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PubMed | Medical Genome Center, Meiji Pharmaceutical University, Hirosaki University, Innovation Center for Clinical Research and 2 more.
Type: | Journal: Biomarker research | Year: 2016

Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia including Alzheimers disease. Early detection of dementia, and MCI, is a crucial issue in terms of secondary prevention. Blood biomarker detection is a possible way for early detection of MCI. Although disease biomarkers are detected by, in general, using single molecular analysis such as t-test, another possible approach is based on interaction between molecules.Differential correlation analysis, which detects difference on correlation of two variables in case/control study, was carried out to plasma microRNA (miRNA) expression profiles of 30 age- and race-matched controls and 23 Japanese MCI patients. The 20 pairs of miRNAs, which consist of 20 miRNAs, were selected as MCI markers. Two pairs of miRNAs (hsa-miR-191 and hsa-miR-101, and hsa-miR-103 and hsa-miR-222) out of 20 attained the highest area under the curve (AUC) value of 0.962 for MCI detection. Other two miRNA pairs that include hsa-miR-191 and hsa-miR-125b also attained high AUC value of 0.95. Pathway analysis was performed to the MCI markers for further understanding of biological implications. As a result, collapsed correlation on hsa-miR-191 and emerged correlation on hsa-miR-125b might have key role in MCI and dementia progression.Differential correlation analysis, a bioinformatics tool to elucidate complicated and interdependent biological systems behind diseases, detects effective MCI markers that cannot be found by single molecule analysis such as t-test.


PubMed | Hannan Hospital, Medical Genome Center, Osaka City University, RIKEN and Tani Mental Clinic
Type: | Journal: Psychiatry and clinical neurosciences | Year: 2016

There is an urgent need for diagnostic biomarkers of bipolar disorder (BD) and schizophrenia (SZ); however, confounding effects of medication hamper biomarker discovery. In this study, we conducted metabolome analyses to identify novel plasma biomarkers in drug-free patients with BD and SZ.We comprehensively analyzed plasma metabolites using capillary electrophoresis time-of-flight mass spectrometry in patients with SZ (n=17), BD (n=6), and major depressive disorder (n=9) who had not received psychotropics for at least 2weeks, and in matched healthy controls (n=19). The results were compared with previous reports, or verified in an independent sample set using an alternative analytical approach.Lower creatine level and higher 2-hydroxybutyric acid level were observed in SZ than in controls (uncorrected P =0.016 and 0.043, respectively), whereas they were unaltered in a previously reported dataset. Citrulline was nominally significantly decreased in BD compared to controls (uncorrected P =0.043); however, this finding was not replicated in an independent sample set of medicated patients with BD. N -methyl-norsalsolinol, a metabolite of dopamine, was suggested as a candidate biomarker of BD; however, it was not detected by the other analytical method. Levels of betaine, a previously reported candidate biomarker of schizophrenia, were unchanged in the current dataset.Our preliminary findings suggest that the effect of confounding factors, such as duration of illness and medication, should be carefully controlled when searching for plasma biomarkers. Further studies are required to establish robust biomarkers for these disorders.


PubMed | Medical Genome Center, Kobe University, Comprehensive Care and National Center for Geriatrics and Gerontology
Type: | Journal: Journal of Alzheimer's disease : JAD | Year: 2016

Urinary incontinence (UI) is frequently observed in patients with Alzheimers disease (AD). Although previous works highlight the association between frontal lobe-related function and UI, causal relationship is unclear.To clarify the longitudinal association between frontal lobe function and the incidence of UI at 1 year in patients with AD.The subjects were 215 continent AD patients who attended the Memory Clinic of the National Center for Geriatrics and Gerontology of Japan during the period from March 2011 to December 2014. The absence or presence of UI was operationally assigned by the dementia behavior disturbance scale subscale, which was completed by the patients caregivers. Frontal lobe function was assessed using the Frontal Assessment Battery (FAB). Other confounding factors including demographic data, cognitive status, vitality, mood, physical performance, and use of medication (cholinesterase inhibitors, calcium channel blockers [CCBs], diuretics, alpha blockers and anticholinergic drugs) were assessed.During 1-year follow up (mean: 377.483.7 days), the incidence of UI was 12.1% (n=26). Patients with UI had significantly lower FAB performance at baseline (no UI versus UI=9.32.8 versus 7.82.7). In multivariate analysis, stepwise logistic regression analysis demonstrated that FAB (odds ratio [OR]=0.79, 95% confidence interval [CI]=0.66-0.94) and the use of CCB (OR=2.72, 95% CI=1.09-6.77) were significantly associated with UI at 1 year.The results of study indicate that frontal lobe dysfunction is predictor for UI in patients with AD.


Hatakeyama H.,National Institute of Neuroscience | Hatakeyama H.,Japan Science and Technology Agency | Goto Y.-I.,National Institute of Neuroscience | Goto Y.-I.,Medical Genome Center | Goto Y.-I.,Japan Science and Technology Agency
Stem Cells | Year: 2016

Mitochondria contain multiple copies of their own genome (mitochondrial DNA; mtDNA). Once mitochondria are damaged by mutant mtDNA, mitochondrial dysfunction is strongly induced, followed by symptomatic appearance of mitochondrial diseases. Major genetic causes of mitochondrial diseases are defects in mtDNA, and the others are defects of mitochondria-associating genes that are encoded in nuclear DNA (nDNA). Numerous pathogenic mutations responsible for various types of mitochondrial diseases have been identified in mtDNA; however, it remains uncertain why mitochondrial diseases present a wide variety of clinical spectrum even among patients carrying the same mtDNA mutations (e.g., variations in age of onset, in affected tissues and organs, or in disease progression and phenotypic severity). Disease-relevant induced pluripotent stem cells (iPSCs) derived from mitochondrial disease patients have therefore opened new avenues for understanding the definitive genotype-phenotype relationship of affected tissues and organs in various types of mitochondrial diseases triggered by mtDNA mutations. In this concise review, we briefly summarize several recent approaches using patient-derived iPSCs and their derivatives carrying various mtDNA mutations for applications in human mitochondrial disease modeling, drug discovery, and future regenerative therapeutics. © 2016 AlphaMed Press.


Yokota M.,National Institute of Neuroscience | Yokota M.,Japan Science and Technology Agency | Hatakeyama H.,National Institute of Neuroscience | Hatakeyama H.,Japan Science and Technology Agency | And 5 more authors.
Human Molecular Genetics | Year: 2015

Mitochondrial dysfunction caused by pathogenic mutations in mitochondrial tRNA genes emerges only when mutant mitochondrial DNA (mtDNA) proportions exceed intrinsic pathogenic thresholds; however, little is known about the actual proportions of mutant mtDNA that can affect particular cellular lineage-determining processes. Here, we mainly focused on the effects of mitochondrial respiratory dysfunction caused by m.3243A>G heteroplasmy in MT-TL1 gene on cellular reprogramming. We found that generation of induced pluripotent stem cells (iPSCs) was drastically depressed only by high proportions of mutant mtDNA (≥90% m.3243A>G), and these proportions were strongly associated with the degree of induced mitochondrial respiratory dysfunction. Nevertheless, all established iPSCs, even those carrying ~100% m.3243A>G, exhibited an embryonic stem cell-like pluripotent state. Therefore, our findings clearly demonstrate that loss of physiological integrity in mitochondria triggered by mutant mtDNA constitute a roadblock to cellular rejuvenation, but do not affect the maintenance of the pluripotent state. © The Author 2015. Published by Oxford University Press. All rights reserved.


Uruha A.,Medical Genome Center | Uruha A.,National Institute of Neuroscience | Noguchi S.,Medical Genome Center | Noguchi S.,National Institute of Neuroscience | And 8 more authors.
Neurology | Year: 2016

Objective: To clarify whether there is any association between inclusion body myositis (IBM) and hepatitis C virus (HCV) infection. Methods: We assessed the prevalence of HCV infection in 114 patients with IBM whose muscle biopsies were analyzed pathologically for diagnostic purpose from 2002 to 2012 and in 44 agematched patients with polymyositis diagnosed in the same period as a control by administering a questionnaire survey to the physicians in charge. We also compared clinicopathologic features including the duration from onset to development of representative symptoms of IBM and the extent of representative pathologic changes between patients with IBM with and without HCV infection. Results: A significantly higher number of patients with IBM (28%) had anti-HCV antibodies as compared with patients with polymyositis (4.5%; odds ratio 8.2, 95% confidence interval 1.9-36) and the general Japanese population in their 60s (3.4%). Furthermore, between patients with IBM with and without HCV infection, we did not find any significant difference in the clinicopathologic features, indicating that the 2 groups have essentially the same disease regardless of HCV infection. Conclusion: Our results provide the statistical evidence for an association between IBM and HCV infection, suggesting a possible pathomechanistic link between the 2 conditions. © 2015 American Academy of Neurology.


PubMed | Medical Genome Center and National Institute of Neuroscience
Type: Journal Article | Journal: Cell death & disease | Year: 2017

Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development.


PubMed | Medical Genome Center and National Institute of Neuroscience
Type: Journal Article | Journal: Journal of human genetics | Year: 2016

Duchenne and Becker muscular dystrophies (DMD/BMD) are the most common inherited neuromuscular disease. The genetic diagnosis is not easily made because of the large size of the dystrophin gene, complex mutational spectrum and high number of tests patients undergo for diagnosis. Multiplex ligation-dependent probe amplification (MLPA) has been used as the initial diagnostic test of choice. Although MLPA can diagnose 70% of DMD/BMD patients having deletions/duplications, the remaining 30% of patients with small mutations require further analysis, such as Sanger sequencing. We applied a high-throughput method using Ion Torrent next-generation sequencing technology and diagnosed 92% of patients with DMD/BMD in a single analysis. We designed a multiplex primer pool for DMD and sequenced 67 cases having different mutations: 37 with deletions/duplications and 30 with small mutations or short insertions/deletions in DMD, using an Ion PGM sequencer. The results were compared with those from MLPA or Sanger sequencing. All deletions were detected. In contrast, 50% of duplications were correctly identified compared with the MLPA method. Small insertions in consecutive bases could not be detected. We estimated that Ion Torrent sequencing could diagnose ~92% of DMD/BMD patients according to the mutational spectrum of our cohort. Our results clearly indicate that this method is suitable for routine clinical practice providing novel insights into comprehensive genetic information for future molecular therapy.


PubMed | Medical Genome Center
Type: Review | Journal: International journal of molecular sciences | Year: 2016

Calcium is a crucial mediator of cell signaling in skeletal muscles for basic cellular functions and specific functions, including contraction, fiber-type differentiation and energy production. The sarcoplasmic reticulum (SR) is an organelle that provides a large supply of intracellular Ca


PubMed | National Center Hospital and Medical Genome Center
Type: | Journal: Muscle & nerve | Year: 2016

Little is known about the frequency of cardiopulmonary failure in limb-girdle muscular dystrophy type 2A (calpainopathy) patients, although some studies have reported severe cardiomyopathy or respiratory failure.To clarify the frequency of cardiopulmonary dysfunction in this patient population, we retrospectively reviewed the respiratory and cardiac function of 43 patients with calpainopathy.Nine of the 43 patients had forced vital capacity (FVC) <80%, and 3 used non-invasive positive pressure ventilation. Mean FVC was significantly lower in patients who were non-ambulant and had normal CK levels. Only 1 patient had a prolonged QRS complex duration. Echocardiography revealed that 1 patient had very mild left ventricular dysfunction.These findings suggest that patients with calpainopathy may develop severe respiratory failure, but cardiac dysfunction is infrequent. This article is protected by copyright. All rights reserved.

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