasma Hcy levels, the impact of the C677T polymorphism on the development of AD is controversial. Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD). In our study, the MTHFR gene had four major regional haplotypes: Haplotype A (677C-1298A-1793G), Haplotype B (677T-1298A-1793G), Haplotype C (677C-1298C-1793G), and Haplotype D (677C-1298C-1793A). The frequency of Haplotype C in LOAD was significantly lower than that in control group. Furthermore, the benefit conferred by the presence of at least one Haplotype C was stronger in LOAD patients who lacked the ApoE 4 allele (OR=0.293; 95% CI=0.115-0.744; P=0.010). The results indicate that Haplotype C of the MTHFR gene is protective against the development of LOAD.

Wakutani Y, Kowa H, Kusumi M, Nakaso K, Isoe-Wada K, Yano H, Urakami K, Takeshima T, Nakashima K. · Department of Neurology, Institute of Neurological Sciences, Tottori University, Yonago, Japan. · Dement Geriatr Cogn Disord. · Pubmed #14739536 No free full text.

Abstract: Recent epidemiological studies have emphasized the impact of elevated blood homocysteine levels on the pathogenesis of Alzheimer's disease (AD). In spite of a significant impact of a MTHFR C677T polymorphism on the blood homocysteine levels, the association between the C677T polymorphism and AD remains controversial. Therefore, other unidentified genetic factor(s) that regulate blood homocysteine levels may exist. Here, we have analyzed the 5'-upstream region of the MTHFR gene and examined AD patients (n = 223) and nondemented individuals (n = 323) for polymorphisms in the 5'-upstream region of the MTHFR gene. We identified two polymorphisms (-713G/A and -393C/A, upstream of the start codon). We found no significant relationship between AD and the 5'-upstream region polymorphisms of the MTHFR gene. Thus, our study does not reinforce the hypothesis of an independent involvement of the MTHFR gene upstream region polymorphisms in AD risk.