Publications by authors named "Yuko Saito"

216 Publications

Diffusion-Weighted Imaging is Key to Diagnosing Specific Diseases.

Magn Reson Imaging Clin N Am 2021 May;29(2):163-183

Brain Bank for Aging Research, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo 173-0015, Japan; Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child Development, Osaka University, 2-2, Yamadaoka, Suita-shi, Osaka-fu 565-0871, Japan.

This article reviews diseases for which persistent signal abnormalities on diffusion-weighted imaging are the key to their diagnosis. Specifically, updated knowledge regarding the neuroimaging patterns of the following diseases is summarized: sporadic Creutzfeldt-Jakob disease, neuronal intranuclear inclusion disease, and hereditary diffuse leukoencephalopathy with axonal spheroids-colony-stimulating factor receptors/adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. In addition, their differential diagnoses; clinical manifestations; and pathologic, genetic, and imaging correlates are discussed.
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http://dx.doi.org/10.1016/j.mric.2021.02.001DOI Listing
May 2021

Involvement of cytotoxic Eomes-expressing CD4 T cells in secondary progressive multiple sclerosis.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502 Japan;

Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4 T cells expressing Eomes (Eomes Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes Th cells circulate in RRMS patient peripheral blood ( = 44), primary progressive MS (PPMS) patients ( = 25), or healthy controls ( = 42), but Eomes Th cells were significantly increased in SPMS ( = 105, < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4 T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases ( < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
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http://dx.doi.org/10.1073/pnas.2021818118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980371PMC
March 2021

Human tauopathy-derived tau strains determine the substrates recruited for templated amplification.

Brain 2021 Mar 9. Epub 2021 Mar 9.

Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-8506, Japan.

Tauopathies are a subset of neurodegenerative diseases characterized by abnormal tau inclusions. Specifically, three-repeat tau and four-repeat tau in Alzheimer's disease (AD), three-repeat tau in Pick's disease (PiD) and four-repeat in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) form amyloid-like fibrous structures that accumulate in neurons and/or glial cells. Amplification and cell-to-cell transmission of abnormal tau based on the prion hypothesis are believed to explain the onset and progression of tauopathies. Recent studies support not only the self-propagation of abnormal tau, but also the presence of conformationally distinct tau aggregates, namely tau strains. Cryo-electron microscopy analyses of patient-derived tau filaments have revealed disease-specific ordered tau structures. However, it remains unclear whether the ultrastructural and biochemical properties of tau strains are inherited during the amplification of abnormal tau in the brain. In this study, we investigated template-dependent amplification of tau aggregates using a cellular model of seeded aggregation. Tau strains extracted from human tauopathies caused strain-dependent accumulation of insoluble filamentous tau in SH-SY5Y cells. The seeding activity towards full-length four-repeat tau substrate was highest in CBD-tau seeds, followed by PSP-tau and AD-tau seeds, while AD-tau seeds showed higher seeding activity than PiD-tau seeds towards three-repeat tau substrates. Abnormal tau amplified in cells inherited the ultrastructural and biochemical properties of the original seeds. These results strongly suggest that the structural differences of patient-derived tau strains underlie the diversity of tauopathies, and that seeded aggregation and filament formation mimicking the pathogenesis of sporadic tauopathy can be reproduced in cultured cells. Our results indicate that the disease-specific conformation of tau aggregates determines the tau isoform substrate that is recruited for templated amplification, and also influences the prion-like seeding activity.
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http://dx.doi.org/10.1093/brain/awab091DOI Listing
March 2021

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP-43 proteinopathy.

Neuropathology 2021 Apr 7;41(2):118-126. Epub 2021 Jan 7.

Department of Neurology and Neuropathology (The Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.

We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.
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http://dx.doi.org/10.1111/neup.12710DOI Listing
April 2021

Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy.

Neurol Genet 2020 Dec 19;6(6):e531. Epub 2020 Nov 19.

Department of Neurology (T.I., T.O., Y. Saitoh, S.O., Y.T.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Human Genetics (K.S., A.F., H.F., N. Miyake, T.M., N. Matsumoto), Yokohama City University Graduate School of Medicine, Kanagawa; Department of Pathology and Laboratory Medicine (T.S., Y. Saito), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (T.Y.), Iida Municipal Hospital, Shinshu University School of Medicine, Nagano; Department of Medicine (Neurology and Rheumatology) (Y.M., Y. Sekijima), Shinshu University School of Medicine, Nagano; and Department of Neurology and Stroke Medicine (H.F.), Yokohama City University, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713717PMC
December 2020

Comparison of Common and Disease-Specific Post-translational Modifications of Pathological Tau Associated With a Wide Range of Tauopathies.

Front Neurosci 2020 4;14:581936. Epub 2020 Nov 4.

Department of Brain and Neuroscience, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

Tauopathies are the most common type of neurodegenerative proteinopathy, being characterized by cytoplasmic aggregates of hyperphosphorylated tau protein. The formation and morphologies of these tau inclusions, the distribution of the lesions and related metabolic changes in cytoplasm differ among different tauopathies. The aim of this study was to examine whether there are differences in the post-translational modifications (PTMs) in the pathological tau proteins. We analyzed sarkosyl-insoluble pathological tau proteins prepared from brains of patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathy, and frontotemporal dementia and parkinsonisms linked to chromosome 17 with tau inclusions using liquid chromatography mass spectrometry. In pathological tau proteins associated with a wide range of tauopathies, 170 PTMs in total were identified including new PTMs. Among them, common PTMs were localized in the N- and C-terminal flanking regions of the microtubule binding repeats and PTMs, which were considered to be disease-specific, were found in microtubule binding repeats forming filament core. These suggested that the differences in PTMs reflected the differences in tau filament core structures in each disease.
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http://dx.doi.org/10.3389/fnins.2020.581936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672045PMC
November 2020

Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases.

Acta Neuropathol 2021 01 5;141(1):25-37. Epub 2020 Nov 5.

Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

Lewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson's disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach's plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner's plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.
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http://dx.doi.org/10.1007/s00401-020-02233-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785549PMC
January 2021

Reactive astrocytes express Aggregatin () in the brains of Alzheimer's disease and Nasu-Hakola disease.

Intractable Rare Dis Res 2020 Nov;9(4):217-221

Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

By combining genomic data and brain imaging data, a recent study has identified a novel gene named that participates in the formation of amyloid-β (Aβ) plaques and brain atrophy in Alzheimer's disease (AD). encodes a 47-kDa protein designated Aggregatin that accumulates in the center of amyloid plaques and physically interacts with Aβ to facilitate Aβ aggregation. Aggregatin is expressed predominantly in the central nervous system (CNS) and its levels are increased in brains of the patients with AD and in mouse models of AD. However, at present, the precise cell types that express Aggregatin in the human CNS remain unknown. By immunohistochemistry, we studied Aggregatin expression in the frontal lobe of the patients with AD, Nasu-Hakola disease (NHD), and the subjects who died of non-neurological causes (NNC). We identified the clusters of Aggregatin-positive reactive astrocytes distributed widely in the cerebral cortex of most cases examined. In contrast, small numbers of cortical neurons showed variable immunoreactivities for Aggregatin, whereas microglia and oligodendrocytes did not express Aggregatin. Importantly, amyloid plaques were not clearly labelled with anti-Aggregatin antibody. These results suggest that Aggregatin plays a primarily role in generation of reactive astrocytes in the human CNS.
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http://dx.doi.org/10.5582/irdr.2020.03080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586878PMC
November 2020

High-Contrast In Vivo Imaging of Tau Pathologies in Alzheimer's and Non-Alzheimer's Disease Tauopathies.

Neuron 2021 01 29;109(1):42-58.e8. Epub 2020 Oct 29.

National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Aichi 474-8511, Japan.

A panel of radiochemicals has enabled in vivo positron emission tomography (PET) of tau pathologies in Alzheimer's disease (AD), although sensitive detection of frontotemporal lobar degeneration (FTLD) tau inclusions has been unsuccessful. Here, we generated an imaging probe, PM-PBB3, for capturing diverse tau deposits. In vitro assays demonstrated the reactivity of this compound with tau pathologies in AD and FTLD. We could also utilize PM-PBB3 for optical/PET imaging of a living murine tauopathy model. A subsequent clinical PET study revealed increased binding of F-PM-PBB3 in diseased patients, reflecting cortical-dominant AD and subcortical-dominant progressive supranuclear palsy (PSP) tau topologies. Notably, the in vivo reactivity of F-PM-PBB3 with FTLD tau inclusion was strongly supported by neuropathological examinations of brains derived from Pick's disease, PSP, and corticobasal degeneration patients who underwent PET scans. Finally, visual inspection of F-PM-PBB3-PET images was indicated to facilitate individually based identification of diverse clinical phenotypes of FTLD on a neuropathological basis.
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http://dx.doi.org/10.1016/j.neuron.2020.09.042DOI Listing
January 2021

Direct Gas-Phase Derivatization by Employing Tandem μ-Reactor-Gas Chromatography/Mass Spectrometry: Case Study of Trifluoroacetylation of 4,4'-Methylenedianiline.

Anal Chem 2020 11 2;92(22):14924-14929. Epub 2020 Oct 2.

Graduate School of Environmental Studies, Tohoku University, 6-6-07 Aoba, Aramaki-aza, Aoba-ku, Sendai, Miyagi 980-8579, Japan.

Pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) is a promising technique allowing the rapid characterization of the polymer structure and additives of microgram-scale plastics. However, the Py-GC/MS analysis of polymers with urethane bonds is challenging because they produce highly reactive pyrolyzates such as amines and isocyanates polymerizing in the GC column, which limits the efforts to elucidate the pyrolysis mechanism and plastic characterization by online GC analysis. Herein, a novel pyrolysis-gas-phase derivatization-GC/MS (Py-GPD-GC/MS) technique was developed, allowing the pyrolysis of polymers and the subsequent direct gas-phase derivatization of pyrolyzates, employing a modified tandem μ-reactor-GC/MS system. This work conducted the gas-phase trifluoroacetylation of 4,4'-methylenedianiline (MDA), which is one of the major polyurethane (PU) pyrolyzates, using -methyl-bis-trifluoroacetamide (MBTFA) as a derivatization agent. The trifluoroacetylation gas-phase reaction was monitored by GC/MS analysis and the effects of derivatization conditions were investigated. The highest MDA conversion observed was 65.6 area %. Furthermore, the sequential PU pyrolysis and direct trifluoroacetylation of PU pyrolyzates in the first μ-reactor and second μ-reactor, respectively, were successfully operated, achieving the inhibited polymerization and detection of trifluoroacetylated derivatives. Thus, the Py-GPD-GC/MS method has a significant potential to be applied for other combinations of pyrolyzates and derivatization reactions, enabling deeper characterization of plastics producing highly reactive pyrolyzates that cannot be accurately analyzed by conventional Py-GC/MS analysis.
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http://dx.doi.org/10.1021/acs.analchem.0c01830DOI Listing
November 2020

TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons.

Acta Neuropathol 2020 11 16;140(5):695-713. Epub 2020 Aug 16.

Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Mislocalization and abnormal deposition of TDP-43 into the cytoplasm (TDP-43 proteinopathy) is a hallmark in neurons of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). However, the pathogenic mechanism of the diseases linked to TDP-43 is largely unknown. We hypothesized that the failure of mRNA transport to neuronal axons by TDP-43 may contribute to neurodegeneration in ALS and FTLD, and sought to examine the function of TDP-43 by identifying its target mRNA for axonal transport. We found that mRNAs related to translational function including ribosomal proteins (RPs) were decreased by shRNA-based TDP-43 knock-down in neurites of cortical neurons. TDP-43 binds to and transports the RP mRNAs through their 5' untranslated region, which contains a common 5' terminal oligopyrimidine tract motif and a downstream GC-rich region. We showed by employing in vitro and in vivo models that the RP mRNAs were translated and incorporated into native ribosomes locally in axons to maintain functionality of axonal ribosomes, which is required for local protein synthesis in response to stimulation and stress to axons. We also found that RP mRNAs were reduced in the pyramidal tract of sporadic ALS cases harboring TDP-43 pathology. Our results elucidated a novel function of TDP-43 to control transport of RP mRNAs and local translation by ribosomes to maintain morphological integrity of neuronal axons, and proved the influence of this function of TDP-43 on neurodegeneration in ALS and FTLD associated with TDP-43 proteinopathy.
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http://dx.doi.org/10.1007/s00401-020-02205-yDOI Listing
November 2020

The cerebellar white matter lesions in dentatorubral-pallidoluysian atrophy.

J Neurol Sci 2020 Sep 16;416:117040. Epub 2020 Jul 16.

Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in atrophin 1. A previous report described cerebellar white matter lesions on magnetic resonance imaging (MRI) in elderly-onset DRPLA patients, but this finding has not been fully investigated in a total population of DRPLA patients, including juvenile or early-adult onset patients. Herein, we attempted to determine the frequency, distribution pattern, and features of the cerebellar white matter lesions in 30 consecutive DRPLA patients. We also assessed the relationships between the cerebellar white matter lesions and clinical parameters and other MRI findings. The cerebellar white matter lesions were found in 43% of the 30 DRPLA patients, and in 70% of the late adult-onset DRPLA patients. In approx. Two-thirds of the patients with cerebellar white matter lesions, the lesions were localized in the paravermal area (paravermal lesions). Multiple logistic regression analyses revealed that the Fazekas grade of 'cerebral' white matter lesions was independently associated with 'cerebellar' white matter lesions. In conclusion, cerebellar white matter lesions are one of the distinctive MRI features in DRPLA patients, especially in patients with older age at onset. Cerebellar white matter lesions, as well as cerebral white matter lesions, might originate from the disease process of DRPLA itself, and they often have a characteristic distribution of paravermal lesions.
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http://dx.doi.org/10.1016/j.jns.2020.117040DOI Listing
September 2020

Respiratory Dysfunction in Becker Muscular Dystrophy Patients: A Case Series and Autopsy Report.

J Neuromuscul Dis 2020 ;7(4):425-431

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Ogawahigashi, Kodaira, Tokyo, Japan.

Background: Few studies have examined respiratory dysfunction in patients with Becker muscular dystrophy (BMD).

Objective: This study aimed to examine the characteristics of respiratory dysfunction in patients with BMD.

Methods: The present retrospective study assessed respiratory parameters of adult BMD patients using medical records and compared these parameters with various patient characteristics to identify correlations. BMD patients aged 17 years and older who had been diagnosed genetically and/or pathologically were included in the analysis.

Results: Of the source population of 133 patients, respiratory function was assessed in 85. Two of these patients had no symptoms, and eight had died. Mean % forced vital capacity (% FVC) was 94.2+/-21.7% (median, 96.1%; range, 5.1-134.1%). In 16 (19%) of the 85 patients, % FVC was <80%. Of these, seven were non-ambulant. Age, ambulation, and cardiac function did not significantly differ between patients with or without respiratory dysfunction, whereas age at onset was significantly lower in patients with respiratory dysfunction (7.7+/-4.7 years vs. 14.4+/-11.9 years; p = 0.001). One non-ambulant patient was a continuous NPPV user, and one patient had been recommended NPPV use but refused. Autopsy of one patient revealed that the diaphragm and intercostal muscles were less affected than proximal skeletal muscles.

Conclusion: BMD patients are at risk of developing respiratory dysfunction due to dystrophic changes in respiratory muscles. Respiratory function should be carefully and periodically monitored in these patients.
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http://dx.doi.org/10.3233/JND-190438DOI Listing
January 2020

Simultaneous recovery of high-purity Cu and poly(vinyl chloride) from waste wire harness via swelling followed by ball milling.

Sci Rep 2020 Jul 1;10(1):10754. Epub 2020 Jul 1.

Graduate School of Environmental Studies, Tohoku University, 6-6-07 Aoba, Aramaki-Aza, Aoba-ku, Sendai, Miyagi, 980-8579, Japan.

Poly(vinyl chloride) (PVC) swelling coupled with ball milling was employed for the simultaneous recovery of high-purity Cu and PVC from waste wire harness under ambient conditions. The experimentally determined performances of 15 organic solvents for PVC swelling and phthalate plasticiser extraction were compared with those predicted considering Hansen solubility parameters. As a result, n-butyl acetate and acetone were identified as the two best solvents for adequate PVC swelling without PVC dissolution and almost complete plasticiser extraction within 60 min. The swelling was concluded to contribute to the control of phthalate plasticisers, the use of which in wire harness has recently been limited by the Restriction of Hazardous Substances (RoHS) directive. Cables swollen with n-butyl acetate or acetone were subjected to dry ball milling for ~ 60 min to completely separate PVC and Cu and achieve the quantitative recovery of these components from 20-cm-long cables. Thus, this work unveils the high potential of recycling the otherwise non-recyclable long and non-uniform waste wire harness cables and is expected to impact the related (e.g., automotive, electrical, and electronics) industries, contributing to the establishment of a more sustainable society.
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http://dx.doi.org/10.1038/s41598-020-67795-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329881PMC
July 2020

Reactive bite-related tongue lesions in cognitively impaired epilepsy patients: A report of two cases.

Spec Care Dentist 2020 May 22;40(3):285-290. Epub 2020 May 22.

Department of Oral and Maxillofacial Surgery, Tokai University School of Medicine, Tokyo, Japan.

Aim: Tongue bites frequently occur during seizures in epilepsy patients. We report two cases of cognitively impaired Lennox-Gastaut syndrome patients with reactive lesions on the tongues.

Case Presentations: Case 1 was a 30-year-old man whose chief complaint was mouth pain. Local finding was a small bean-sized pedunculated mass on the tongue, histopathologically diagnosed as inflammatory fibrous hyperplasia. Case 2 was a 45-year-old man whose chief complaint was bleeding from the mouth. His clinical finding was blood loss anemia. Local finding was a 20-mm-diameter pedunculated mass on the tongue, histopathologically diagnosed as pyogenic granuloma.

Conclusion: These mass lesions were believed to be reactive, caused by repetitive minor damage involving reparative fibrous tissue response. Therefore, the two cases may have involved reparative responses to mucosal injury incurred by accidental bites during epileptic seizures. Intellectual disability made medical treatment difficult and had allowed the massive lesions to form. It is necessary for cognitively impaired epilepsy patients to undergo regular dental examinations in order to get used to dental checks and to increase the number of intraoral observations in the context of close cooperation between dentists and epilepsy therapists.
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http://dx.doi.org/10.1111/scd.12470DOI Listing
May 2020

Arginine is a disease modifier for polyQ disease models that stabilizes polyQ protein conformation.

Brain 2020 06;143(6):1811-1825

Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington's disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood-brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.
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http://dx.doi.org/10.1093/brain/awaa115DOI Listing
June 2020

Ethnicity-Dependent Effects of Schizophrenia Risk Variants of the OLIG2 Gene on OLIG2 Transcription and White Matter Integrity.

Schizophr Bull 2020 12;46(6):1619-1628

Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Previous studies have indicated associations between several OLIG2 gene single-nucleotide polymorphisms (SNPs) and susceptibility to schizophrenia among Caucasians. Consistent with these findings, postmortem brain and diffusion tensor imaging studies have indicated that the schizophrenia-risk-associated allele (A) in the OLIG2 SNP rs1059004 predicts lower OLIG2 gene expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients and reduced white matter (WM) integrity of the corona radiata in normal brains among Caucasians. In an effort to replicate the association between this variant and WM integrity among healthy Japanese, we found that the number of A alleles was positively correlated with WM integrity in some fiber tracts, including the right posterior limb of the internal capsule, and with mean blood flow in a widespread area, including the inferior frontal operculum, orbital area, and triangular gyrus. Because the A allele affected WM integrity in opposite directions in Japanese and Caucasians, we investigated a possible association between the OLIG2 gene SNPs and the expression level of OLIG2 transcripts in postmortem DLPFCs. We evaluated rs1059004 and additional SNPs in the 5' upstream and 3' downstream regions of rs1059004 to cover the broader region of the OLIG2 gene. The 2 SNPs (rs1059004 and rs9653711) had opposite effects on OLIG2 gene expression in the DLPFC in Japanese and Caucasians. These findings suggest ethnicity-dependent opposite effects of OLIG2 gene SNPs on WM integrity and OLIG2 gene expression in the brain, which may partially explain the failures in replicating associations between genetic variants and psychiatric phenotypes among ethnicities.
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http://dx.doi.org/10.1093/schbul/sbaa049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846078PMC
December 2020

A 67-Year-Old Man with Leg Weakness and Hypertrophic Cardiomyopathy.

Brain Pathol 2020 03;30(2):427-428

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.

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http://dx.doi.org/10.1111/bpa.12824DOI Listing
March 2020

A case of asymptomatic complete tracheal rings in an adult: case report.

JA Clin Rep 2019 Jul 12;5(1):45. Epub 2019 Jul 12.

Osaki Citizen Hospital, 3-8-1 Furukawa Homami Osaki-shi, Miyagi, Japan.

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http://dx.doi.org/10.1186/s40981-019-0265-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967212PMC
July 2019

YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.

Nat Commun 2020 01 24;11(1):507. Epub 2020 Jan 24.

Department of Neuropathology, Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.
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http://dx.doi.org/10.1038/s41467-020-14353-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981281PMC
January 2020

Corticobasal degeneration with deep white matter lesion diagnosed by brain biopsy.

Neuropathology 2020 Jun 10;40(3):287-294. Epub 2020 Jan 10.

Department of Neurology, Tokyo Teishin Hospital, Tokyo, Japan.

Corticobasal degeneration (CBD) is a rare progressive neurodegenerative disorder characterized by asymmetric presentation of cerebral cortex signs, cortical sensory disturbance and extrapyramidal signs. Herein, we report a case of a 66-year-old Japanese woman who presented with apraxia of the right hand. She subsequently developed postural instability and cognitive impairments that rapidly worsened. One and a half years later, the patient was wheelchair-bound and severely demented. Brain magnetic resonance imaging revealed left dominant atrophy of the frontoparietal lobe. There was a hyperintense lesion in the deep white matter expanding toward the subcortical area on fluid-attenuated inversion recovery (FLAIR) images. In order to rule out the possibility of an intracranial tumor such as an astrocytoma or malignant lymphoma, we performed a brain biopsy of the left frontal middle gyrus. The patient became bedridden and showed akinetic mutism 1 year after biopsy. Pathological examination revealed a large amount of 4-repeat tau-immunoreactive neuropil threads scattered predominantly in the corticomedullary junction and tau-immunoreactive structures, consistent with CBD. Immunostaining for p53 showed no positive cells, and there were very few Ki-67-positive cells. On immunoblots of sarkosyl-insoluble brain extracts, a major doublet of 64 and 68 kDa full-length tau with two closely related fragments of approximately 37 kDa were detected. Based on these results, the patient was pathologically diagnosed as having CBD, excluding the possibility of tumor. Taken together with previous similar case reports, our findings indicate that a deep white matter hyperintense lesion on FLAIR images may be a useful clue to CBD, predicting rapid clinical progression with severe dementia based on severe white matter degeneration with a large amount of tau accumulation on pathological examination.
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http://dx.doi.org/10.1111/neup.12638DOI Listing
June 2020

Microglia express TMEM119 in the brains of Nasu-Hakola disease.

Intractable Rare Dis Res 2019 Nov;8(4):260-265

Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.

We previously identified an evolutionarily conserved protein named transmembrane protein 119 (TMEM119) as the most reliable maker for human microglia. Recent studies showed that under homeostatic conditions, microglia intensely express TMEM119, whereas the expression levels are greatly reduced in disease-associated microglia (DAM) activated at the site of neurodegeneration. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, pathologically characterized by leukoencephalopathy, astrogliosis, axonal spheroids, and accumulation of microglia. However, it remains unknown whether microglia are homeostatic or activated in NHD brains. In the present study, we identified TMEM119 on microglia in NHD brains by immunohistochemistry. TMEM119 was expressed on microglia in NHD brains as well as in the brains of non-neurological controls (NC) and Alzheimer's disease (AD) patients, although TMEM119-immunolabeled areas exhibited great variability from case to case without significant differences among the study population. These results suggest that TMEM119 expression on microglia might play a key role in steady-state brain maintenance in NHD, AD and controls.
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http://dx.doi.org/10.5582/irdr.2019.01123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929589PMC
November 2019

Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies.

Brain Sci 2019 Dec 20;10(1). Epub 2019 Dec 20.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The mechanism of neuronal dysfunction via tau aggregation in tauopathy patients is controversial. In Alzheimer's disease (AD), we previously reported mislocalization of the DNA repair nuclear protein BRCA1, its coaggregation with tau, and the possible importance of the subsequent DNA repair dysfunction. However, whether this dysfunction in BRCA1 also occurs in other tauopathies is unknown. The aim of this study was to evaluate whether BRCA1 colocalizes with tau aggregates in the cytoplasm in the brains of the patients with tauopathy. We evaluated four AD, two Pick's disease (PiD), three progressive supranuclear palsy (PSP), three corticobasal degeneration (CBD), four normal control, and four disease control autopsy brains. Immunohistochemistry was performed using antibodies against BRCA1 and phosphorylated tau (AT8). Colocalization was confirmed by immunofluorescence double staining. Colocalization of BRCA1 with tau aggregates was observed in neurofibrillary tangles and neuropil threads in AD, pick bodies in PiD, and globose neurofibrillary tangles and glial coiled bodies in PSP. However, only partial colocalization was observed in tuft-shaped astrocytes in PSP, and no colocalization was observed in CBD. Mislocalization of BRCA1 was not observed in disease controls. BRCA1 was mislocalized to the cytoplasm and colocalized with tau aggregates in not only AD but also in PiD and PSP. Mislocalization of BRCA1 by tau aggregates may be involved in the pathogenesis of PiD and PSP.
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http://dx.doi.org/10.3390/brainsci10010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016802PMC
December 2019

Practical dechlorination of polyvinyl chloride wastes in NaOH/ethylene glycol using an up-scale ball mill reactor and validation by discrete element method simulations.

Waste Manag 2019 Nov 27;99:31-41. Epub 2019 Aug 27.

Graduate School of Environmental Studies, Tohoku University, 6-6-07 Aoba, Aramaki-aza, Aoba-ku, Sendai, Miyagi 980-8579, Japan.

To avoid the formation of undesired Cl compounds during polyvinyl chloride (PVC) wastes treatment and facilitate the recycling of valuable NaCl and dechlorinated hydrocarbons as feedstocks, advanced dechlorination (de-Cl) process should be developed. Here, an up-scale ball mill reactor was established for the de-Cl of real PVC wastes, including sealing strips from waste refrigerators and crushed cable coverings from waste cables. The effects of NaOH on de-Cl were validated with lab-scale studies and the influences of mechanical conditions were innovatively investigated. A maximum de-Cl degree of 99% was obtained with 1 M NaOH in ethylene glycol for sealing strips, whereas a maximum de-Cl degree of 92% was obtained with Φ1.27 cm stainless steel balls at a moderate rotation speed for cable coverings. The remaining Cl content in the sample residues was small and decreased with decreasing residue size, resulting in minimum contents of 0.49% and 0.61% for sealing strips and cable coverings, respectively. The de-Cl behavior was consistent with a shrinking-core model and the meaning of kinetic parameters was illustrated. The ball milling process was simulated by discrete element method (DEM). A positive correlation was observed between the apparent rate constant of the experimental de-Cl process and the specific impact energy calculated using DEM simulations. The combined experimental and simulation approach suggested that the surface of PVC is first dechlorinated and then crushed into fine particles by ball milling to expose the inner unreacted surface. For industrial application, the balance of chemical and mechanical conditions should be optimized.
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http://dx.doi.org/10.1016/j.wasman.2019.08.034DOI Listing
November 2019

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Nat Genet 2019 08 22;51(8):1222-1232. Epub 2019 Jul 22.

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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http://dx.doi.org/10.1038/s41588-019-0458-zDOI Listing
August 2019

Separation mechanism of polyvinyl chloride and copper components from swollen electric cables by mechanical agitation.

Waste Manag 2019 Jun 21;93:54-62. Epub 2019 May 21.

Graduate School of Environmental Studies, Tohoku University, 6-6-07 Aoba Aramaki-Aza, Aoba-ku, Sendai, Miyagi 980-8579, Japan.

In this study, a high-accuracy separation process is proposed for recycling pure polyvinyl chloride (PVC) and Cu from the thin electric cables of electrical, electronic, and automotive wastes by PVC swelling and mechanical agitation in hydrophobic organic solvent mixed with water. The high stirring speed and low blade height combined with proper blade type and reactor tank shape ensure a separation rate of over 98%. By conducting computational fluid dynamic and discrete element model simulations, quantitative force, fluid velocity, and data visualization analyses were performed. The obtained separation rate exhibited strong positive correlations with the resultant, drag, and centripetal forces at various stirring speeds and blade heights. Using the experimental and simulation data, a plausible separation mechanism was suggested. It was found that Cu pieces could slip out from swollen PVC covers under the action of external forces, while the stirring speed should be high enough to apply sufficient external forces to cables via either blade-to-cable collisions or fluid drag. Furthermore, the vertical motion of cables induced by the low blade height was essential because the rotation in the bottom reactor part inhibited the slipping of Cu pieces.
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http://dx.doi.org/10.1016/j.wasman.2019.05.024DOI Listing
June 2019

Microglia express GPNMB in the brains of Alzheimer's disease and Nasu-Hakola disease.

Intractable Rare Dis Res 2019 May;8(2):120-128

Department of Laboratory Medicine, National Center Hospital, NCNP, Tokyo, Japan.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a type I transmembrane glycoprotein first identified in low-metastatic human melanoma cell lines as a regulator of tumor growth. GPNMB is widely expressed in various tissues, where it is involved in cell differentiation, migration, inflammation/anti-inflammation, tissue regeneration, and neuroprotection. GPNMB is identified in microglia of adult rat brains, neurons and astrocytes of GPNMB transgenic (Tg) mouse brains, and motor neurons of amyotrophic lateral sclerosis (ALS) patients. Nasu-Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of either () or . TREM2 and DAP12 constitute a receptor/adaptor signaling complex expressed exclusively on osteoclasts, dendritic cells, macrophages, and microglia. Pathologically, the brains of NHD patients exhibit leukoencephalopathy, astrogliosis, accumulation of axonal spheroids, and remarkable activation of microglia predominantly in the white matter of frontal and temporal lobes and the basal ganglia. At present, molecular mechanisms responsible for development of leukoencephaolpathy in NHD brains remain totally unknown. Recent evidence indicates that disease-associated microglia (DAM) that cluster around amyloid plaques express high levels of GPNMB in Alzheimer's disease (AD) brains. Because microglia act as a key regulator of leukoencephalopathy in NHD brains, it is proposed that GPNMB expressed on microglia might play a protective role in progression of leukoencephalopathy possibly active phagocytosis of myelin debris. In the present study using immunohistochemistry, we have attempted to clarify the expression of GPNMB in NHD brains, compared with AD brains. We found that microglia accumulating in the white matter express an intense GPNMB immunoreactivity in both NHD and AD brains, suggesting that the accumulation of GPNMB-immunoreactive microglia is a general phenomenon in neurodegenerative brains.
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http://dx.doi.org/10.5582/irdr.2019.01049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557242PMC
May 2019

Altered immunoreactivity of ErbB4, a causative gene product for ALS19, in the spinal cord of patients with sporadic ALS.

Neuropathology 2019 Aug 24;39(4):268-278. Epub 2019 May 24.

Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan.

ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG-1, suggesting that the disruption of the NRG-ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA-binding protein 43 kDa (TDP-43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG-ErbB4 pathway may underlie the TDP-43-dependent motor neuron degeneration in ALS.
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http://dx.doi.org/10.1111/neup.12558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852233PMC
August 2019

A combined kinetic and thermodynamic approach for interpreting the complex interactions during chloride volatilization of heavy metals in municipal solid waste fly ash.

Waste Manag 2019 Mar 10;87:204-217. Epub 2019 Feb 10.

Graduate School of Environmental Studies, Tohoku University, 6-6-07 Aoba, Aramaki-aza, Aoba-ku, Sendai, Miyagi 980-8579, Japan.

This study elucidated complex interactions during the chloride volatilization of heavy metals (Pb, Cu, Zn, Mn, and Cr) from municipal solid waste fly ash by combining thermodynamic and kinetic approaches. Chloride volatilization tests under HCl flow at 900 °C and subsequent rinsing with water achieved almost complete removal of Pb, Zn, and Mn. In contrast, almost 100 % of Cr and ∼40 % of Cu were not removed by either volatilization or rinsing processes. Kinetics indicated that the chlorination of Pb, Zn, and Mn followed a pseudo second order reaction and their apparent activation energies were 96.3, 89.2, and 43.5 kJ/mol, respectively. Further thermodynamic calculation revealed that the components contained in fly ash greatly influenced the chlorination of each heavy metal. Unburned carbon facilitated the chlorination of Pb, Zn, and Mn, while it inhibited Cu chlorination. MgO immobilized Cr and inhibited chlorination. KCl and NaCl promoted Zn and Mn chlorination, respectively. The revealed chloride volatilization behavior and effects of co-existing elements could be useful in the design of high-efficiency recovery process of heavy metals from fly ash and the utilization of residues as raw materials for cement. Furthermore, these findings could guide the realization of a recycling-oriented society in terms of reducing waste disposal.
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http://dx.doi.org/10.1016/j.wasman.2019.02.007DOI Listing
March 2019