Alzheimer Disease: Asada T

Asada T. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #17131547 No free full text.

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Asada T. · Department of Neuropsychiatry, Institute of Clinical Medicine, University of Tsukuba. · Nippon Rinsho. · Pubmed #15011323 No free full text.

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Asada T. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #12577975 No free full text.

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Asada T, Ishijima M. · Department of Psychiatry, Musashi Hospital, Tokyo, Japan. · No To Shinkei. · Pubmed #10769840 No free full text.

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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.

Sato S, Mizukami K, Asada T. · Department of Psychiatry, Tsukuba Memorial Hospital, Tsukuba, Japan. · Int J Neuropsychopharmacol. · Pubmed #16817981 No free full text.

Abstract: The aim of this study was to assess the efficacy and safety of tandospirone, a 5-HT1A partial agonist, for treatment of behavioural and psychological symptoms of dementia (BPSD). Thirteen outpatients with DSM-IV diagnosis of Alzheimer's type or vascular dementia were enrolled in this study. Their BPSD and cognitive functions were evaluated with the Neuropsychiatric Inventory (NPI) and Mini-Mental State Examination, respectively, for an 8-wk period of treatment. The maximum benefit of tandospirone was achieved at a mean dose of 19.6 mg/d. There were significant improvements in the NPI subscores for delusion, agitation, depression, anxiety, and irritability at 2 or 4 wk after the start of administration of tandospirone. No patients experienced severe adverse effects. The results suggest that tandospirone was effective at improving BPSD symptoms and well-tolerated in elderly demented patients.

Mizukami K, Tanaka Y, Asada T. · Department of Psychiatry, Institute of Clinical Medicine University of Tsukuba, Japan, 1-1-1Tennodai, Tsukuba City, Ibaraki 305-8575, Japan. <> · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #16603301 No free full text.

Abstract: An open-labeled study was conducted to examine the efficacy of selective serotonin and noradrenaline reuptake inhibitor (SNRI), milnacipran in treating depression in Alzheimer's disease (AD) patients. Eleven patients with AD showing major depressive symptoms were examined. Ten of 11 patients demonstrated an over 50% decrease in their HAM-D scores from the baseline, and 8 of 11 patients reached remission (HAM-D score<==7) within 12 weeks of the start of milnacipran treatment, and their GAF score was also remarkably improved. Although in 11 patients, two patients showed a mild hypomanic state and one patient showed daytime somnolence, these problems were quickly solved after a decrease in the daily dose or discontinuation of milnacipran. In addition, the treatment had no negative effects on cognitive function of the patients. Our study results suggest that milnacipran is a promising medicine for depressive state in AD patients.

Imabayashi E, Matsuda H, Asada T, Ohnishi T, Sakamoto S, Nakano S, Inoue T. · Department of Radiology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Tokyo, Japan. · J Nucl Med. · Pubmed #15347711 links to  free full text

Abstract: In Alzheimer's disease (AD), regional cerebral blood flow (rCBF) in the posterior cingulate gyri and precunei has been reported to decrease even at a very early stage. It may be helpful to use statistical image analysis to distinguish slight decreases in rCBF in this area. We compared a 3-dimensional stereotactic surface projection (3D-SSP) technique with visual inspection in the discrimination of patients with very early AD from age-matched controls using brain perfusion SPECT. METHODS: SPECT was obtained in 38 patients with probable AD at a very early stage and after a mean interval of 15 mo and in 76 age-matched healthy volunteers. We randomly divided these subjects into 2 groups. The first group was used to identify the areas with significant decreases of rCBF in patients compared with healthy control subjects based on the voxel-based analysis using 3D-SSP. The second group was used to compare the discrimination ability between patients and control subjects by 3D-SSP with that by visual inspection. In the second group, a Z-score map for a SPECT image of a subject was obtained by comparison with mean and SD SPECT images of control subjects for each voxel after anatomic standardization and voxel normalization to reference regions. Receiver operating characteristic (ROC) curves for a Z-score discriminating patients with AD from control subjects were analyzed in areas with significant decreases of rCBF identified in the first group. For visual inspection, 6 physicians graded the rCBF decrease on SPECT images for ROC curves. They inspected the images twice at an interval of >2 wk, and intra- and interobserver reliabilities were determined. RESULTS: Visual inspection showed fair-to-excellent intra- and interobserver reliabilities. The 3D-SSP demonstrated an accuracy of 86.2% for discriminating patients with AD from control subjects when analyzing the posterior cingulate gyri and precunei with global mean normalization. In contrast, visual inspection did not show an accuracy of >74.0% for this discrimination. CONCLUSION: The ability of 3D-SSP to discriminate patients with very early AD from control subjects is superior to that of visual inspection. It is clinically useful and reliable to adopt the use of 3D-SSP as an adjunct to visual interpretation.

Kanetaka H, Matsuda H, Asada T, Ohnishi T, Yamashita F, Imabayashi E, Tanaka F, Nakano S, Takasaki M. · Department of Radiology, National Center Hospital for Mental, Nervous and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan. · Eur J Nucl Med Mol Imaging. · Pubmed #14991240 No free full text.

Abstract: We assessed the accuracy of brain perfusion single-photon emission computed tomography (SPECT) in discriminating between patients with probable Alzheimer's disease (AD) at the very early stage and age-matched controls before and after partial volume correction (PVC). Three-dimensional MRI was used for PVC. We randomly divided the subjects into two groups. The first group, comprising 30 patients and 30 healthy volunteers, was used to identify the brain area with the most significant decrease in regional cerebral blood flow (rCBF) in patients compared with normal controls based on the voxel-based analysis of a group comparison. The second group, comprising 31 patients and 31 healthy volunteers, was used to study the improvement in diagnostic accuracy provided by PVC. A Z score map for a SPECT image of a subject was obtained by comparison with mean and standard deviation SPECT images of the healthy volunteers for each voxel after anatomical standardization and voxel normalization to global mean or cerebellar values using the following equation: Z score = ([control mean]-[individual value] )/(control SD). Analysis of receiver operating characteristics curves for a Z score discriminating AD and controls in the posterior cingulate gyrus, where a significant decrease in rCBF was identified in the first group, showed that the PVC significantly enhanced the accuracy of the SPECT diagnosis of very early AD from 73.9% to 83.7% with global mean normalization. The PVC mildly enhanced the accuracy from 73.1% to 76.3% with cerebellar normalization. This result suggests that early diagnosis of AD requires PVC in a SPECT study.

Matsuda H, Kanetaka H, Ohnishi T, Asada T, Imabayashi E, Nakano S, Katoh A, Tanaka F. · Department of Radiology, National Center Hospital for Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashi, Kodaira, 187-8551, Tokyo, Japan. · Eur J Nucl Med Mol Imaging. · Pubmed #12397471 No free full text.

Abstract: The aim of this study was to determine which brain structures show the greatest influence of partial volume effects (PVE) in single-photon emission tomography (SPET) studies on Alzheimer's disease (AD). Brain perfusion SPET was performed in 30 patients with probable AD and 62 age-matched healthy volunteers. SPET images were corrected for PVE using grey matter volume segmented from magnetic resonance images. The most prominent changes after PVE correction were observed in the medial temporal structures. The PVE correction revealed a selective decrease in regional cerebral blood flow (rCBF) in the parahippocampal gyrus of AD without rCBF decreases in the hippocampus, which had been observed before correction. This correction seems to be essential in order to achieve accurate measurements of rCBF in SPET, which has limited spatial resolution.

Musha T, Asada T, Yamashita F, Kinoshita T, Chen Z, Matsuda H, Uno M, Shankle WR. · Brain Functions Laboratory Inc., KSP Building E211, Sakado, Takatsu Kawasaki, Kanagawa-pref. 213-0012, Japan. · Clin Neurophysiol. · Pubmed #12088699 No free full text.

Abstract: OBJECTIVES: To test the hypothesis that elecetroencephalographic (EEG) analysis is sensitive to cortical neuronal impairment in early stage Alzheimer's disease (AD), and that this analysis correlates with corresponding changes in cerebral blood flow.METHODS: We examined an EEG measure of neuronal impairment in the cerebral cortex in terms of its ability to detect very mild AD. This measure, the mean value of the resting state EEG alpha dipolarity (D(alpha)), approaches unity without cortical sulcal lesions, whereas brains with randomly distributed cortical sulcal lesions lower D(alpha) values well below unity. D(alpha) was evaluated in 25 patients with very mild AD, 33 patients with moderately severe AD, and 56 normal age-matched subjects. These subjects also received SPECT, and strong correlation between D(alpha) and regional cerebral blood flow (rCBF) was observed.RESULTS: D(alpha) values greater than 0.977 correctly classified normal subjects, but also included 10% of very mild AD. D(alpha) values less than 0.952 correctly classified very mild AD as well as moderately severe AD, but also included 10% of normal subjects. D(alpha) values also correlated positively with bilateral temporal-parietal rCBF (a characteristic finding in AD patients); both declined with increasing dementia severity.CONCLUSIONS: Analysis of D(alpha) in this sample supports the hypothesis that early stages of AD can be discriminated from normal aging using measures of cortical neuronal impairment. Furthermore, dementia severity, as reflected by the degree of impairment, is reflected in declining D(alpha) values and increasing variance (greater spread of the D(alpha) values).

Nakano S, Asada T, Matsuda H, Uno M, Takasaki M. · Department of Geriatric Medicine, National Center Hospital for Mental, Nervous, and Muscular Disorders, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8551, Japan. · J Nucl Med. · Pubmed #11585854 links to  free full text

Abstract: The aim of this SPECT study was to investigate the effects of donepezil on regional cerebral blood flow (rCBF) in patients with mild to moderate Alzheimer's disease (AD) using statistical parametric mapping. METHODS: rCBF was noninvasively measured using (99m)Tc-ethyl cysteinate dimer in 35 AD patients with a Mini-Mental State Examination score > 16 on initial evaluation. Baseline and follow-up SPECT studies with a mean interval of 12 mo were performed on these patients. We used the adjusted rCBF images in the relative flow distribution (normalization of global cerebral blood flow for each patient to 50 mL/100 g/min with proportional scaling) to compare these groups through statistical parametric mapping. RESULTS: In the follow-up study, the adjusted rCBF was significantly preserved in the right and left anterior cingulate gyri, right middle temporal gyrus, right inferior parietal lobules, and prefrontal cortex of donepezil-treated AD patients, compared with placebo-treated AD patients. CONCLUSION: Treatment with donepezil for 1 y appears to reduce the decline in rCBF, suggesting preservation of functional brain activity.

Kogure D, Matsuda H, Ohnishi T, Kunihiro T, Uno M, Asada T, Takasaki M. · Department of Geriatric Medicine, Tokyo Medical College. · Kaku Igaku. · Pubmed #10213976 No free full text.

Abstract: Regional cerebral blood flow (rCBF) measurements using a Patlak plot method of 99mTc-ECD were performed in early dementia of Alzheimer type (DAT) with both HDS-R and MMSE of over 20 to investigate initial abnormality and longitudinal changes of rCBF. A fusion technique of MRI and SPECT images was developed for MRI-guided analysis of regions of interest in hippocampal areas and statistical parametric mapping (SPM) was used for automated and objective approach to analysis of SPECT image data. Seventeen patients with clinically diagnosed early DAT and age-matched 32 normal control subjects were studied. At the first SPECT studies, the mean cerebral blood flow (mCBF) of 38.6 +/- 4.7 ml/100 g/min (mean +/- SD) for early DAT did not show significant reduction as compared with the normal control value of 42.0 +/- 3.8, whereas the rCBF values in the bilateral hippocampi (right; 26.8 +/- 4.7, left; 26.7 +/- 5.2) showed significant reduction (p < 0.05) as compared with the normal control values (right; 38.3 +/- 4.2, left; 38.4 +/- 3.8). The SPM analysis (voxel height; p < 0.001, Bonferroni correction; p < 0.05) of the first SPECT images revealed significant selective decrease of relative rCBF in the bilateral posterior cingulate gyri. At the second SPECT studies after 1.4 year on the average from the first studies, mCBF for early DAT showed a slight decrease by 1.7 +/- 3.8 ml/100 g/min/year. Bilateral hippocampi showed a greater decrease with slight left-side dominance by 3.8 +/- 3.3 on the right and 4.4 +/- 3.2 on the left side. The SPM analysis demonstrated significant decrease of relative rCBF in the basal fore-brain area, the left hippocampus, the left amygdala, and the left parahippocampal area. These results suggest that the MRI-guided ROI analysis of rCBF values in the hippocampus and the SPM analysis of SPECT images are quite useful for early diagnosis and follow-up of DAT.

Mizukami K, Homma T, Aonuma K, Kinoshita T, Kosaka K, Asada T. · Department of Psychiatry, University of Tsukuba, Tsukuba City, Ibaraki, Japan. · Ann Neurol. · Pubmed #19475659 No free full text.

Abstract: A systematic autonomic dysfunction observed among patients with dementia with Lewy bodies (DLB) has recently attracted close attention. Here, we compare cardiovascular and pulmonary autonomic functions among patients with DLB, patients with Alzheimer's disease, and healthy control subjects. All 15 DLB patients demonstrated severely low ventilatory response to hypercapnia, whereas none of the other subjects demonstrated abnormal results. The majority of the DLB patients showed impaired heart rate variability, low uptake on (123)I-metaiodobenzylguanidine myocardial scintigraphy, and orthostatic hypotension. Ventilatory response to hypercapnia as a marker of respiratory autonomic function is a promising diagnostic tool for DLB.

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.

Asada T. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #19378510 No free full text.

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Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T, Takita M, Arimoto I, Koma H, Takase T, Ohbayashi T. · Dementia Interventional Research Group, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. · Dement Geriatr Cogn Disord. · Pubmed #19246907 No free full text.

Abstract: BACKGROUND/AIMS: A 6-month, randomized, double-blind, placebo-controlled study was extended to evaluate long-term safety and efficacy of donepezil in community-dwelling Japanese patients with severe Alzheimer's disease (AD). METHODS: 189 patients were enrolled from the double-blind study into a 52-week, open-label extension study. After a 2- to 8-week washout, donepezil was escalated within 6 weeks to 10 mg/day. Main outcomes were Severe Impairment Battery (SIB), Alzheimer's Disease Cooperative Study-Activities of Daily Living scale for severe AD (ADCS-ADL-sev) and Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). Safety parameters were monitored throughout. RESULTS: Overall, mean change from extension study baseline in SIB scores improved until week 24; however, scores were influenced by prior treatment during the double-blind study and by length of washout. Patients treated with donepezil retained some treatment benefits after a washout of 2-4 weeks but lost all treatment benefits after a washout of 4-8 weeks. There was no change in ADCS-ADL-sev or BEHAVE-AD scores. Adverse events were consistent with the known donepezil safety profile. CONCLUSION: Donepezil is effective and safe for symptomatic treatment of severe AD for at least 1 year. Patients who receive donepezil 10 mg daily with little or no interruption achieve the best long-term outcome.

Mizukami K, Hatanaka K, Tanaka Y, Sato S, Asada T. · Department of Psychiatry, Institute of Clinical Medicine, University of Tsukuba, Tsukuba City, Japan. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #19166899 No free full text.

Abstract: To clarify the profile of depressive symptoms in major depressive episodes in patients with Alzheimer's disease (AD-MD), we compared AD-MD with major depressive disorder in non-demented elderly patients (MDD) matched for age, using the 17-item Hamilton Rating Scale for Depression (HAM-D(17)). In addition, to clarify which depressive symptoms of AD patients respond to treatment with the selective serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran, we compared the HAM-D(17) average score and the score of each HAM-D item, the mini-mental state examination (MMSE) score, and GAF score according to the DSM-IV evaluation of AD-MD patients at baseline and at the endpoint (12 weeks). Depressive mood, loss of interest in hobbies and social activities and anxiety (psychic) scored the highest in both AD-MD and MDD groups, while psychomotor retardation scored significantly higher in AD-MD, and insomnia and anxiety (somatic) significantly did so in MDD. We also found that depressive mood, suicidal tendency, loss of interest, psychomotor retardation, anxiety (psychic), gastrointestinal symptoms, general somatic symptoms, and hypochondriasis remarkably improved in patients of AD-MD treated with milnacipran. Our results suggest that in general the profiles of depression in AD-MD and MDD are similar, despite some different clinical features between both conditions. Our study also suggests that milnacipran is promising to treat a broad range of depressive symptoms in AD-MD patients.

Hashimoto R, Hirata Y, Asada T, Yamashita F, Nemoto K, Mori T, Moriguchi Y, Kunugi H, Arima K, Ohnishi T. · Department of Clinical Disorder Research, The Osaka-Hamamatsu Joint Research Center For Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. · Genes Brain Behav. · Pubmed #18786162 No free full text.

Abstract: Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE epsilon4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, epsilon4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.

Yasuno F, Ota M, Kosaka J, Ito H, Higuchi M, Doronbekov TK, Nozaki S, Fujimura Y, Koeda M, Asada T, Suhara T. · Clinical Neuroimaging Section, Department of Molecular Neuroimaging, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. · Biol Psychiatry. · Pubmed #18514164 No free full text.

Abstract: BACKGROUND: Peripheral benzodiazepine receptor (PBR) in the brain of Alzheimer's disease (AD) patients has been discussed in relation to the role of gliosis in AD. The PBR was shown to have the ability to reflect activated glial cells, including microglia. The role of activated microglia in AD is an important topic in the pathophysiology of AD. The aim of this study was to quantify PBR in AD brain with a new high-sensitive PBR ligand, [(11)C]DAA1106. METHODS: Positron emission tomography (PET) scans with [(11)C]DAA1106, a potent and selective ligand for PBR, were performed on 10 patients with AD and 10 age-matched control subjects. All patients had mild to moderate dementia. Duration of illness was 1-3 years at the time of the scans. The PBR binding in the regions of interest was quantified by binding potential (BP) obtained from compartmental model analysis with plasma input function. RESULTS: Mean BP was increased in the brain of AD patients compared with control subjects in all measured regions. Statistical significance reached across many of the regions examined, including dorsal and medial prefrontal cortex, lateral temporal cortex, parietal cortex, occipital cortex, anterior cingulate cortex, striatum, and cerebellum. CONCLUSIONS: The broad increase of PBR binding measured with [(11)C]DAA1106 in the brain of AD patients suggests a widespread existence of cellular reactions with PBR in relatively early-stage AD.

Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T, Takita M, Arimoto I, Koma H, Ohbayashi T. · Dementia Interventional Research Group, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan. · Dement Geriatr Cogn Disord. · Pubmed #18391486 No free full text.

Abstract: BACKGROUND/AIMS: A 24-week, randomized, parallel-group, double-blind placebo-controlled study was conducted to evaluate the efficacy and tolerability of donepezil in severe Alzheimer's disease (AD). METHODS: Patients with severe AD (Mini-Mental State Examination score 1-12; modified Hachinski Ischemic Score < or =6; Functional Assessment Staging > or =6) were enrolled in this study in Japan. A total of 325 patients were randomized to donepezil 5 mg/day (n = 110), donepezil 10 mg/day (n = 103) or placebo (n = 112). Primary outcome measures were change from baseline to endpoint in the Severe Impairment Battery (SIB) and Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIC-plus) at the endpoint visit. RESULTS: Donepezil 5 mg/day and 10 mg/day were significantly superior to placebo on the SIB, with a least-squares mean treatment difference of 6.7 and 9.0, respectively (p < 0.001 compared with placebo). CIBIC-plus analyses showed significant differences in favor of donepezil 10 mg/day over placebo at endpoint (p = 0.003). A statistically significant dose-response relationship was demonstrated with the SIB and CIBIC-plus. Donepezil was well tolerated. CONCLUSION: This study confirmed the effectiveness of donepezil 10 mg/day in patients with severe AD and demonstrated a significant dose-response relationship. Donepezil at dosages of both 5 mg/day and 10 mg/day is safe and well tolerated in Japanese patients with severe 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.

Meguro K, Ishii H, Kasuya M, Akanuma K, Meguro M, Kasai M, Lee E, Hashimoto R, Yamaguchi S, Asada T. · Department of Geriatric Behavioral Neurology, Tohoku University Graduate School of Medicine, Japan. · J Neurol Sci. · Pubmed #17553526 No free full text.

Abstract: The incidence of dementia and risk factors has not been fully investigated in Japan. Following a prevalence study in 1998, we investigated the incidence and associated factors in the same population in 2003 and 2005. Randomly selected 771 residents in Tajiri were targeted. The final participants included 204 (65.2%) healthy older adults (Clinical Dementia Rating, CDR 0) and 335 (73.1%) people with questionable dementia (CDR 0.5). We analyzed the incidence of dementia and dementing diseases, and possible risk factors. The risk factors included demographics, lifestyle-related factors, vascular risk factors, cognitive functions, and MRI findings. Overall, 3.9% of the CDR 0 and 37.0% of the CDR 0.5 participants developed dementia during the 5-year period, whereas 40.2% of the CDR 0.5 participants developed dementia during the 7-year period. Older adults had a higher incidence. Higher CDR Box scores had a higher incidence. Of the dementing diseases, 60.8% of participants developed Alzheimer' disease (AD), followed by vascular dementia (VaD), 17.9%. Logistic regression analyses showed that age, MMSE, cognitive functions such as recent memory, and generalized atrophy were significant predictors of progression to AD. Similarly, predictive factors for progression to VaD were age, MMSE, cognitive functions such as frontal function, and white matter lesions and cerebrovascular diseases. A comprehensive system including CDR, cognitive tests, and MRI, is recommended in community-based health policy planning.

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.

Asada T. · No affiliation provided · Seishin Shinkeigaku Zasshi. · Pubmed #16683356 No free full text.

This publication has no abstract.