Y Hashizume

Choju Medical Institute, Kioto, Kyōto, Japan

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Publications (262)862.27 Total impact

  • [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 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.
    Journal of the Neurological Sciences. 06/2014; 341(s 1–2):97–104.
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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; · 2.32 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; · 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; · 5.70 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. · 5.08 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; · 4.84 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 12/2012; · 7.80 Impact Factor
  • Journal of the American Geriatrics Society 11/2012; 60(11):2169-2170. · 3.98 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. · 1.34 Impact Factor
  • Arthritis Research & Therapy 02/2012; 14(1). · 4.30 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. · 1.91 Impact Factor
  • Schizophrenia Research 01/2012; 2(1):128. · 4.59 Impact Factor
  • Clinical neurology and neurosurgery 12/2011; 114(6):728-31. · 1.30 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. · 3.17 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.
  • Journal of Neurology, Neurosurgery, and Psychiatry. 08/2011; 82(12):1402-1403.
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    ABSTRACT: Sulfatide (ST) is a sphingolipid with an important role in the central nervous system as a major component of the myelin sheath. ST contains a structurally variable ceramide moiety, with a fatty acid substituent of varying carbon-chain length and double-bond number. Hydroxylation at the α-2 carbon position of the fatty acid is found in half the population of ST molecules. Recent genetic studies of fatty acid 2-hydroxylase (FA2H) indicate that these hydroxylated sphingolipids influence myelin sheath stability. However, their distribution is unknown. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) enables the analysis of distinct distributions of individual ST molecular species in tissue section. We examined human cerebral cortex tissue sections with MALDI-IMS, identifying and characterizing the distributions of 14 ST species. The distribution analysis reveals that the composition ratios of non-hydroxylated/hydroxylated STs are clearly reversed at the border between white and gray matter; the hydroxylated group is the dominant ST species in the gray matter. These results suggest that hydroxylated STs are highly expressed in oligodendrocytes in gray matter and might form stable myelin sheaths. As a clinical application, we analyzed a brain with Alzheimer's disease (AD) as a representative neurodegenerative disease. Although previous studies of AD pathology have reported that the amount of total ST is decreased in the cerebral cortex, as far as the compositional distributions of STs are concerned, AD brains were similar to those in control brains. In conclusion, we suggest that MALDI-IMS is a useful tool for analysis of the distributions of various STs and this application might provide novel insight in the clinical study of demyelinating diseases.
    Neuroscience 07/2011; 193:44-53. · 3.12 Impact Factor
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    ABSTRACT: It is not known whether the clinical course of Japanese sporadic Creutzfeldt-Jakob disease (sCJD) cases differs from that of Caucasian sCJD cases. To investigate the clinical course of Japanese sCJD, clinical findings from 29 patients with Japanese MM1-type sCJD were retrospectively evaluated and compared to Caucasian sCJD findings. Survival of Japanese MM1-type sCJD up to the time of akinetic mutism state is similar to that of Caucasian subjects. However, the total disease duration of Japanese patients was approximately three times longer. The present observations indicate that Japanese sCJD cases generally show a longer disease duration because of the longer survival period after reaching the akinetic mutism state.
    European Journal of Neurology 07/2011; 18(7):999-1002. · 4.16 Impact Factor
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    ABSTRACT: Intramedullary + extramedullary hemangioblastomas with largely extramedullary growth are rare and often incorrectly assigned as intradural-extramedullary tumors preoperatively. Preoperative evaluation of the precise tumor location is important for total resection of tumor and improving the surgical outcome. The aim of this study was to provide the first identification of the key differences among of preoperative MR images of hemangioblastomas in different locations and to correlate these with pathological findings. The subjects were 26 patients with surgery for spinal hemangioblastoma in our department, including 6 with an intramedullary tumor who were complicated with von Hippel Lindau disease. Intramedullary, intramedullary + extramedullary, and intradural-extramedullary tumors were present in 22, 3 and 1 cases, respectively. Sagittal MR images showed that intramedullary and intramedullary + extramedullary tumors gave intramedullary T2 high intensity areas (HIAs) spreading toward the craniocaudal sides of the tumor, whereas such findings were absent for the intradural-extramedullary tumor. All the tumors showed strong contrast on axial images, with focal enhancement of hemangioblastomas limited to the intramedullary region (focal type); smooth boundary lines between the spinal cord and the extramedullary tumor (smooth type); and a snowman sign for intramedullary + extramedullary tumors, which provided a key characteristic for differentiating intramedullary + extramedullary tumors from those limited to the extramedullary region. In pathological findings, the Ki67 activity was less than 1% for intramedullary and intradural-extramedullary tumors, but 18-25% in all cases with an intramedullary + extramedullary tumor. In conclusion, on preoperative MRI, a change in the intramedullary HIAs spreading the craniocaudal sides of the tumor on sagittal T2 weighted image (T2WI) and a snowman sign on contrast axial T1WI may be important for differentiation among spinal hemangioblastomas in different locations. Pathologically, we found that intramedullary + extramedullary hemangioblastoma has high cell proliferative activity, which may suggest that enlargement of this tumor occurs faster than that of intramedullary hemangioblastoma.
    European Spine Journal 04/2011; 20(8):1377-84. · 2.47 Impact Factor
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    ABSTRACT: Schizophrenia is one of the major psychiatric disorders, and lipids have focused on the important roles in this disorder. In fact, lipids related to various functions in the brain. Previous studies have indicated that phospholipids, particularly ones containing polyunsaturated fatty acyl residues, are deficient in postmortem brains from patients with schizophrenia. However, due to the difficulties in handling human postmortem brains, particularly the large size and complex structures of the human brain, there is little agreement regarding the qualitative and quantitative abnormalities of phospholipids in brains from patients with schizophrenia, particularly if corresponding brain regions are not used. In this study, to overcome these problems, we employed matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS), enabling direct microregion analysis of phospholipids in the postmortem brain of a patient with schizophrenia via brain sections prepared on glass slides. With integration of traditional histochemical examination, we could analyze regions of interest in the brain at the micrometric level. We found abnormal phospholipid distributions within internal brain structures, namely, the frontal cortex and occipital cortex. IMS revealed abnormal distributions of phosphatidylcholine molecular species particularly in the cortical layer of frontal cortex region. In addition, the combined use of liquid chromatography/electrospray ionization tandem mass spectrometry strengthened the capability for identification of numerous lipid molecular species. Our results are expected to further elucidate various metabolic processes in the neural system.
    Analytical and Bioanalytical Chemistry 04/2011; 400(7):1933-43. · 3.66 Impact Factor

Publication Stats

4k Citations
862.27 Total Impact Points

Institutions

  • 2012–2014
    • Choju Medical Institute
      Kioto, Kyōto, Japan
    • Toyohashi Municipal Hospital
      Toyohasi, Aichi, Japan
  • 1988–2012
    • Aichi Medical University
      • • Department of Endocrinology and Metabolism
      • • Institute for Medical Science of Aging
      • • Department of Neurology
      • • Department of Neurological Surgery
      • • Division of Internal Medicine
      Toyohasi, Aichi, Japan
  • 2009–2011
    • Oyamada Memorial Spa Hospital
      Yamatamachi, Iwate, Japan
    • Anjo Kosei Hospital
      Anjō, Aichi, Japan
  • 2007–2011
    • Kasugai Municipal Hospital
      Касугай, Aichi, Japan
    • National Center for Geriatrics and Gerontology
      • Department of Geriatric Medicine
      Ōbu, Aichi-ken, Japan
    • Nagoya City University
      Nagoya, Aichi, Japan
  • 2010
    • National Hospital Organization Nagoya Medical Center
      Nagoya, Aichi, Japan
  • 2005–2010
    • Tokyo Medical and Dental University
      • Department of Neurology and Neurological Science
      Tokyo, Tokyo-to, Japan
    • Tokyo Metropolitan Matsuzawa Hospital
      Edo, Tōkyō, Japan
  • 2006
    • Fudan University
      • Department of Neurology
      Shanghai, Shanghai Shi, China
    • Fujita Health University
      • Department of Neurology
      Nagoya, Aichi, Japan
  • 2002–2006
    • Hokuriku Central Hospital
      Nanto-shi, Toyama, Japan
  • 2004–2005
    • Numazu City Hospital
      Sizuoka, Shizuoka, Japan
  • 1989–2004
    • Nagoya University
      • • Division of Orthopedics Surgery
      • • Division of Neurology
      • • Division of Pathology
      Nagoya-shi, Aichi-ken, Japan
  • 1998
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
  • 1997
    • Nagoya Institute of Technology
      Nagoya, Aichi, Japan
  • 1991
    • Nagoya Second Red Cross Hospital
      Nagoya, Aichi, Japan