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Miyashita A.,Niigata University | Hatsuta H.,Tokyo Metropolitan Geriatric Hospital | Kikuchi M.,Research Association for Biotechnology | Nakaya A.,Niigata University | And 12 more authors.
Translational Psychiatry | Year: 2014

The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N = 13), I-II (N = 20), III-IV (N = 19) and V-VI (N = 19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N = 30), and in patients with late-onset AD (N = 37), dementia with Lewy bodies (N = 17) and Parkinson disease (N = 36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development. © 2014 Macmillan Publishers Limited.

Wen Y.,Niigata University | Miyashita A.,Niigata University | Kitamura N.,Niigata University | Tsukie T.,Research Association for Biotechnology | And 12 more authors.
Journal of Alzheimer's Disease | Year: 2013

SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD. © 2013 - IOS Press and the authors. All rights reserved.

Maikusa N.,Integrative Brain Imaging Center | Yamashita F.,Iwate Medical University | Tanaka K.,Research Association for Biotechnology | Abe O.,Nihon University | And 8 more authors.
Medical Physics | Year: 2013

Purpose: Serial magnetic resonance imaging (MRI) images acquired from multisite and multivendor MRI scanners are widely used in measuring longitudinal structural changes in the brain. Precise and accurate measurements are important in understanding the natural progression of neurodegenerative disorders such as Alzheimer's disease. However, geometric distortions in MRI images decrease the accuracy and precision of volumetric or morphometric measurements. To solve this problem, the authors suggest a commercially available phantom-based distortion correction method that accommodates the variation in geometric distortion within MRI images obtained with multivendor MRI scanners. Methods: The authors' method is based on image warping using a polynomial function. The method detects fiducial points within a phantom image using phantom analysis software developed by the Mayo Clinic and calculates warping functions for distortion correction. To quantify the effectiveness of the authors' method, the authors corrected phantom images obtained from multivendor MRI scanners and calculated the root-mean-square (RMS) of fiducial errors and the circularity ratio as evaluation values. The authors also compared the performance of the authors' method with that of a distortion correction method based on a spherical harmonics description of the generic gradient design parameters. Moreover, the authors evaluated whether this correction improves the test-retest reproducibility of voxel-based morphometry in human studies. Results: A Wilcoxon signed-rank test with uncorrected and corrected images was performed. The root-mean-square errors and circularity ratios for all slices significantly improved (p < 0.0001) after the authors' distortion correction. Additionally, the authors' method was significantly better than a distortion correction method based on a description of spherical harmonics in improving the distortion of root-mean-square errors (p < 0.001 and 0.0337, respectively). Moreover, the authors' method reduced the RMS error arising from gradient nonlinearity more than gradwarp methods. In human studies, the coefficient of variation of voxel-based morphometry analysis of the whole brain improved significantly from 3.46% to 2.70% after distortion correction of the whole gray matter using the authors' method (Wilcoxon signed-rank test, p < 0.05). Conclusions: The authors proposed a phantom-based distortion correction method to improve reproducibility in longitudinal structural brain analysis using multivendor MRI. The authors evaluated the authors' method for phantom images in terms of two geometrical values and for human images in terms of test-retest reproducibility. The results showed that distortion was corrected significantly using the authors' method. In human studies, the reproducibility of voxel-based morphometry analysis for the whole gray matter significantly improved after distortion correction using the authors' method. © 2013 American Association of Physicists in Medicine.

Yamane T.,Institute of Biomedical Research and Innovation | Ikari Y.,Institute of Biomedical Research and Innovation | Ikari Y.,Research Association for Biotechnology | Nishio T.,Institute of Biomedical Research and Innovation | And 11 more authors.
American Journal of Neuroradiology | Year: 2014

BACKGROUND AND PURPOSE: The role of 18F-FDG-PET in the diagnosis of Alzheimer disease is increasing and should be validated. The aim of this study was to assess the inter-rater variability in the interpretation of 18F-FDG-PET images obtained in the Japanese Alzheimer's Disease Neuroimaging Initiative, a multicenter clinical research project. MATERIALS AND METHODS: This study analyzed 274 18F-FDG-PET scans (67 mild Alzheimer disease, 100 mild cognitive impairment, and 107 normal cognitive) as baseline scans for the Japanese Alzheimer's Disease Neuroimaging Initiative, which were acquired with various types of PET or PET/CT scanners in 23 facilities. Three independent raters interpreted all PET images by using a combined visual-statistical method. The images were classified into 7 (FDG-7) patterns by the criteria of Silverman et al and further into 2 (FDG-2) patterns. RESULTS: Agreement among the 7 visual-statistical categories by at least 2 of the 3 readers occurred in >94% of cases for all groups: Alzheimer disease, mild cognitive impairment, and normal cognitive. Perfect matches by all 3 raters were observed for 62% of the cases by FDG-7 and 76 by FDG-2. Inter-rater concordance was moderate by FDG-7 (κ = 0.57) and substantial in FDG-2 (κ = 0.67) on average. The FDG-PET score, an automated quantitative index developed by Herholz et al, increased as the number of raters who voted for the AD pattern increased (ρ = 0.59, P < .0001), and the FDG-PET score decreased as those for normal pattern increased (ρ =-0.64, P < .0001). CONCLUSIONS: Inter-rater agreement was moderate to substantial for the combined visual-statistical interpretation of 18F-FDG-PET and was also significantly associated with automated quantitative assessment.

Matsuda H.,International University of Japan | Mizumura S.,Toho University | Nemoto K.,University of Tsukuba | Yamashita F.,Research Association for Biotechnology | And 3 more authors.
American Journal of Neuroradiology | Year: 2012

BACKGROUND AND PURPOSE: The necessity for structural MRI is greater than ever to both diagnose AD in its early stage and objectively evaluate its progression. We propose a new VBM-based software program for automatic detection of early specific atrophy in AD. MATERIALS AND METHODS: A target VOI was determined by group comparison of 30 patients with very mild AD and 40 age-matched healthy controls by using SPM. Then this target VOI was incorporated into a newly developed automated software program independently running on a Windows PC for VBM by using SPM8 plus DARTEL. ROC analysis was performed for discrimination of 116 other patients with AD with very mild stage (n = 45), mild stage (n = 30) and moderate-to-advanced stages (n = 41) from 40 other age-matched healthy controls by using a z score map in the target VOI. RESULTS: Medial temporal structures involving the entire region of the entorhinal cortex, hippocampus, and amygdala showed significant atrophy in the patients with very mild AD and were determined as a target VOI. When we used the severity score of atrophy in this target VOI, 91.6%, 95.8%, and 98.2% accuracies were obtained in the very mild AD, mild AD, and moderate-to-severe AD groups, respectively. In the very mild AD group, a high specificity of 97.5% with a sensitivity of 86.4% was obtained, and age at onset of AD did not influence this accuracy. CONCLUSIONS: This software program with application of SPM8 plus DARTEL to VBM provides a high performance for AD diagnosis by using MRI.

Kikuchi M.,Tokyo Medical and Dental University | Kikuchi M.,Niigata University | Kikuchi M.,Research Association for Biotechnology | Ogishima S.,Tohoku University | And 6 more authors.
PLoS ONE | Year: 2013

Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than upregulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation- associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. © 2013 Kikuchi et al.

Ikari Y.,Institute of Biomedical Research and Innovation | Ikari Y.,Research Association for Biotechnology | Nishio T.,Institute of Biomedical Research and Innovation | Nishio T.,Research Association for Biotechnology | And 7 more authors.
Annals of Nuclear Medicine | Year: 2012

Objective Head motion during 30-min (six 5-min frames) brain PET scans starting 30 min post-injection of FDG was evaluated together with the effect of post hoc motion correction between frames in J-ADNI multicenter study carried out in 24 PET centers on a total of 172 subjects consisting of 81 normal subjects, 55 mild cognitive impairment (MCI) and 36 mild Alzheimer's disease (AD) patients. Methods Based on the magnitude of the between-frame co-registration parameters, the scans were classified into six levels (A-F) of motion degree. The effect of motion and its correction was evaluated using between-frame variation of the regional FDG uptake values on ROIs placed over cerebral cortical areas. Result Although AD patients tended to present larger motion (motion level E or F in 22 % of the subjects) than MCI (3 %) and normal (4 %) subjects, unignorable motion was observed in a small number of subjects in the latter groups as well. The between-frame coefficient of variation (SD/mean) was 0.5 % in the frontal, 0.6 % in the parietal and 1.8 % in the posterior cingulate ROI for the scans of motion level 1. The respective values were 1.5, 1.4, and 3.6 % for the scans of motion level F, but reduced by the motion correction to 0.5, 0.4 and 0.8 %, respectively. The motion correction changed the ROI value for the posterior cingulate cortex by 11.6 % in the case of severest motion. Conclusion Substantial head motion occurs in a fraction of subjects in a multicenter setup which includes PET centers lacking sufficient experience in imaging demented patients. A simple frame-by-frame co-registration technique that can be applied to any PET camera model is effective in correcting for motion and improving quantitative capability. © The Japanese Society of Nuclear Medicine 2012.

Masaike Y.,Tokyo Institute of Technology | Takagi T.,Tokyo Institute of Technology | Hirota M.,Tokyo Institute of Technology | Yamada J.,Tokyo Institute of Technology | And 10 more authors.
Molecular Pharmacology | Year: 2010

Nitrogen-containing bisphosphonates are pyrophosphate analogs that have long been the preferred prescription for treating osteoporosis. Although these drugs are considered inhibitors of prenylation and are believed to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation seems to be insufficient. Because other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, we first investigated here the effects of bisphosphonates on simian virus 40 and adenovirus infections and, to our surprise, found that viral infections are suppressed by bisphosphonates through a prenylation-independent pathway. By in-house affinity-capture techniques, dynamin-2 was identified as a new molecular target of bisphosphonates. We present evidence that certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2. Hence, this study has uncovered a previously unknown mechanism of action of bisphosphonates and offers potential novel use for these drugs. © 2010 The American Society for Pharmacology and Experimental Therapeutics.

Kamiyama S.,Soka University | Kamiyama S.,Research Association for Biotechnology | Kamiyama S.,Niigata University | Ichimiya T.,Soka University | And 13 more authors.
Glycobiology | Year: 2011

Sulfation represents an essential modification for various molecules and regulates many biological processes. The sulfation of glycans requires a specific transporter for 3'- phosphoadenosine 5'-phosphosulfate (PAPS) on the Golgi apparatus. This study investigated the expression of PAPS transporter genes in colorectal carcinomas and the significance of Golgi-specific sulfation in the proliferation of colorectal carcinoma cells. The relative amount of PAPST1 transcripts was found to be higher than those of PAPST2 in colorectal cancerous tissues. Immunohistochemically, the enhanced expression of PAPST1 was observed in fibroblasts in the vicinity of invasive cancer cells, whereas the expression of PAPST2 was decreased in the epithelial cells. RNA interference of either of the two PAPS transporter genes reduced the extent of sulfation of cellular proteins and cellular proliferation of DLD-1 human colorectal carcinoma cells. Silencing the PAPS transporter genes reduced fibroblast growth factor signaling in DLD-1 cells. These findings indicate that PAPS transporters play a role in the proliferation of colorectal carcinoma cells themselves and take part in a desmoplastic reaction to support cancer growth by controlling their sulfation status. ©The Author 2010. Published by Oxford University Press.

Tomabechi Y.,Tokai University | Odate Y.,Tokai University | Izumi R.,Research Association for Biotechnology | Haneda K.,Tokai University | Inazu T.,Tokai University
Carbohydrate Research | Year: 2010

To determine the structural specificity of the glycosyl acceptor of the transglycosylation reaction using endo-β-N-acetylglucosaminidase (ENGase) (EC from Mucor hiemalis (Endo-M), several acceptor derivatives were designed and synthesized. The narrow regions of the 1,3-diol structure from the 4- to 6-hydroxy functions of GlcNAc were found to be essential for the transglycosylation reaction using Endo-M. Furthermore, it was determined that Endo-M strictly recognizes a 1,3-diol structure consisting of primary and secondary hydroxyl groups. © 2010 Elsevier Ltd. All rights reserved.

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