Yoshio Hashizume

Choju Medical Institute, Kioto, Kyōto, Japan

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Publications (267)964.62 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and definitive diagnosis of Alzheimer's disease (AD) can lead to a better and more-targeted treatment and/or prevention for patients. In the diagnostic biomarkers of AD, the blood sample represents a more non-invasive, inexpensive and acceptable sources for repeated measurements than the cerebrospinal fluid. In this study, the fingerprinting metabolomics was proposed for the challenge of the blood-based diagnosis of defined AD by hydrophilic interaction liquid chromatography mass spectrometry (HILIC/MS). These plasma samples were selected from postmortem specimens based on these pathological examinations. Firstly, we compared these HILIC columns for the non-targeted metabolic assay using pooled plasma. The principal component analysis plot of these seven columns was performed using the repeatability of these chromatograms, and can be used to visualize trends in data sets by three-dimensional dispersion, contributory standard deviation and the number of detections. Based on these results, TSK-Amide 80 and TSKgel-NH2 columns are used as a reliable HILIC/MS assay of blood-based AD metabolomics that showed metabolic profiling of the AD pathology in MS chromatograms that ranged from 1182 to 2284 compounds. A total of 54 peaks were evaluated in order to identify useful ion signal candidates using an orthogonal partial least-squares-discriminant analysis. These peaks were then specifically analyzed using the HILIC-tandem MS assay by a receiver operating characteristic curve and linear discriminant analysis for the diagnosis of the defined AD. The fingerprinting metabolomics can overcome the limitations of previous challenging blood-based diagnosis of AD, and directly evaluates the specific comparative statistical values from the raw data.
    Journal of Chromatography B 01/2015; 974. DOI:10.1016/j.jchromb.2014.10.022 · 2.69 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P657. DOI:10.1016/j.jalz.2014.05.1170 · 17.47 Impact Factor
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    ABSTRACT: In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt–Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.
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    [Show abstract] [Hide abstract]
    ABSTRACT: In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.
    Journal of the neurological sciences 04/2014; 341(1-2). DOI:10.1016/j.jns.2014.04.011 · 2.26 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of Aβ accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aβ accumulation. To avoid detecting secondarily affected genes by Aβ, we used non-Tg mice in the absence of Aβ pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an Aβ modifier, indicating a role for intracellular trafficking in Aβ accumulation. Aβ levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of Aβ, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aβ pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.
    Proceedings of the National Academy of Sciences 02/2014; DOI:10.1073/pnas.1307345111 · 9.81 Impact Factor
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    ABSTRACT: Typical markers of protein aging are spontaneous post-translational modifications such as amino acid racemization (AAR) and amino acid isomerization (AAI) during the degradation of peptides. The post-translational AAR and AAI could significantly induce the density and localization of plaque deposition in brain tissues. Alzheimer's disease (AD) is reliably related to the formation and aggregation of amyloid-β peptide (Aβ) plaques in the human brain. No current analytical methods can simultaneously determine AAR and AAI during the degradation of Aβ from AD patients. We now report a covalent chiral derivatized ultra-performance liquid chromatography tandem mass spectrometry (CCD-UPLC-MS/MS) method for the determination of post-translational AAR and AAI of N-terminal Aβ (N-Aβ1-5) in human brain tissues. When subjected to tryptic N-A1-5 from post-transnationally modified nature Aβ in focal brain tissues by the CCD procedure, it was monitored at m/z 989.6→637.0/678.9 during electrospray collision-induced dissociation. These N-Aβ1-5 fragments with L-aspartic acid (L-Asp), D-Asp, L-isoAsp and D-isoAsp could be separated using the UPLC system with a conventional reversed-phase column and mobile phase. The quantification of these peptides were used of a stable isotope [15N]-labeled Aβ1-40 internal standard. The CCD-UPLC-MS/MS assay of potential N-Aβ1-5 allowed for the discovery of the present and ratio levels of these N-Aβ1-5 sequences with L-Asp, D-Asp, L-isoAsp and D-isoAsp.
    Analytical Chemistry 11/2013; 86(1). DOI:10.1021/ac403315h · 5.83 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is an irreversible, progressive brain disease and can be definitively diagnosed after death through an examination of senile plaques and neurofibrillary tangles in several brain regions. It is to be expected that changes in the concentration and/or localization of low-molecular-weight molecules are linked to the pathological changes that occur in AD, and determining their identity would provide valuable information regarding AD processes. Here, we propose definitive brain metabolic profiling using ultra-performance liquid chromatography coupled with electrospray time-of-flight mass spectrometry analysis. The acquired data were subjected to principal components analysis to differentiate the frontal and parietal lobes of the AD/Control groups. Significant differences in the levels of spermine and spermidine were identified using S-plot, mass spectra, databases and standards. Based on the investigation of the polyamine metabolite pathway, these data establish that the downstream metabolites of ornithine are increased, potentially implicating ornithine decarboxylase activity in AD pathology.
    Scientific Reports 08/2013; 3:2364. DOI:10.1038/srep02364 · 5.58 Impact Factor
  • Alzheimer's and Dementia 07/2013; 9(4):P209. DOI:10.1016/j.jalz.2013.05.386 · 17.47 Impact Factor
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    ABSTRACT: Myotonic dystrophy (MD) is an autosomal-dominantly inherited muscular disease characterized by myotonia, progressive muscle weakness and multisystem complications, including frontal baldness, cataracts, cardiac conduction defects, hypogonadism, endocrine deficiency and cognitive impairment [1]. Neuropathological observations of the brain in MD exhibit the appearance of neurofibrillary tangles (NFTs) without senile plaques in the limbic system and brainstem, even in relatively young patients [2, 3]. By chance, we found NFTs in the sympathetic ganglion (SG) of one MD patient. Intrigued by this case, we investigated the occurrence of NFTs in the SG and spinal ganglia from a series of MD patients and control subjects.
    Neuropathology and Applied Neurobiology 03/2013; DOI:10.1111/nan.12043 · 4.97 Impact Factor
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    ABSTRACT: Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons.
    EMBO Molecular Medicine 02/2013; 5(2). DOI:10.1002/emmm.201202303 · 8.25 Impact Factor
  • Journal of the American Geriatrics Society 11/2012; 60(11):2169-2170. DOI:10.1111/j.1532-5415.2012.04224.x · 4.22 Impact Factor
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    ABSTRACT: Nuclear factor κ B (NF-κB) is involved in the pathogenesis of a number of neurodegenerative disorders with neuroinflammation. In order to clarify the role of NF-κB in ALS, immunohistochemical studies with an antibody that recognizes the p65 subunit of NF-κB were performed on the spinal anterior horn of 4 patients with sporadic ALS (sALS), 1 patient with optineurin-mutated ALS (OPTN-ALS), and 3 normal controls (NC). In patients with sALS or OPTN-ALS, the expression pattern of NF-κB was altered when compared to that of NC; NF-κB immunoreactivity tended to be absent from neuronal nucleus and was increased in microglia. The down-regulation of NF-κB in neuronal nucleus might contribute to a loss of neuroprotection, or neurons with nuclear NF-κB might be lost immediately after its activation. The microglial induction of NF-κB might contribute to neuroinflammation. In conclusion, NF-κB signaling pathway could have a key role in the pathomechanism of ALS.
    Clinical neuropathology 07/2012; 31(6):418-423. DOI:10.5414/NP300493 · 1.31 Impact Factor
  • Alzheimer's and Dementia 07/2012; 8(4):P496-P497. DOI:10.1016/j.jalz.2012.05.1349 · 17.47 Impact Factor
  • Takuya Tamura, Mari Yoshida, Yoshio Hashizume, Gen Sobue
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    ABSTRACT: Incidental Lewy body disease (ILBD) represents the early asymptomatic phase of Lewy body diseases (LBD), including idiopathic Parkinson's disease (PD). Although pathological disturbances in the spinal cord, which connects the brain to the peripheral nervous system, plays an important role, the pathology of ILBD has not been adequately examined. Eighteen ILBD and eight age-matched LBD cases were enrolled in the present study. LB-related pathology was immunohistochemically evaluated using anti-phosphorylated α-synuclein (pαSyn) antibodies, revealing LB-related pathology in the spinal cords of 15 (83.3%) of the ILBD cases. Attempts were made to identify the early pattern of pαSyn deposition in the spinal cord by comparing the cervical, thoracic, lumbar and sacral segments in detail. Most pαSyn-positive structures were distributed in and around the autonomic nuclei of the spinal cord. The intermediolateral nuclei in the thoracic segments (Th/IML) were the most frequently and severely affected region, suggesting that Th/IML are the first structures affected. Furthermore, following analysis of the distribution pattern of the pαSyn-positive structures, it is suspected that LB-related pathology progresses toward the caudal vertebrae by involving neurons in the spinal cord that are vulnerable to αSyn. It should be noted that the ILBD cases enrolled in the present study were in an earlier stage than the PD cases enrolled in the previous study, and that the present study provides new, previously undescribed information.
    Neuropathology 02/2012; 32(1):13-22. DOI:10.1111/j.1440-1789.2011.01211.x · 1.80 Impact Factor
  • Arthritis Research & Therapy 02/2012; 14(1). DOI:10.1186/ar3603 · 4.12 Impact Factor
  • Schizophrenia Research 01/2012; 2(1):128. · 4.43 Impact Factor
  • Clinical neurology and neurosurgery 12/2011; 114(6):728-31. DOI:10.1016/j.clineuro.2011.12.010 · 1.25 Impact Factor
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    ABSTRACT: Abnormal distributions of transition metals inside the brain are potential diagnostic markers for several central nervous system diseases, including Alzheimer's disease (AD), Parkinson's disease, dementia with Lewy bodies (DLB), bipolar disorders and depression. To further explore this possibility, the total concentrations of iron, zinc, copper, manganese, aluminum, chromium and cadmium were measured in post-mortem hippocampus and amygdala tissues taken from AD, DLB and Control patients. A statistically significant near fifty percent reduction in the total copper levels of AD patients was observed in both the hippocampus and amygdala. The statistical power of the hippocampus and amygdala copper analysis was found to be 86 and 74% respectively. No statistically significant deviations in the total metal concentrations were found for zinc, manganese, chromium or aluminum. Iron was found to be increased by 38% in AD amygdala tissues, but was unchanged in AD hippocampus tissues. Accounting for differences in tissue water content, as a function of both tissue type and disease state, revealed more consistencies with previous literature. To aid in the design of future experiments, the effect sizes for all tissue types and metals studied are also presented.
    Biology of Metals 11/2011; 25(2):337-50. DOI:10.1007/s10534-011-9504-8 · 2.69 Impact Factor
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    ABSTRACT: A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.
    Neuropathology 10/2011; 31(5):540-8. DOI:10.1111/j.1440-1789.2010.01192.x · 1.80 Impact Factor
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    ABSTRACT: A 41-year-old man diagnosed with malignant lymphoma (MLy) in November 2007 developed paralysis that worsened rapidly in January 2008. Magnetic resonance imaging (MRI) showed multifocal T2 high-intensity lesions without edema or gadolinium enhancement in the white matter. The lesions were characterized by a central core with low signal intensity, surrounded by a rim of high signal intensity on diffusion-weighted images (DWIs). At first, we suspected brain metastasis of MLy and used anti-cancer drugs, but the patient's condition worsened. A brain biopsy was then taken to determine whether the patient had MLy metastasis or progressive multifocal leukoencephalopathy (PML) so that an appropriate course of treatment could be determined. The biopsy contained no characteristic nuclear inclusions of PML, but we were able to rule out MLy; therefore, the patient was treated with cytarabine in February 2008, but he died because of sepsis in March. Upon autopsy, many characteristic nuclear inclusions of PML were found in the periphery of the lesions, and in the central core, there was severe demyelinating and tissue softening without typical nuclear inclusions of oligodendroglias. This structure is similar to the structure observed on DWIs, in which a low signal intensity core is surrounded by a rim of high signal intensity. The presence of inclusion bodies in the rim would correspond to the high signal intensity area on DWIs. The peripheral area may have given high signal intensity on DWIs because of the active findings of many swelling oligodendroglias with typical nuclear inclusions. Conversely, the central lesions would give low signals on DWIs because of demyelination and softening. Hence, the region with high signal intensity adjacent to the central low signal area on DWIs would be an appropriate biopsy point for PML diagnosis. ).
    Brain and nerve = Shinkei kenkyū no shinpo 09/2011; 63(9):1001-7.

Publication Stats

5k Citations
964.62 Total Impact Points

Institutions

  • 2011–2015
    • Choju Medical Institute
      Kioto, Kyōto, Japan
  • 2013
    • Toyohashi Municipal Hospital
      Toyohasi, Aichi, Japan
  • 1988–2011
    • Aichi Medical University
      • • Institute for Medical Science of Aging
      • • Department of Neurological Surgery
      • • Department of Neurology
      • • Division of Internal Medicine
      Okazaki, Aichi, Japan
  • 2009–2010
    • Oyamada Memorial Spa Hospital
      Yamatamachi, Iwate, Japan
    • Anjo Kosei Hospital
      Anjō, Aichi, Japan
  • 2007
    • Kasugai Municipal Hospital
      Касугай, Aichi, Japan
  • 1988–2004
    • Nagoya University
      • • Division of Orthopedics Surgery
      • • Division of Pathology
      • • Division of of Internal Medicine
      Nagoya-shi, Aichi-ken, Japan
  • 1999
    • Fujita Health University
      Nagoya, Aichi, Japan
    • Shinshu University
      Shonai, Nagano, Japan
  • 1998
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1997
    • Nagoya Institute of Technology
      Nagoya, Aichi, Japan
  • 1992
    • Montefiore Medical Center
      • Department of Pathology
      New York City, New York, United States
  • 1991
    • Nagoya Second Red Cross Hospital
      Nagoya, Aichi, Japan
  • 1989
    • Meijo University
      Nagoya, Aichi, Japan